The University of California, San Diego School of Medicine announced today that it is a Grand Challenges Explorations winner, an initiative funded by the Bill & Melinda Gates Foundation.  Greg G. Goldgof, a graduate student in UC San Diego’s Biomedical Sciences Graduate Program and the Medical Science Training Program will pursue an innovative global health and development research project, titled “Outsmarting Malaria: Developing next generation anti-malarials that prevent the evolution of drug resistance.”

Greg G. Goldgof

Grand Challenges Explorations (GCE) funds individuals worldwide to explore ideas that can break the mold in how we solve persistent global health and development challenges.  Goldgof’s project is one of over 50 Grand Challenges Explorations Round 10 grants announced today by the Bill & Melinda Gates Foundation. 

To receive funding, Goldgof and other Grand Challenges Explorations Round 10 winners demonstrated in a two-page online application a bold idea in one of four critical global heath and development topic areas that included agriculture development, neglected tropical diseases and communications.

Goldgof works in the lab of Elizabeth Winzeler, PhD, a professor in the Department of Pediatrics at UC San Diego School of Medicine.  The Bill & Melinda Gates Foundation grant will support Goldgof’s work to use genetically engineered yeast to rapidly evolve resistance to potential anti-malarial therapies, and then sequence the resistant strains' genomes to discover the mechanism for resistance to each drug. The hope is that this information will guide development of the next-generation of drugs that can overcome drug resistance to successfully fight malaria, which kills more than a million men, women and children each year, many of them in underdeveloped countries.

“I am very appreciative that the Bill & Melinda Gates Foundation has funded my proposal to develop a new technology for drug development to treat malaria,” said Goldgof.  “This information will be used to prioritize drug candidates for clinical trials and to identify new malaria drug targets for future therapies.”

Goldgof will use genetically engineered yeast developed by collaborator Yo Suzuki, PhD, an assistant professor at J. Craig Venter Institute in La Jolla. 

About Grand Challenges Explorations
Grand Challenges Explorations is a US $100 million initiative funded by the Bill & Melinda Gates Foundation.  Launched in 2008, over 800 people in more than 50 countries have received Grand Challenges Explorations grants.  The grant program is open to anyone from any discipline and from any organization.  The initiative uses an agile, accelerated grant-making process with short two-page online applications and no preliminary data required.  Initial grants of US $100,000 are awarded twice a year. Successful projects have the opportunity to receive a follow-on grant of up to US $1 million.

About the Medical Science Training Program at UC San Diego
The MSTP is an inter-institutional collaboration that combines clinical training under the auspices of the UCSD School of Medicine with research training from UC San Diego and other world-renowned research institutions in the San Diego region.  Funded in part by the National Institutes of Health, its graduates earn both MD and PhD degrees.  There are currently 75 students in the MSTP program who are training to become the next generation of physician scientists.  For more information, visit http://mstp.ucsd.edu

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Researchers at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center report that cancers physically alter cells in the lymphatic system – a network of vessels that transports and stores immune cells throughout the body – to promote the spread of disease, a process called metastasis.  

The findings are published in this week’s online Early Edition of the Proceedings of the National Academy of Sciences.

Roughly 90 percent of all cancer deaths are due to metastasis – the disease spreading from the original tumor site to multiple, distant tissues and finally overwhelming the patient’s body. Lymph vessels are often the path of transmission, with circulating tumor cells lodging in the lymph nodes – organs distributed throughout the body that act as immune system garrisons and traps for pathogens and foreign particles.

The researchers, led by principal investigator Judith A. Varner, PhD, professor of medicine at UC San Diego Moores Cancer Center, found that a protein growth factor expressed by tumors called VEGF-C activates a receptor called integrin α4β1 on lymphatic vessels in lymph node tissues, making them more attractive and sticky to metastatic tumor cells.

“One of the most significant features of this work is that it highlights the way that tumors can have long-range effects on other parts of the body, which can then impact tumor metastasis or growth,” said Varner.

Varner said α4β1 could prove to be a valuable biomarker for measuring cancer risk, since increased levels of the activated protein in lymph tissues is an indirect indicator that an undetected tumor may be nearby.

She said whole-body imaging scans of the lymphatic network might identify problem areas relatively quickly and effectively. “The idea is that a radiolabeled or otherwise labeled anti-integrin α4β1 antibody could be injected into the lymphatic circulation, and it would only bind to and highlight the lymphatic vessels that have been activated by the presence of a tumor.”

Varner noted that α4β1 levels correlate with metastasis – the higher the level, the greater the chance of the cancer spreading. With additional research and clinical studies, doctors could refine treatment protocols so that patients at higher risk are treated appropriately, but patients at lower or no risk of metastasis are not over-treated.

The researchers noted in their studies that it is possible to suppress tumor metastasis by reducing growth factor levels or by blocking activation of the α4β1 receptor. Varner said an antibody to VEGF-R3 is currently in Phase 1 clinical trials. An approved humanized anti-α4β1 antibody is currently approved for the treatment of multiple sclerosis and Crohn’s disease. Varner said her lab at UC San Diego Moores Cancer Center is investigating the possibility of developing one for treating cancer.

Co-authors include Barbara Garmy-Susini, Christie J. Avraamides, Michael C. Schmid and Philippe Foubert, UC San Diego Moores Cancer Center; Jay S. Desgrosellier, UC San Diego Moores Cancer Center and UCSD Department of Pathology; Lesley G. Ellies, Scott R. Vanderberg, Brian Datnow, Huan-You Wang and David A. Cheresh, UCSD Department of Pathology; Andrew M. Lowy and Sarah L. Blair, UC San Diego Moores Cancer Center and UCSD Department of Surgery.

Funding for this research came, in part, from National Institutes of Health grants CA83133 and CA126820; Department of Defense grant W81XWH-06-1-052 and NIH-National Cancer Institute grant U54 CA119335.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Countries in which girls are commonly married before the age of 18 have significantly higher rates of maternal and infant mortality, report researchers in the current online issue of the journal Violence Against Women.

The study, by Anita Raj, PhD, a professor in the Department of Medicine in the University of California, San Diego School of Medicine and Ulrike Boehmer, PhD, an associate professor in the Boston University School of Public Health, is the first published ecological analysis of child marriage and maternal mortality. The study demonstrates that a 10 percent reduction in girl child marriage could be associated with at 70 percent reduction in a country's maternal mortality rate.

Countries with higher rates of child bride marriages have higher rates of maternal and infant mortality.

“Our analyses accounted for development indicators and world region, and still documented that nations with higher rates of girl child marriage are significantly more likely to contend with higher rates of maternal and infant mortality and non-utilization of maternal health services,” said Raj.

“Though child marriage is not highly common in the United States,” said Raj, “these findings are meaningful because they hold true for adolescent pregnancy, regardless of marriage. Young age at childbirth increases risk for both maternal and infant mortality.”

Girl child marriage is defined as the marriage of girls age 17 and younger. Although the practice has generally declined in recent years, it remains relatively common in regions like South Asia and sub-Saharan Africa, where up to 70 percent of females in some countries are married as minors. Worldwide, the United Nations estimates more than 60 million women and girls are affected, and considers girl child marriage to be a health and human rights violation.

Raj and Boehmer said certain social contexts increase the likelihood of child marriage, among them rural and impoverished areas with low access to health care and girl education. Regional conflict and instability tend to worsen the situation.

“Girl marriage is viewed as a means of protection from both economic instability and rape due to perceptions of sexual availability of unmarried girls and women,” said Raj. “Poverty and conflict can exacerbate parents’ desire to have their girl married at a younger age.”

Child brides are also more likely to experience social inequities – reduced status and access to education or jobs – and suffer gender-based abuse. The effects extend into personal health: Girls married as minors are more likely to bear children as minors, resulting in higher risk for delivery complications, low infant birth weight and child malnutrition.

The new study builds upon earlier findings. Raj and Boehmer compared maternal and child health indicators and HIV prevalence with girl child marriage rates for 97 nations in which relevant data was available. They found strong associations between high child marriage rates and poor health indicators, but no evidence of higher child bride-higher HIV prevalence. The HIV finding, said the researchers, may be the result of a lack of evidence, underscoring the complexity of HIV and its effects in diverse societies.

Nonetheless, the authors say their latest work supports greater advocacy and action to reduce child marriage rates.

“Currently, many nations, such as Yemen and Saudi Arabia, are considering whether or not to alter policies allowing marriage of minor-aged girls, while other nations like India and Nepal are struggling with enforcement of existing policies,” Raj said. “These findings suggest policy and programmatic work to restrict and eliminate the practice of child marriage may be effective in improving national levels of maternal and child health.”

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Experts Provide Free Answers about Medications and More during Pregnancy and Breastfeeding

As Mother's Day approaches, the University of California, San Diego School of Medicine announces MotherToBaby CA, the new name of its free, statewide counseling service that connects experts in the field of birth defects research with moms-to-be and the general public. MotherToBaby CA was formerly known as the California Teratogen Information Service (CTIS) Pregnancy Health Information Line and is housed at the Center for the Promotion of Maternal Health and Infant Development, a division of UC San Diego and Rady Children's Hospital.

MotherToBaby CA is an affiliate of the international non-profit Organization of Teratology Information Specialists (OTIS), a prestigious professional society that supports and contributes to worldwide initiatives for teratology education and research. MotherToBaby affiliates and OTIS, which are suggested resources by many agencies including the Centers for Disease Control and Prevention (CDC), are dedicated to providing evidence-based information to mothers, health care professionals, and the general public about medications and other exposures during pregnancy and while breastfeeding.

“In addition to my primary health care provider, MotherToBaby experts offered me an added layer of support by giving me an individualized risk assessment,” said Pamela Salgado, a San Diego resident who called the service when she was thinking about getting pregnant. She had questions about the safety of a long-term medication she was taking and its potential risks during pregnancy. “Afterwards, I felt informed and empowered to make smart decisions about my health. Today, I have a healthy three-year-old boy.”

All North Americans can be connected with MotherToBaby experts toll free through its phone counseling service 866-626-6847 or online at MotherToBabyCA.org, where a private, online chat counseling service is also offered.

“In a day and age where reliable information about the risks of medications, alcohol, chemicals, beauty products and other exposures during pregnancy or while breastfeeding is hard to find, especially online, we realized how important it was to make sure women and health care providers knew that experts up-to-date on the most cutting edge research were readily available to them,” explained Kenneth Lyons Jones, MD, a professor at UC San Diego and the current MotherToBaby CA medical director.  Jones was the first researcher to identify Fetal Alcohol Syndrome (FAS) in 1973. “What is passed from mother to baby is exactly what we educate the public about, which is why we strongly believe MotherToBaby and the service it represents will resonate well with the general public.”

Jones further explains the need for this sort of counseling since approximately 50 percent of women report taking at least one medication during pregnancy. “The average woman doesn’t find out she’s pregnant until she’s five or six weeks along,” said Jones. “That means a woman could have been consuming alcohol or taking medications during that time without knowing she’s pregnant. She then finds herself deeply concerned about what it might mean for her developing baby.”

For more information about MotherToBaby CA, please visit MotherToBabyCA.org.

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Media Contact: Nicole Chavez, 858-246-1745, ncchavez@ucsd.edu
Interviews in Spanish can be arranged.

American College of Surgeons’ Commission on Cancer Recognizes Quality Care

UC San Diego Health System is a recipient of the 2012 Outstanding Achievement Award from the American College of Surgeons’ Commission on Cancer. Seventy-nine cancer care programs—three in California—received this national award based on excellence in providing quality care to cancer patients.

“These 79 cancer programs, surveyed in 2012, currently represent the best of the best—so to speak—when it comes to cancer care,” said Daniel P. McKellar, MD, FACS, chair of the Commission on Cancer. “Each of these facilities is not just meeting nationally recognized standards for the delivery of quality cancer care, they are exceeding them.”

UC San Diego Moores Cancer Center

Established in 2004, the honor was awarded to only 19 percent of the cancer care programs surveyed in 2012. The award is designed to recognize quality cancer care and to help patients make an informed decision on where to seek superior treatment.

UC San Diego Moores Cancer Center is recognized as an innovative leader in cancer treatment and research. Home to 413 physicians and scientists, it employs a multidisciplinary team approach to patient care that includes surgical oncology, medical oncology, gynecologic oncology, radiation oncology, pathology, diagnostic radiology, interventional radiology, palliative care, integrative medicine, psychology and nutrition.

“This award distinguishes us as part of an elite group of cancer programs in the United States that are being recognized for providing the highest quality cancer care,” said Jason Sicklick, MD, FACS, surgical oncologist and UC San Diego’s cancer liaison physician to the Commission on Cancer. “It highlights our multidisciplinary approach and allows us to share our best practices with other institutions in order to improve patient care not only in San Diego, but nationwide.”

The Moores Cancer Center is the region’s only National Cancer Institute-designated comprehensive cancer center, capable of conducting both leading-edge research and advanced clinical treatments. There are just 41 such centers in the country. In March, the Moores Cancer Center also became the first San Diego-based member of the National Comprehensive Cancer Network, an elite consortium of institutions across the country that develop and improve the standards of cancer care.

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Media Contact: Yadira Galindo, 619-543-6163, ygalindo@ucsd.edu

Raul Coimbra, MD, PhD, FACS, is the only trauma surgeon in the western United States recently invited to be part of the Global Alliance for the Care of the Injured (GACI) – a World Health Organization initiative to improve trauma care in low and middle income countries.

“One of the goals of the GACI is to teach standards in trauma care, data collection, injury surveillance and quality improvement,” said Coimbra, chief, Division of Trauma, Surgical Critical Care and Burns at UC San Diego Health System. “It is crucial that we share our experiences in the United States around the world.  Trauma is a major public health problem, and extending high quality of care to patients worldwide will also improve the way Americans traveling receive health care.” 

Raul Coimbra, MD, PhD, chief, Division of Trauma, Surgical Critical Care and Burns

As president of the first World Trauma Congress held in Rio de Janeiro last year and president of the World Coalition for Trauma Care, a collaborative of multiple professional organizations to advance trauma care, education, prevention and systems development, Coimbra is deeply devoted to international outreach.

“Trauma is a disease that exhibits a pattern with causes that can be defined. It is preventable. If we treat trauma as a disease, with efforts toward prevention, we’ll save lives and make people and communities safer,” said Coimbra.

UC San Diego Health System established the region’s first Level I Trauma Center, and the highly trained personnel and special facilities are part of the collaborative San Diego Trauma System. Coimbra is recognized internationally as a trauma care expert and pioneer. The San Diego Trauma System has become a model for trauma centers around the world and for the upcoming 2014 World Soccer Cup and 2016 Olympic Games in Brazil.

“Statistics show that wherever a trauma program is in place, death rates for trauma cases decrease by at least 25 percent,” said Coimbra. 

As part of the GACI outreach, UC San Diego Health System’s trauma program will take center stage as an example of a world class program that is bringing opportunities for research and education to underserved areas.

“Being part of this prestigious group is giving our trauma center visibility beyond our county, region and nation,” said Coimbra.  “It is an honor to be part of this global project and to truly be making a difference.”

Learn more about UC San Diego Health System’s Trauma Center at: http://health.ucsd.edu/specialties/surgery/trauma-burn/trauma-center/Pages/default.aspx

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

Researchers from the University of California, San Diego Department of Pediatrics and Rady Children's Hospital-San Diego, a research affiliate of UC San Diego School of Medicine, have found a link between multivitamin use and alcohol consumption before pregnancy, uncovering a need for education about the importance of vitamin supplementation, particularly among women who drink alcohol during their childbearing years. The study was published online this month in Alcoholism: Clinical and Experimental Research.

Researchers examined data collected from the Centers For Disease Control and Prevention’s multiple-state Pregnancy Risk Assessment Monitoring System (PRAMS) of more than 100,000 women between 2004 and 2008. The women answered a series of questions about alcohol use before their pregnancies as well as multivitamin supplement use.  The study found women who reported consuming alcohol regularly or binge drinking were significantly less likely to take a multivitamin supplement compared with those who did not report alcohol consumption.

“It’s likely a woman may consume alcohol before she even realizes she’s pregnant, therefore, these findings are significant,” explained Lauren Bartell Weiss, PhD, a postdoctoral research fellow at UC San Diego’s Center for the Promotion of Maternal Health and Infant Development and co-author of the study. “If a woman is drinking alcohol regularly and unintentionally becomes pregnant, not only does her unborn child have a greater risk of being affected by the alcohol, but other studies suggest that alcohol can also alter the metabolism of nutrients and interfere with the nutritional supply to the developing baby.”

Since pregnancy increases the demand for several vitamins and minerals in order to adequately support a developing fetus, Weiss said the alcohol interference with nutritional supply means a woman’s unborn child may also have a greater risk of developing other birth defects, such as neural tube defects, if she hasn’t been taking a multi-vitamin.

“These findings emphasize the need for educating all women of childbearing age, especially those who drink alcohol, about the importance of taking multivitamins regularly whether they’re planning to have children or not,” said Weiss.

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Media Contact: Nicole Chavez, 858-246-1745, ncchavez@ucsd.edu

With two new methods, UC San Diego scientists hope to improve genome-wide association studies

As scientists probe and parse the genetic bases of what makes a human a human (or one human different from another), and vigorously push for greater use of whole genome sequencing, they find themselves increasingly threatened by the unthinkable: Too much data to make full sense of. 

In a pair of papers published in the April 25, 2013 issue of PLOS Genetics, two diverse teams of scientists, both headed by researchers at the University of California, San Diego School of Medicine, describe novel statistical models that more broadly and deeply identify associations between bits of sequenced DNA called single nucleotide polymorphisms or SNPs and say lead to a more complete and accurate understanding of the genetic underpinnings of many diseases and how best to treat them.      

“It’s increasingly evident that highly heritable diseases and traits are influenced by a large number of genetic variants in different parts of the genome, each with small effects,” said Anders M. Dale, PhD, a professor in the departments of Radiology, Neurosciences and Psychiatry at the UC San Diego School of Medicine. “Unfortunately, it’s also increasingly evident that existing statistical methods, like genome-wide association studies (GWAS) that look for associations between SNPs and diseases, are severely underpowered and can’t adequately incorporate all of this new, exciting and exceedingly rich data.”

Dale cited, for example, a recent study published in Nature Genetics in which researchers used traditional GWAS to raise the number of SNPs associated with primary sclerosing cholangitis from four to 16. The scientists then applied the new statistical methods to identify 33 additional SNPs, more than tripling the number of genome locations associated with the life-threatening liver disease.

Generally speaking, the new methods boost researchers’ analytical powers by incorporating a priori or prior knowledge about the function of SNPs with their pleiotrophic relationships to  multiple phenotypes. Pleiotrophy occurs when one gene influences multiple sets of observed traits or phenotypes.

Dale and colleagues believe the new methods could lead to a paradigm shift in CWAS analysis, with profound implications across a broad range of complex traits and disorders.

“There is ever-greater emphasis being placed on expensive whole genome sequencing efforts,” he said, “but as the science advances, the challenges become larger. The needle in the haystack of traditional GWAS involves searching through about one million SNPs. This will increase 10- to 100-fold, to about 3 billion positions. We think these new methodologies allow us to more completely exploit our resources, to extract the most information possible, which we think has important implications for gene discovery, drug development and more accurately assessing a person’s overall genetic risk of developing a certain disease.”

“All SNPs are not created equal: Genome-wide association studies reveal a consisten pattern of enrichment among functionally annotated SNPs.” Authors include Andrew J. Schork, UCSD Cognitive Sciences Graduate Program, UCSD Center for Human Development and UCSD Multimodal Imaging Laboratory; Wesley K. Thompson and John R. Kelsoe, Department of Psychiatry, UCSD; Phillip Pham, Scripps Health, The Scripps Research Institute (TSRI); Ali Torkamani and Nicholas J. Schork, Scripps Health, TSRI; J. Cooper Roddy, UCSD Multimodal Laboratory; Patrick F. Sullivan, University of North Carolina; Michael C. O’Donovan, Cardiff University, United Kingdom; Helena Furberg, Memorial Sloan Kettering Cancer Center; The Tobacco and Genetics Consortium, The Bipolar Disorder Psychiatric Genomics Consortium, The Schizophrenic Psychiatric Genomics Consortium; and Ole A. Andreassen, UCSD Department of Psychiatry, University of Oslo and Oslo University Hospital.

“Improved detection of common variants associated with schizophrenia and bipolar disorder using pleiotropy-informed conditional False Discovery Rate.” Authors include Ole A. Andreassen, University of Oslo, Oslo University Hospital and UCSD Department of Psychiatry; Wesley K. Thompson and John R. Kelsoe, UCSD Department of Psychiatry; Stephan Ripke, Massachusetts General Hospital, Boston; Andrew J. Schork, UCSD Multimodal Laboratory, UCSD Cognitive Sciences Graduate Program, UCSD Center for Human Development; Morten Mattingsdal, University of Oslo; Kenneth S. Kendler, Virginia Commonwealth University; Michael C. O’Donovan, Cardiff University, United Kingdom; Dan Rujescu, University of Halle-Wittenberg, Germany; Thomas Werge, University of Copenhagen; Pamela Sklar, Mount Sinai School of Medicine; The Psychiatric Genomics Consortium; Bipolar Disorder and Schizophrenia Working Groups; J. Cooper Roddey, Linda McEvoy and Rahul S. Desikan, UCSD Multimodal Imaging Laboratory, UCSD Department of Radiology; Chi-Hua Chen, UCSD Department of Psychiatry and UCSD Multimodal Imaging Laboratory; and Srdjan Djurovic, University of Oslo and Oslo University Hospital, Norway.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

UC San Diego scientists recall EP, perhaps the world’s second-most famous amnesiac

An international team of neuroscientists has described for the first time in exhaustive detail the underlying neurobiology of an amnesiac who suffered from profound memory loss after damage to key portions of his brain.

Writing in this week’s Online Early Edition of PNAS, principal investigator Larry R. Squire, PhD, professor in the departments of Neurosciences, Psychiatry and Psychology at the University of California, San Diego School of Medicine and Veteran Affairs San Diego Healthcare System (VASDHS) – with colleagues at UC Davis and the University of Castilla-La Mancha in Spain – recount the case of EP, a man who suffered radical memory loss and dysfunction following a bout of viral encephalitis.

These photomicrographs depict comparative stained sections of a healthy brain (top) and of patient EP, in which significant structures in the medial temporal lobe are heavily damaged or missing. The letters identify specific brain structures, such as EC and PRC for entorhinal cortex and perirhinal cortex, respectively, both important to memory formation and function.

EP’s story is strikingly similar to the more famous case of HM, who also suffered permanent, dramatic memory loss after small portions of his medial temporal lobes were removed by doctors in 1953 to relieve severe epileptic seizures. The surgery was successful, but left HM unable to form new memories or recall people, places or events post-operation.

HM (later identified as Henry Gustav Molaison) was the subject of intense scientific scrutiny and study for the remainder of his life. When he died in 2008 at the age of 82, he was popularized as “the world’s most famous amnesiac.” His brain was removed and digitally preserved at The Brain Observatory, a UC San Diego-based lab headed by Jacopo Annese, PhD, an assistant adjunct professor in the Department of Radiology and a co-author of the PNAS paper.

Like Molaison, EP was also something of a scientific celebrity, albeit purposefully anonymous. In 1992, at the age of 70, he was diagnosed with viral encephalitis. He recovered, but the illness resulted in devastating neurological loss, both physiologically and psychologically.

Not only did he also lose the ability to form new memories, EP suffered a modest impairment in his semantic knowledge – the knowledge of things like words and the names of objects. Between 1994, when he moved to San Diego County, and his death 14 years later, EP was a subject of continued study, which included hundreds of different assessments of cognitive function.

“The work was long-term,” said Squire, a Career Research Scientist at the VASDHS. “We probably visited his house 200 times. We knew his family.” In a 2000 paper, Squire and colleagues described EP as a 6-foot-2, 192-pound affable fellow with a fascination for the computers used in his testing. He was always agreeable and pleasant. “He had a sense of humor,” said Squire.

After his death, EP’s brain was also processed at The Brain Observatory. The last five years have been spent parsing the data and painting a full picture of what happened to EP and why. Squire said EP’s viral encephalitis infection wreaked havoc upon his brain: Large, bilateral, symmetrical lesions were found in the medial temporal lobe, portions of the brain responsible for formation of long-term memory; and whole, crucial structures were eliminated – the amygdala and hippocampus among them.  Additionally, other brain regions had atrophied and white matter – the support fibers that transmit signals between brain structures – had become gliotic or scarred.

Though HM is generally considered the “gold standard” of amnesia patients – “he was the first case and studied so elegantly,” said Squire – EP provides new and surprising twists in understanding how memory functions and fails.

For example, HM’s declarative memory was almost nil – half an hour after lunch, he would have forgotten what he ate or if he had eaten at all – but in tests, HM showed some small capacity to learn new things. “His ability to learn was nowhere close to zero,” Squire said, “so the thinking was that maybe there were other ways that information was getting in, that there was something special about the capacity for learning facts.”

EP undermines that notion. Due to the total destruction of specific memory-linked brain structures, EP was utterly unable to learn anything new. “It really was absolutely zero,” said Squire. “That suggests there isn’t any special mechanism. HM simply retained some ability because he retained some residual tissue.”

Squire noted that the massive scope of EP’s brain damage also appeared to trigger secondary consequences. “If a lesion gets large enough, it results in other negative changes due to the loss of connectivity,” he said. In EP’s case, one result was his impaired semantic knowledge, which wouldn’t have been harmed by damage to medial temporal lobes, but was the consequence of subsequent atrophy in adjacent tissues.

Finally, EP presents a continuing, confounding mystery. In most patients with retrograde amnesia, memory loss is limited. They can’t remember things within a few months or years of the brain impairment. In EP’s case, he suffered amnesia extending back 40 to 50 years, affecting memories that theoretically should have been well-established and consolidated, though he could recall his childhood on a central California farm.

Squire said the effect is likely the result of lateral temporal damage caused as a secondary consequence of the initial disease-related brain damage. For researchers and clinicians, he said, EP is a cautionary and troubling tale.

Co-authors are Ricardo Insausti, Department of Psychiatry and Behavioral Sciences and the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, UC Davis and Laboratory of Human Neuroanatomy, Department of Health Services and Regional Center for Biomedical Research, School of Medicine, University of Castilla-La Mancha, Spain and David G. Amaral, Department of Psychiatry and Behavioral Sciences and the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute.

Funding for this research came, in part, from the Medical Research Service, Department of Veterans Affairs, National Institute of Mental Health (grants 24600 and 84756), NEI grant 18359, National Institute of Neurological Disorders and Stroke grant 16980 and grants TSI-020110-2009-362, BFU 2009-0434 and PR 2010-0434.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Researchers at the University of California, San Diego School of Medicine have identified a previously unknown biological mechanism involved in the regulation of pancreatic islet beta cells, whose role is to produce and release insulin. The discovery suggests a new therapeutic target for treating dysfunctional beta cells and type 2 diabetes, a disease affecting more than 25 million Americans.

Writing in the April 11, 2013 issue of Cell, Jerrold M. Olefsky, MD, associate dean for scientific affairs and distinguished professor of medicine, and colleagues say a transmembrane binding protein called fractalkine, which typically mediates cell-to-cell adhesion though its receptor, CX3CR1, can also be released from cells to circulate in the blood and stimulate insulin secretion.

“Our discovery of fractalkine’s role in beta cells is novel and has never been talked about in prior literature,” said Olefsky. More importantly, the research highlights fractalkine’s apparently vital role in normal, healthy beta cell function. In mouse models and in cultured human islets, the researchers found administering the protein stimulated insulin secretion and improved glucose tolerance, both key factors in diabetes.  In contrast, fractalkine had no effect in mice or islets when the fractalkine receptor was deleted.

“Whether or not decreased fractalkine or impaired fractalkine signaling are causes of decreased beta cell function in diabetes is unknown,” said Olefsky. “What we do know, without doubt, is that administration of fractalkine improves or restores insulin secretion in all of the mouse models we have examined, as well as in human islet cells.”

Olefsky said fractalkine or a protein analog could prove “a potential treatment to improve insulin secretion in type 2 diabetic patients. It might also improve beta cell function or beta cell health, beyond simply increasing insulin secretion, since fractalkine prevents beta cell apoptosis (cell death) and promotes the beta cell differentiation program.

“If successfully developed, this could be an important new complement to the therapeutic arsenal we use in type 2 diabetes,” Olefsky continued. “It is not likely to ‘cure’ diabetes, but it would certainly do a good job at providing glycemic control.” 

Co-authors of this study include Yun Sok Lee, Hidetaka Morinaga, and William Lagakos, UCSD Department of Medicine, Division of Endocrinology and Metabolism; Jane J. Kim and Ayse G. Kayali, UCSD Department of Pediatrics; Susan Taylor and Malik Keshwani, UCSD Department of Pharmacology; Guy Perkins, National Center for Microscopy and Imaging Research at UCSD; Hui Dong, UCSD Department of Medicine, Division of Gastroenterology; and Ian R. Sweet, Department of Medicine, University of Washington.

Funding came, in part, from the National Institutes of Health (grants DK-033651, DK-074868, T32-DK-007494 and DK-063491) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH (U54-HD-012303-25).

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Current treatments for anorexia and bulimia nervosa, which afflict an estimated 10 to 24 million Americans, are often limited and ineffective. Patients relapse. They become chronically ill. They face a higher risk of dying.

“A major reason contributing to the difficulty in developing new treatments for these disorders is our limited understanding of how brain function may contribute to eating disorder symptoms,” said Walter H. Kaye, MD, professor of psychiatry and director of the Eating Disorder Treatment and Research Program at the University of California, San Diego School of Medicine.

In recent, published papers, Kaye and colleagues report the situation is changing. Advanced brain imaging technologies, supported by grants from the National Institute of Mental Health, are beginning to be used to study and improve eating disorder treatments. Indeed, with funding from the Global Foundation for Eating Disorders (GFED), a New York City-based group that promotes eating disorder (ED) research and improved treatments, the UC San Diego Eating Disorders Center for Treatment and Research has launched a new initiative to create more effective ED therapies based upon brain imaging studies.

“Brain imaging research has allowed for a shift from simply describing a symptom to understanding the cause of a symptom,” said Kaye. “In the case of anorexia nervosa, imaging studies have helped us understand why people avoid eating and food and develop treatments that address the cause of the problem rather than secondary behaviors or symptoms.

“This is an important shift in the world of psychiatry similar to what revolutionized medical care decades ago. Today, if you show up at the doctor’s office with a bad cough, he or she might run diagnostics to determine whether the cough was bacterial or viral in order to administer the appropriate treatment. Similarly, the more we understand the specific causes of eating disorders, the more effective and targeted our treatments can become.”

The UC San Diego program, under the directorship of Kaye, Kerri Boutelle, PhD, associate professor of pediatrics and psychiatry, Leslie Karwoski Anderson, PhD, clinical assistant professor of psychiatry and GFED scholars Stephanie Knatz and June Liang, is developing an imaging-based treatment package specifically to address the neurobiology of anorexia nervosa, in which patients obsess about being or becoming overweight. To prevent weight gain or lose weight, people with anorexia nervosa typical may starve themselves or exercise excessively.

Kaye said one neurobiological target of anorexia and other eating disorders is anxiety. Most people get irritable when they do not eat and experience eating as both a reward and pleasant experience. Conversely, anorexic individuals frequently feel extreme anxiety when eating food – or even just anticipating eating – which results in severely reducing their food intake as a means of reducing their feelings of anxiety.

“Recent imaging research has uncovered specific alterations in the brain associated with this link between food and anxiety in anorexic individuals,” said Kaye. “This finding is important because it helps explain the of cause food restriction, the most critical and dangerous behavior in anorexia.”

The UC San Diego researchers have used the new information to create new treatment strategies, including psychoeducation – teaching patients why symptoms occur and how to more effectively cope.

“Many patients have described finally feeling a wave of relief after learning that the anxiety they experience is not their fault, but partly due to how their brain is responding to food,” said Kaye.  “Understanding why their eating disorder is driving them to restrict allows them to better target their anxiety around meals. Strategies such as developing routines before meals have shown promise in reducing the anticipatory anxiety leading up to meals and food restriction.”

Kaye said the brain-based therapy also benefits families of patients with eating disorders.

“Through a better understanding of their family member’s eating disorder and its causes, family members have found comfort and hope with a ‘road map’ guiding them through the recovery.”

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Media Contacts: Debra Kain, 619-543-6163, ddkain@ucsd.edu; Scott LaFee, 619-543-6163, slafee@ucsd.edu

UC San Diego Researchers and CHP Educate Public on Driving Laws and Safety Tips

According to experts in the Training, Research and Education for Driving Safety (TREDS) program at the University of California, San Diego School of Medicine, there were approximately 3,300 deaths and 400,000 injuries nationwide in 2011 due to collisions involving distracted driving.  The use of cell phones while operating a vehicle is currently the leading cause of driver distraction crashes in California.  With April being national distracted driving awareness month, a team of researchers released survey results that reveal the habits of San Diego County drivers who use their cell phone while behind the wheel.

“Studies have shown that phoning and driving increases the risk of crashes four-fold, with hands-free and handheld devices equally dangerous; this is the same as driving with a blood alcohol content (BAC) at the legal limit of .08.  Texting increases this risk eight to 16 times,” said Linda Hill, MD, MPH, clinical professor in the Department of Family and Preventive Medicine at UC San Diego School of Medicine.  “A key initiative for the TREDS program and goal of the survey is to understand distracted driving behavior and work on strategies to improve road safety.” 

According to the California Highway Patrol (CHP), cell phone use while driving is not the only issue. 

“Anything from drinking coffee to managing children can take your mind off the road at a critical moment.  Most drivers are distracted at one time or another. However, minimizing distractions in your own driving can prevent injury and save lives,” said John Antillon, CHP border division assistant chief.

The Adult Cell Phone Survey, conducted February 8, 2013 through March 31, 2013, focused on the driving habits of San Diego County residents, ages 30 to 64.  The survey used an anonymous, online questionnaire to examine drivers’ attitudes about cell phone use and to quantify the amount of time that respondents use cell phones to text or call others while on the road. Overall, 715 participants completed the survey: 75 percent female, two thirds married, and the average age was 46-years-old.

The survey revealed:

• Of the 512 respondents driving an average of one to two hours per day, the reported use of cell phones for talking, texting and other applications was: 30 percent ranged from sometimes to frequently, 53 percent rarely and 17 percent never.
• 56 percent reported driving with a handheld phone and 92 percent drive with a hands-free phone.
• Of the 261 respondents with children younger than 11-years-old in the car, 65 percent drive with a cell phone and 36 percent text.
  Of the 193 respondents with children 12 to 17-years-old in the car, 63 percent use a phone while driving and 31 percent text.
• Adults with children younger than 11-years-old in the car were significantly more likely to text and to talk on a handheld phone.
• 31 percent of respondents feel obliged to take a work-related call while driving.

“In this study, we were looking for the distracted driving trends of adults with children and employees.  The results highlight the dangerous behavior of adults driving distracted, especially with children in the car, exposing both themselves and their children to increased risk for a crash,” said Hill.  “Moreover, employers should be aware that encouraging workers to initiate and receive calls while driving on the job is putting their employees at risk and exposing their companies to potential liability.”

“We know from prior research that parents are the number one source of information for teen drivers,” said Freddy Santos, corporate relations manager with Allstate. “When adults choose safe driving habits over distractions, it reinforces to teens, children and California’s new and future drivers the importance of driving safely.”

The survey was supported by a gift from Allstate Insurance Company.

The survey team, led by Hill, includes deputy director Jill Rybar, MPH, and PhD student Jessa Engelberg. 

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

As part of a multicenter clinical trial, researchers at University of California, San Diego School of Medicine are evaluating Pexa-Vec (JX-594) to slow the progression of hepatocellular carcinoma (HCC) or liver cancer. Pexa-Vec is a genetically engineered virus that is used in the smallpox vaccine.

“This clinical trial is evaluating a drug already known to be safe as a vaccine. We are applying it as a potential destructive agent for liver cancer,” said Tony Reid, MD, PhD, professor of medicine, UC San Diego School of Medicine and medical oncologist at UC San Diego Moores Cancer Center. “The goal of the trial is to evaluate if Pexa-Vec can extend patients’ survival through its ability to selectively target and kill cancer cells, cut off the tumor’s blood supply, and activate the body’s own immune system to fight the cancer.”

UC San Diego Moores Cancer Center

Patients who are eligible for this Phase 2b randomized clinical trial have a diagnosis of HCC and have been found to be unresponsive to sorafenib, the only systemic therapy currently approved by the FDA.

The clinical trial is designed to compare overall survival for patients receiving the drug combined with palliative care (such as hydration, nutrition and pain management) to patients who receive palliation alone with no additional drug treatment.

While Pexa-Vec is derived from vaccinia virus and is similar to smallpox, it doesn’t contain smallpox and cannot cause the disease. The virus was chosen for study because it shows an ability to target cancerous tissues relative to normal tissues.

During the 18-week trial, Pexa-Vec is given both intravenously and injected directly into the tumor. Common side effects include flu-like symptoms including fevers, chills and fatigue that generally last less than 24 hours.

Hepatocellular carcinoma is estimated to be the third most common cause of cancer-related deaths world-wide, and the 5th most common cancer diagnosis. It is estimated that 22,000 people were diagnosed in the U.S. last year, and 16,000 people died from the illness.

The Pexa-Vec clinical trial, known as TRAVERSE, is sponsored by Jennerex  Biotherapeutics, Inc. of San Francisco, California.

Patients seeking more information about this clinical trial at UC San Diego Moores Cancer may call 858-822-5354 or go to http://traversetrial.com

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

It is known that family-based treatment that combines nutrition and exercise education, along with behavior modification, is a good approach to help children lose weight.  But clinic-based weight-control programs for childhood obesity are not accessible to many families, due to issues such as cost or time commitment.

Initial studies at the University of California, San Diego School of Medicine indicate that a self-help treatment program for overweight children and their parents, guided by clinical experts, may be an effective solution.  The study, led by Kerri Boutelle, PhD, associate professor of pediatrics and psychiatry at UC San Diego School of Medicine – the first to demonstrate the effectiveness of such a program – will be published in the journal Pediatrics on April 1.

Boutelle and colleagues enrolled 50 overweight or obese children between the ages of 8 and 12 and their family members in a low-intensity, 5-month long treatment for childhood obesity, measuring the effects on a child’s weight (measured as body mass index or BMI) immediately post-treatment and six months later.  The researchers also evaluated whether the intervention promoted improvements in eating behavior and physical activity among children and parents. The results of the guided, self-help intervention program showed a significant decrease in BMI immediately after completing the 5-month treatment, losses that were maintained six months later.

According to the UCSD researchers, such a program may be an improvement over current methods, especially because the program is designed to fit a busy family's schedule.

“The guided self-help treatment includes offering structure along with a self-help program to help families stick to the program,” said Boutelle.  “Parents and their children are given a manual, and each week they read a chapter and try to apply the skills at home.  Every other week they come in to our clinic at UC San Diego School of Medicine for 20 minutes and discuss how things were going with an interventionist.  This is very different than traditional weight control programs where parents and kids come in every week for an hour-and-a-half-long group-based program.”

“Importantly, the initial results of this study showed that that a self-help program, guided by professionals, may be as effective in helping kids to lose weight as a traditional, clinic-based weight loss program,” Boutelle concluded. 

Those interested in enrolling their family in such a program, or finding out more about weight-loss programs for kids and teens should email kidsweight@ucsd.edu, call 855-827-3498 or visit the Center for Healthy Eating and Activity Research (CHEAR) Web site at obesitytreatment.ucsd.edu

Additional contributors to the study include Gregory J. Norman, Cheryl L. Rock, PhD, and Kyung E. Rhee, MD, MSC, of UC San Diego; and Scott J. Crow, MD, University of Minnesota. 

This project was funded by grant #DK080266 from the National Institutes of Health.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

On Saturday, April 13 from 8 a.m. to 3:00 p.m., UC San Diego Health System is hosting an interactive conference in La Jolla, focused on women’s health.  The event is free and open to the public. Fifteen leading experts will host insightful talks on subjects, including stress reduction, gene therapy for heart repair, cancer prevention, successfully reducing menopause symptoms, and achieving longevity through diet and fitness.

Keynote speaker Tahir Bhatti, MD, associate clinical professor in UC San Diego School of Medicine’s Department of Psychiatry, will share practical strategies on how to minimize stress in everyday life.

“Stress reduction is a powerful factor in reducing heart disease, accelerating the immune response and maintaining overall wellness.  We will look at how inter-connected the human mind is to our body systems and how these systems in turn respond to the quality of the relationships we have with friends, spouses, families and co-workers,” said Bhatti. “Listeners will get practical advice on how to reduce stress based on a woman’s physiology and how wellness can be achieved through activities as simple as human touch and conversation.”

Cheryl Saenz, MD, and colleagues invite you to Women's Wellness Day on April 13.

Physicians and scientists from the UCSD School of Medicine will offer engaging 30-minute lectures derived from the forefront of science, medicine and surgery. The conference will take place in the new state-of the-art Medical Education and Telemedicine Building on UC San Diego’s La Jolla campus, where attendees will connect directly with the speakers with opportunities for questions and answers.

“Obtaining accurate information is one of the best ways a woman can take control of her health,” said Cheryl Saenz, MD, robotic surgeon at UC San Diego Health System. “At this conference, listeners will receive easy-to-understand scientific information direct from the researchers and clinicians who are developing new treatments and therapies for conditions that may affect all women at some point in their lives.”

Lecture topics include: technological advances to repair the heart, hereditary components of ovarian cancer, stroke prevention strategies and treatments, managing menopause symptoms, staying young through physical fitness, mindful eating, new techniques to manage breast cancer, incontinence and prolapse repair, screening for gynecologic cancers, osteoporosis prevention and care, breast enhancements and body contouring.

Conference attendees may customize their day by selecting their desired lecture topics and opting for activities, such as heart health screenings or complimentary chair massages.

Both breakfast and lunch will be served and include a fresh juice bar, salad bar, and gluten-free diet options. Cooking demonstrations will be performed by Lauray MacElhern of the Center for Integrative Medicine at UC San Diego Health System. Participants can take home collectible color recipe cards for carrot bisque and Asian cole slaw.

Guided tours of the Center of the Future of Surgery will be provided by Santiago Horgan, MD, chief of minimally invasive surgery at UC San Diego Health System, a surgical innovator who has developed scarless surgical techniques specifically for women.

Registration is required to attend this free conference. Please visit http://health.ucsd.edu/wellness

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Schwann cell protein plays major role in neuropathic pain

An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, says a key protein in Schwann cells performs a critical, perhaps overarching, role in regulating the recovery of peripheral nerves after injury. The discovery has implications for improving the treatment of neuropathic pain, a complex and largely mysterious form of chronic pain that afflicts over 100 million Americans.

The findings are published in the March 27, 2013 issue of the Journal of Neuroscience.

Schwann cells (colored purple) forming myelin sheathes (green) around axons (brown). Image courtesy of David Furness, Wellcome Images.

Neuropathic pain occurs when peripheral nerve fibers (those outside of the brain and spinal cord) are damaged or dysfunctional, resulting in incorrect signals sent to the brain. Perceived pain sensations are frequently likened to ongoing burning, coldness or “pins and needles.” The phenomenon also involves changes to nerve function at both the injury site and surrounding tissues.

Not surprisingly, much of the effort to explain the causes and mechanisms of neuropathic pain has focused upon peripheral nerve cells themselves. The new study by principal investigator Wendy Campana, PhD, associate professor in UC San Diego’s Department of Anesthesiology, with colleagues at UC San Diego and in Japan, Italy and New York, points to a surprisingly critical role for Schwann cells – a type of glial support cell.

Schwann cells promote the growth and survival of neurons by releasing molecules called trophic factors, and by supplying the myelin used to sheathe neuronal axons. Myelination of axons helps increase the speed and efficacy of neural impulses, much as plastic insulation does with electrical wiring.

“When Schwann cells are deficient they can’t perform these functions,” said Campana. “Impaired neurons remain impaired and acute damage may transition to become chronic damage, which can mean lasting neuropathic pain for which there is currently no effective treatment.”

Specifically, the scientists investigated a protein called LRP1, which Campana and colleagues had first identified in 2008 as a potential basis for new pain-relieving drugs due to its signal-blocking, anti-inflammatory effects.

The researchers found that mice genetically engineered to lack the gene that produces LRP1 in Schwann cells suffered from abnormalities in axon myelination and in Remak bundles – multiple non-myelinated pain transmitting axons grouped together by Schwann cells. In both cases, one result was neuropathic pain, even in the absence of an actual injury.

Moreover, injured mice lacking the LRP1 gene showed accelerated cell death and poor neural repair compared to controls, again resulting in significantly increased and sustained neuropathic pain and loss of motor function.

“LRP1 helps mediate normal interactions between Schwann cells and axons and, when  peripheral nerves have been injured, plays a critical role in regulating the steps that lead to eventual nerve regeneration,” said Campana. “When LRP1 is deficient, defects and problems become worse. They may go from acute to chronic, with increasing levels of pain.”

Campana and others are now pursuing development of a small molecule drug that can mimic LRP1, binding to receptors in Schwann cells to improve their health and ability to repair damaged nerve cells. “By targeting Schwann cells and LRP1, I think we can improve cells’ response to injury, including reducing or eliminating chronic neuropathic pain.”

Co-authors include Sumihisa Orita, Kazuyo Yamauchi and Tetsuhiro Ishikawa, UCSD Department of Anesthesiology and Department of Orthopedic Surgery, Chiba University, Japan; Kenneth Henry, Elisabetta Mantuano and Melanie Pollack, UCSD Department of Anesthesiology; Alice De Corato, UCSD Department of Anesthesiology and Department of Pharmacology, Cattolica University, Italy;  M. Laura Feltri and Lawrence Wrabetz, Hunter James Kelly Research Institute, State University of New York at Buffalo; Alban Gaultier and Steven L. Gonias, UCSD Department of Pathology; Mark Ellisman, UCSD Department of Neurosciences; and Kazuhisa Takahashi, Department of Orthopedic Surgery, Chiba University, Japan.

Funding for this research come, in part, from the National Institutes of Health (NINDS grants R01 NS-057456, R01 NS-054671, P30 NS47101, NCRR 5P41RR004050-24 and NIGMS P41GM103412-24) and the Uehara Memorial Foundation.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Five University of California, San Diego scientists and professors are among the first class of the Fellows of the American Association for Cancer Research Academy, created to recognize researchers whose scientific contributions have propelled significant innovation and progress against cancer. The entire class consists of 106 individuals, to celebrate the 106 year anniversary of AACR, the world’s first and largest professional organization dedicated to advancing cancer research.

The inaugural class of Fellows of the AACR Academy includes Napoleone Ferrara, MD, UC San Diego Moores Cancer Center, senior deputy director for basic science; Roger Y. Tsien, PhD, UCSD professor of pharmacology and of chemistry and biochemistry; Webster K. Cavenee, PhD, director of the Ludwig Institute for Cancer Research at UC San Diego and UCSD professor of medicine; Tony Hunter, PhD, director of the Salk Institute Cancer Center, and Geoffrey Wahl, PhD, Salk Institute for Biological Studies professor – both UCSD adjunct professors in the division of biological science.

“Our Board of Directors made the decision to establish the AACR Academy as a mechanism for recognizing scientists whose contributions to the cancer field have had an extraordinary impact,” said Margaret Foti, PhD, MD (hc), chief executive officer of the AACR. “Membership in the Fellows of the AACR Academy will be the most prestigious honor bestowed by the American Association for Cancer Research.”

Ferrara, the investigator credited with helping decipher how tumors grow, is recognized for his work identifying the role of vascular endothelial growth factor (VEGF) in promoting angiogenesis—the formation of new blood vessels that can feed tumor growth—and subsequent development of two major monoclonal antibody drugs: Bevacizumab (Avastin), which is used to treat multiple forms of cancer and Ranibizumab (Lucentis), which treats wet age-related macular degeneration, a leading cause of blindness in the elderly.

Tsien, who shared the 2008 Nobel Prize in chemistry for his role in helping develop and expand the use of green fluorescent proteins (GFP), is honored for his revolutionary work in the fields of cell biology and neurobiology. He is known for developing GFPs that allow scientists to peer inside living cells and watch the behavior of molecules in real time. Scientists can track where and when certain genes are expressed in cells or in whole organisms. Tsien is currently building on his fluorescent protein work to develop a novel way to image and possibly deliver specially targeted drugs to cancer tumors.

Cavenee is recognized for having provided the first indisputable evidence of tumor suppressor genes. He has conducted research that has changed the understanding of tumor initiation and progression. Cavenee’s recent research has focused on gliomas—a tumor that begins in the brain or spine –and his team has found that an abnormal version of the protein epidermal growth factor receptor, named EGFRviii, is common in the most rapidly progressive primary brain tumors in humans.

Dubbed the “Kinase King,” Hunter’s work identified one of the critical switches required to initiate normal cell proliferation, and showed that the enzyme tyrosine kinase switch is frequently permanently turned on in cancer cells. His work has led to the discovery and development of many effective drugs targeting abnormal kinase signaling in cancer cells.

A widely recognized expert in understanding the genetic instability of cancer cells and why tumors become resistant to drugs, Wahl’s research showed that such instability often results from mutations in key tumor suppressor genes such as p53. He recently discovered links between embryonic breast stem cells and stem-like cells in some of the most lethal breast cancers. This research is aimed at developing personalized therapeutic strategies to combat cancer.

The inaugural class of Fellows will be inducted into the AACR Academy on Friday, April 5 at the National Museum of Women in the Arts in Washington, D.C.

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Media Contact: Yadira Galindo, 619-543-6163, ygalindo@ucsd.edu

Researchers at the University of California, San Diego Moores Cancer Center have identified a humanized monoclonal antibody that targets and directly kills chronic lymphocytic leukemia (CLL) cells.

The findings, published in the online Early Edition of the Proceedings of the National Academy of Sciences on March 25, 2013 represent a potential new therapy for treating at least some patients with CLL, the most common type of blood cancer in the United States.

Chronic lymphocytic leukemia cells.

CLL cells express high levels of a cell-surface glycoprotein receptor called CD44.  Principal investigator Thomas Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research, and colleagues identified a monoclonal antibody called RG7356 that specifically targeted CD44 and was directly toxic to cancer cells, but had little effect on normal B cells.

Moreover, they found RG7356 induced CLL cells that expressed the protein ZAP-70 to undergo apoptosis or programmed cell death. Roughly half of CLL patients have leukemia cells that express ZAP-70.  Such patients typically have a more aggressive form of the disease than patients with CLL cells that do not express that specific protein.   

Previous research by Kipps and others has shown that CLL cells routinely undergo spontaneous or drug-induced cell death when removed from the body and cultured in the laboratory. They found that CLL cells receive survival signals from surrounding non-tumor cells that are present in the lymph nodes and bone marrow of patients with CLL.  One of these survival signals appears to be transmitted through CD44.  However, when CD44 is bound by the RG7356 monoclonal antibody, it seems to instead convey a death signal to the leukemia cell. 

“By targeting CD44, it may be possible to kill CLL cells regardless of whether there are sufficient numbers of so-called ‘effector cells,’ which ordinarily are required by other monoclonal antibodies to kill tumor cells,” said Kipps. “We plan to initiate clinical trials using this humanized anti-CD44 monoclonal antibody in the not-too-distant future.” 

Co-authors were Suping Zhang, Christina C.N. Wu, Jessie-Farah Fecteau, Bing Cui, Liguang Chen, Ling Zhang, Rongrong Wu, Laura Rassenti, and Fitzgerald S. Lao, Department of Medicine, UCSD Moores Cancer Center; and Stefan Weigand, Roche Diagnostics GmbH, Germany.

Funding for this study came, in part, from the National Institutes of Health (grant PO1-CA081534) and the UC San Diego Moores Cancer Blood Center Research Fund.

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Media Contact : Scott Lafee, 619-543-6163, slafee@ucsd.edu

L.S. “Sam” Skaggs, whose enduring support of pharmacy education and research helped fuel the growth and development of the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California, San Diego, died Thursday at the age of 89 of causes related to age.

L.S. "Sam" Skaggs

Skaggs built a retail food-and-drug business empire, but the Utah businessman also nurtured a decades-long, widespread interest in promoting the health sciences. In 2004, he and his family’s Institute for Research donated $30 million to UC San Diego’s then-2-year-old School of Pharmacy and Pharmaceutical Sciences. It was the largest gift to UC San Diego Health Sciences at the time, and among the largest in UC San Diego history.

“Sam Skaggs was a pioneer, a visionary and a generous philanthropist,” said Chancellor Pradeep K. Khosla.  “He helped ensure the success of the School of Pharmacy and Pharmaceutical Sciences. His legacy lives on through his contributions and dedication to the future of pharmaceutical care. We will always be grateful for the positive impact he’s had on the health and well-being of our campus and community.” 

The Skaggs School of Pharmacy and Pharmaceutical Sciences, named in Sam Skaggs’ honor, is one of just two pharmacy schools in the UC system and a national leader in pharmaceutical education and research. It boasts more than 150 salaried and volunteer faculty members, with a current enrollment of 240 PharmD and 60 PhD students as well as 30 pharmacy residents.

“Sam Skaggs was instrumental in the development of our school,” said Palmer Taylor, PhD, dean of the Skaggs School and associate vice chancellor of health sciences at UC San Diego. “From our humble beginnings in a temporary building, he followed our growth, occasionally offering sage advice. His gift in 2004 was transformational. It gave us the resources and flexibility to not just grow, but excel.”

Skaggs, who resided in Salt Lake City, built his business and fortune growing the Payless Drug Stores chain, which he took over after his father died from a stroke in 1950. He was 26. In 1979, he acquired American Stores, creating the second-largest U.S. food retailer in the United States. In 1995, shortly before he retired, Skaggs headed one of the largest food companies in the world, with 1,700 stores in 26 states and annual revenue exceeding $22 billion.

A significant portion of his wealth was devoted to diverse philanthropic interests, from pharmaceutical education and research throughout the American west to religious interests, which included support of Mater Dei Catholic High School in Chula Vista.

In lieu of flowers, friends may make contributions to the "Skaggs School of Pharmacy Scholarship Fund." Checks payable to the UC San Diego Foundation can be sent to University of California, San Diego, c/o Andrina Marshall, 9500 Gilman Drive #0657, La Jolla, Ca. 92093-0657; donations also can be made online at www.givetoucsd.ucsd.edu. Please type “Skaggs School of Pharmacy Scholarship Fund” in the keyword search section.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Researchers at the University of California, San Diego School of Medicine have released study results that show national treatment trends in the surgical management of patients with kidney disease. The study found that partial and complete kidney removal (total nephrectomy) and energy-based techniques to destroy tumors are all on the rise. Surprisingly, the patients most in need of kidney-sparing surgery are still more likely to undergo total nephrectomy. The findings recently published online in BJU International.

Ithaar Derweesh, MD, urologic oncologist, UC San Diego Moores Cancer Center.

“While the overall proportion of patients receiving kidney preserving treatments for localized kidney tumors continues to grow, the most significant, and perhaps unsettling finding was that patients with kidney insufficiency still undergo complete kidney removal – even though kidney preserving treatment may be indicated,” said senior author Ithaar Derweesh, MD, urologic oncologist at UC San Diego Moores Cancer Center.

The kidney is a vital organ which performs a variety of functions in addition to making urine. It controls blood pressure, bone health, and also makes a hormone to tell the bone marrow to produce red blood cells. Kidney insufficiency is characterized by a progressive decline in kidney function which may affect all of these actions.

“The study, which examined procedures over a 10-year period, found that patients with chronic kidney insufficiency had an almost two-fold higher probability of undergoing total nephrectomy than kidney preserving treatments, such as partial nephrectomy or tumor ablation,” said Derweesh, a pioneer in minimally invasive kidney surgery.

Derweesh added that further investigation is needed to confirm these findings, and to examine what factors are responsible for patient and physician selection of treatment for kidney cancer. He noted that in the case of small renal masses less than four centimeters in size, partial nephrectomy has equivalent outcomes to total nephrectomy, and that ablation techniques, such as cryoablation or radiofrequency ablation, and observation are valid options for select patients. 

While kidney insufficiency may result in total failure of the kidney, most patients do not progress to dialysis dependence. However, patients with worsening degrees of kidney insufficiency are at higher risk of cardiac events, such as heart attack and stroke, and osteoporosis and anemia.

The UC San Diego study utilized data from the Nationwide Inpatient Sample (NIS), the largest database of all annual hospital admissions in the United States. Approximately 443,850 procedures were included in the study.  

Chronic kidney disease (CKD) is a condition characterized by a gradual loss of kidney function over time and affects more than 26 million American adults. The two main causes of chronic kidney disease are diabetes and high blood pressure, which are responsible for up to two-thirds of the cases. Renal cell carcinoma is a commonly diagnosed urological malignancy with an estimated 57,760 new cases and 12,908 deaths in the United States during 2009.

Study contributors include: Jeffrey Woldrich, MD, Kerrin Palazzi, MPH, Sean Stroup, MD, Roger Sur, MD, J. Kellog Parsons, MD, and David Chang, PhD.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Drug Designed and Developed at UC San Diego School of Medicine

Researchers at the University of California, San Diego School of Medicine have shown that a new imaging dye, designed and developed at UC San Diego Moores Cancer Center, is an effective agent in detecting and mapping cancers that have reached the lymph nodes. The radioactive dye called Technetium Tc-99m tilmanocept, successfully identified cancerous lymph nodes and did a better job of marking cancers than the current standard dye. Results of the Phase III clinical trial published online today in the Annals of Surgical Oncology.

“Tilmanocept is a novel engineered radiopharmaceutical specifically designed for sentinel lymph node detection,” said David R. Vera, PhD, the drug’s inventor, who is a professor in the UCSD Department of Radiology. “The molecule, developed at UC San Diego School of Medicine, offers surgeons a new tool to accurately detect and stage melanoma and breast cancers while in the operating room.”

Anne Wallace MD, chief of plastic surgery, UC San Diego Health System

On March 13, 2013, tilmanocept received U.S. Food and Drug Administration (FDA) approval.

After a cancer diagnosis, surgeons want to be sure that the disease has not spread to a patient’s lymph nodes, especially the sentinel nodes that may be the first place that a cancer reaches. The lymphatic system is a network of vessels and ducts that carry disease-fighting cells throughout the body, but can also act as a way for cancer cells to access the bloodstream.  By surgically removing and examining the sentinel nodes that drain a tumor, doctors can better determine if a cancer has spread.

“Tilmanocept advances the molecular targeting in breast cancer. It’s the first agent that is binding to a lymph node because it is a lymph node that plays an important role in metastasis,” said Anne Wallace, MD, professor of surgery, UC San Diego School of Medicine and principal investigator of the study.  “Tilmanocept’s ability to identify more cancer containing nodes will lead to better post-operative care for patients, especially those patients who had more than one positive sentinel node.”

Doctors compared injections of tilmanocept, also called Lymphoseek, and the standard blue dye into the tumor area. Then, using a handheld radiation detector, they found the lymph nodes that had taken up the drugs radioactivity. The researchers found that more than 99 percent of sentinel lymph nodes containing blue dye also contained tilmanocept.  Of these nodes, 18 percent were positive for cancer. Ninety-four percent of the malignancies were detected by the new radiopharmaceutical whereas the blue dye only detected 76 percent.

“Tilmanocept is just as accurate as current techniques, simple to use, takes less time to find lymph nodes and is cleared faster from the body. This could standardize the process of lymph node mapping and make the process easier, particularly for less experienced surgeons,” said Wallace, chief of plastic surgery at UC San Diego Health System and director of the Breast Care Unit at UC San Diego Moores Cancer Center.

Tilmanocept was originally developed at UC San Diego by Vera. Wallace advanced the agent through Phase 1 clinical trials with funding provided by the Susan G. Komen Breast Cancer Foundation and the American Cancer Society. The Phase III study was supported by Navidea Biopharmaceuticals, Inc. based in Dublin, Ohio.

Lymphoseek’s safety and effectiveness were established in two clinical trials of 332 patients with melanoma or breast cancer. The Phase III clinical trial took place at 13 medical centers involving 148 patients who had both melanoma and breast cancer. The most common side effects identified in clinical trials was pain or irritation at the injection site reported by two patients.

Study collaborators include: Linda Han, MD, Indiana University Simon Breast Center; Stephen P. Povoski, MD, Wexner Medical Center; Kenneth Deck, MD, South Orange County Medical; Schlomo Schneebaum, MD, Sourasky Medical Center; Nathan Hall, MD, PhD, Wexner Medical Center; Carl K. Hoh, MD, and Karl Limmer, MD, UC San Diego; Helen Krontiras, MD, University of Alabama; Thomas Frazier, MD, Bryn Mawr Hospital; Charles Cox, MD, University of South Florida; Eli Avisar, Sylvester Comprehensive Cancer Center at University of Miami; Mark Faries, MD, John Wayne Cancer Institute; and Dennis King, PhD, and Lori Christman, PhD, STATKING Clinical Services.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

On March 19, the National Comprehensive Cancer Network^® (NCCN^®) announced the election of University of California, San Diego Moores Cancer Center as the first and only San Diego-based NCCN Member Institution dedicated to improving the quality, effectiveness, and efficiency of care provided to patients with cancer.

UC San Diego Moores Cancer Center was elected as the first and only San Diego-based National Comprehensive Cancer Cneter Network Memeber Institution.

“We are proud to join this prestigious alliance of the world’s leading cancer centers,” said Paul Viviano, CEO of UC San Diego Health System. “The physicians, scientists and clinicians of UC San Diego Moores Cancer Center and NCCN, share a vision of creating a healthier world, one life at a time, through new science, new medicine and new cures.”

As a NCCN Member Institution, UC San Diego Moores Cancer Center will be part of a national network that develops the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) used as the standard for clinical policy in oncology, incorporating expert medical judgment and recommendations of multidisciplinary panels from NCCN Member Institutions.

“The National Comprehensive Cancer Network and the UC San Diego Health System are bringing the most effective therapeutic and prevention strategies to cancer patients,” said Scott M. Lippman, MD, director of the Moores Cancer Center. “We look forward to working with fellow premier NCCN institutions to impact the outcomes of cancer care and to influence the direction of the cancer field.”

Joining 22 other institution members of NCCN, Moores Cancer Center was selected because of its role in transforming cancer care and providing exceptional care to cancer patients. Moores Cancer Center is the only National Cancer Institute (NCI)-designated Comprehensive Cancer Center in the San Diego region. Its multi-disciplinary team approach includes translating the basic scientific discoveries of its research faculty into new treatments for cancer patients in the clinic.

“We are extremely pleased that UC San Diego Moores Cancer Center has been elected to institutional membership in the NCCN,” said Robert Carlson, MD, CEO of the National Comprehensive Cancer Network. “Moores Cancer Center adds substantial strength and expertise to the excellence of cancer care, research, and education characteristic of the other world-class member institutions.”

About the National Comprehensive Cancer Network^®
The National Comprehensive Cancer Network^® (NCCN^®), a not-for-profit alliance of 23 of the world’s leading cancer centers, is dedicated to improving the quality, effectiveness, and efficiency of care provided to patients with cancer. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The primary goal of all NCCN initiatives is to improve the quality, effectiveness, and efficiency of oncology practice so patients can live better lives.

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Media Contact: Yadira Galindo, 619-543-6163, ygalindo@ucsd.edu

Researchers at the University of California, San Diego School of Medicine are principal investigators in three of nine new grants approved today by the governing board of the California Institute for Regenerative Medicine (CIRM).

All of the grants are part of CIRM’s Human Induced Pluripotent Stem Cell (hiPSC) Initiative, an effort to develop and advance research into reprogramming cells, such as skin, into pluripotent stem cells that can then be differentiated into other functional cell types, such as neurons. In this case, the grants focus upon creating and operating long-term repositories of high quality stem cell lines representing different diseases that can be used by researchers everywhere.

The CIRM board approved nine grant proposals to create and store 9,000 cell lines from 3,000 individuals representing 11 diseases at a total cost of $32.3 million. Three of the proposals are based at UC San Diego and total more than $2.5 million. They are:

Kang Zhang, MD, PhD
Blinding eye diseases/$1,034,453
Blindness or impaired vision affects 3.3 million Americans over the age of 40, according to the National Institutes of Health. It’s a phenomenon that increases with age. The NIH projects 5.5 million blind or vision-impaired Americans by 2020.

Chief among vision afflictions are diseases like age-related macular degeneration (AMD), primary open-angle glaucoma (POAG) and proliferative diabetic retinopathy (PDR). Kang Zhang, MD, PhD, professor of ophthalmology and human genetics at the Shiley Eye Center and director of the Institute for Genomic Medicine, both at UC San Diego, and colleagues propose to obtain skin biopsies from patients with AMD, POAG and PDR and develop retina cell lines derived from differentiated hiPSCs. These lines will help researchers better understand the mechanisms of blinding diseases and aid drug development screening and testing. Ultimately, the hiPSCs might be used to replace degenerated or damaged retinal cells and restore vision.

Joseph Gleeson, MD
Childhood neurodevelopmental disorders/$874,135
Many children with brain disorders have symptoms combining autism, cerebral palsy and epilepsy, suggesting underlying and shared mechanisms of dysfunction. In this project, principal investigator Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine, and colleagues aim to identify 500 patients with these disorders, primarily from Rady Children’s Hospital-San Diego.  The goal is to develop a database of biological, medical, radiographic and genetic information that can be used to study stem cell mechanisms of disease and design therapeutic interventions. Please call 858-822-3538 for information or to participate.

Douglas Galasko, MD
Alzheimer’s disease/$643,693
Alzheimer’s disease (AD) is the most common form of dementia in the elderly, affecting more than 5 million Americans, among them 600,000 Californians. There are no treatments to slow the progression or prevent the neurological disorder. With colleagues, Douglas Galasko, MD, director of the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego, will obtain skin cells from 220 persons with AD and 120 controls whose genetic backgrounds have been extensively studied. These cells will be preserved and made available to researchers, in particular hiPSC projects parsing the mechanisms and genetic risk of AD and for screening and testing new AD drugs.

The May 19 grants bring UC San Diego’s total to more than $ 133 million in CIRM funding since the first awards in 2006.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

UC San Diego Integrative Oncology 2013, April 6-7

From Saturday, April 6 to Sunday April 7, the Center for Integrative Medicine at University of California, San Diego School of Medicine is hosting a landmark conference on integrative oncology. Participants will learn what can be done to foster an “anti-cancer” diet and lifestyle to help rectify health imbalances and reduce the drivers of cancer. Integrative oncology addresses all aspects of cancer care, using evidence from cancer epidemiology, basic science, and clinical research – together with ancient knowledge of natural healing systems such as Chinese medicine and Ayurveda, a system of traditional medicine native to India.

“This will be a ‘first-of-its-kind’ conference for the field of oncology,” said Gordon Saxe, MD, PhD, preventive medicine physician and research director, UC San Diego Center for Integrative Medicine. “There will always be a critical need for proven, life-saving treatments targeted at eradicating or controlling the spread of cancer. However, there is also a need for empowering approaches that encourage active patient self-care in support of whole-person health. There is a growing awareness that these approaches must be part of optimal cancer care.”

The weekend course is designed to introduce participants to the concept of integrative oncology.  Conference presenters will discuss the complex relationship between tumor and host, and dietary, lifestyle and environmental factors. The aim of the conference is to provide participants with an understanding of the research behind integrative oncology as well as the tools to apply new and empowering approaches to improve patient care and to translate their knowledge into actionable wellness plans.

“This course is ideal for anyone working in the field of cancer, or those who have otherwise been affected by cancer personally,” said Lauray MacElhern, conference organizer and managing director of the UC San Diego Center for Integrative Medicine.

Offered on the UC San Diego campus in La Jolla, the conference will feature national speakers who focus on three core areas: diet and lifestyle for cancer prevention; evidence-based integrative therapies; and integrative modalities that improve symptoms and enhance the quality of life of cancer patients. Topics include: optimal nutrition, physical activity, massage, manual therapies, acupuncture, herbs, biofeedback, meditation, guided imagery, integrative psychiatry, biofield therapies, expressive arts, yoga, and tai chi.

General registration is $219. Discounts are available to students, residents, and faculty of UC San Diego, Bastyr University California, and Pacific College of Oriental Medicine.  Full scholarships are also available. Breakfast on both days, lunch on Saturday, and parking are included in the fees. Twelve hours of medical education credits are offered with the American Medical Association and American Psychological Association. The course is from 9 a.m. to 6 p.m. on Saturday and 9 a.m. to 12:45 p.m. on Sunday on the UC San Diego campus at the Medical Education and Telemedicine (MET) Building.

More information about integrative medicine at UC San Diego can be found at http://cim.ucsd.edu

To learn more or to register for this conference, call 858-334-4631 or visit: http://cim.ucsd.edu/io2013

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Lewis L. Judd, MD, Distinguished Professor and chair of the Department of Psychiatry, at the University of California, San Diego School of Medicine was selected as recipient of the Award for Research in Mood Disorders by the American College of Psychiatrists. The award  is given to an individual who has advanced the understanding and

Lewis L. Judd, MD, Distinguished Professor and chair of the Department of Psychiatry.
Arno J. Mundt, MD, professor and chair of the Department of Radiation Medicine and Applied Sciences
Robert N. Weinreb, MD, Distinguished Professor of Ophthalmology, chair of the Department of Ophthalmology

treatment of depression and bipolar disorder.  The American College of Psychiatrists presented this award to Judd in recognition of his significant scientific contributions to the awareness of the pathophysiology, clinical structure, and course of illness of both bipolar and unipolar depressive disorders.

Arno J. Mundt, MD, professor and chair of the Department of Radiation Medicine and Applied Sciences, was inaugurated as the president of the American College of Radiation Oncology (ACRO) at the organization’s February 2013 meeting. ACRO is a professional medical society founded in 1990 and comprised of approximately 1,000 practicing radiation oncologists and residents in training in the United States. As president, Mundt will oversee the board of chancellors and will serve as the CEO of the organization for the next two years. Mundt recently led an international medical mission to Senegal, West Africa. The team brought with it Senegal’s first modern high dose rate brachytherapy machine which will allow doctors to better treat cervical cancer and other malignancies.

Robert N. Weinreb, MD, Distinguished Professor of Ophthalmology, chair of the Department of Ophthalmology and director of the Shiley Eye Center received the American Glaucoma Society Innovator Award at the American Glaucoma Society’s annual meeting on March 1, 2013.  The society’s mission is to promote excellence in the care of patients with glaucoma and preserve or enhance vision by supporting glaucoma specialists and scientists through the advancement of education and research. Weinreb, the Morris Gleich chair in Glaucoma, received the Innovator Award for extraordinary contributions to his field. The Innovator Award is given to an individual who has been a champion of advancing glaucoma patient care and discoveries of treatments.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

University of California, San Diego Health System has been named among “100 Hospitals with Great Neurosurgery and Spine Programs” by Becker's Hospital Review, a news publication for hospital and health system leadership.

According to the Becker's Hospital Review editorial team, these hospitals offer outstanding spine and neurosurgical care, and were selected based on nominations, clinical accolades, quality care and other spine and neurosurgical proficiencies.

More than 30 neurosurgeons at UC San Diego Health  System are dedicated to the care of complex neurological diseases.

“The UC San Diego Neurological Institute is proud to have its neurosurgery program recognized as a leading program in complex brain and spine care,” said Bob Carter, MD, PhD, professor of surgery at UC San Diego School of Medicine, and chief of neurosurgery at UC San Diego Health System. “We have been fortunate to attract an outstanding cadre of neurosurgeons to UC San Diego who specialize in every form of neurosurgery, from minimally invasive techniques to the most complex spine and brain surgery.”

These hospitals have been recognized for excellence in this specialty by reputable healthcare rating resources, including U.S. News & World Report, HealthGrades, Truven Health Analytics, Blue Cross Blue Shield Distinction Centers for Spine Surgery, Delta Group CareChex and the American Nurses Credentialing Center.

Bob Carter, MD, PhD, chief of neurosurgery

Carter, who was recruited from Harvard in 2010, noted that a special emphasis has been placed on developing programs that require a multidisciplinary team-based approach. 

“We have been fortunate to partner with our colleagues in neurology and other specialties to create 'Centers of Excellence' in brain tumors, spine and peripheral nerve restoration surgery, stroke and aneurysms, Parkinson’s disease, pediatric neurosurgery and skull base/pituitary surgery.  These centers mean that patients are offered all forms of treatment, both surgical and non-surgical, in one setting.”

The neurosurgery program has more than 30 neurosurgeons dedicated to the care of all forms of brain and neurological disease.  In 2012, UC San Diego Health System became one of the first facilities in the country to be certified as a Comprehensive Stroke Center (CSC), the newest level of certification for advanced stroke care awarded by The Joint Commission.

Patients and families who would like to learn more about the neurosurgery program at UC San Diego Health System may visit: http://health.ucsd.edu/neuro

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

While poverty and under-education continue to dampen contraception use in Nepal, exacerbating the country’s efforts to reduce maternal and child mortality rates, researchers say another, more surprising factor may be more intractable: Deeply held cultural preferences for sons over daughters.

Writing in the March 7, 2013 online International Journal of Gynecology and Obstetrics, scientists from the University of California, San Diego School of Medicine found that geography (urban versus rural), age and levels of education, wealth and social status all predictably influenced whether Nepalese women used birth control.

Young wives in Nepal were among those least likely to use contraceptives, 24 percent of wives ages 20-24 and just 14 percent of wives ages 15 to 19 years old. These low percentages, said first author Anita Raj, PhD, professor of medicine in the UC San Diego School of Medicine, were particularly notable among young wives who did not have any sons.

“Daughter aversion” reflects a profound, historical cultural bias in Nepal and in other central and south Asian countries, said Raj, an international authority on gender issues in the region. Part of the reason is financial, she said. Males traditionally enjoy greater economic opportunity.

“But tradition also says sons take care of parents,” Raj said. “Daughters are supposed to leave the family and become the daughter of the in-laws, no longer the daughter of the parents. Practices like that are going to affect investment in your daughters.”

Raj said son preference was worrisome for a couple of reasons. First, it persists even with improvements in education. Second, it remains strong among the youngest Nepalese wives.
She suggested the latter effect may be due, in part, to the influence of older generations.

“Even after adjusting for child marriage, you see it. Girls who marry younger may be more vulnerable to son preference because they are more likely to have their reproductive decision-making affected – or controlled – by older husbands and in-laws, both of whom may desire sons from these young wives,” she said.

“Until girls are valued as much as boys in families, we will continue to see these findings. We hoped generations (and modernization) would make it better, but this study is with young mothers and demonstrates that the beliefs are being carried into the youngest generation of child-bearers.”

The cross-sectional study was based on data from the 2011 Nepal Demographic and Health Survey, which found that only one in five married adolescent and young women used modern contraception. Rates were lowest among women who resided in rural areas, lacked education or social status, were married as minors or had no sons.

Raj said improved contraception use is linked to reducing maternal and infant or child mortality rates because younger mothers are more at risk.

Co-authors were Roan J. Vims, Division of Global Public Health, Department of Medicine, UC San Diego; Lotus McDougal, Division of Global Public Health, Department of Medicine, UC San Diego and Joint Doctoral Program in Public Health, UC San Diego/San Diego State University; and Jay G. Silverman, Division of Global Public Health, Department of Medicine, UC San Diego and Center on Global Justice, UC San Diego.

Funding for this research came, in part, from the David and Lucile Packard Foundation and the National Institutes of Health (#R01HD061115).

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

An old drug gives hope for new treatment in autism

Autism results from abnormal cell communication. Testing a new theory, researchers at the University of California, San Diego School of Medicine have used a newly discovered function of an old drug to restore cell communications in a mouse model of autism, reversing symptoms of the devastating disorder.

The findings are published in the March 13, 2013 issue of the journal PLOS ONE.

“Our (cell danger) theory suggests that autism happens because cells get stuck in a defensive metabolic mode and fail to talk to each other normally, which can interfere with brain development and function,” said Robert Naviaux, MD, PhD, professor of medicine and co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego. “We used a class of drugs that has been around for almost a century to treat other diseases to block the ‘danger’ signal in a mouse model, allowing cells to return to normal metabolism and restore cell communication.”

“Of course, correcting abnormalities in a mouse is a long way from a cure for humans,” said Naviaux, “but we are encouraged enough to test this approach in a small clinical trial of children with autism spectrum disorder in the coming year. This trial is still in the early stages of development. We think this approach – called antipurinergic therapy or APT – offers a fresh and exciting new path that could lead to development of a new class of drugs to treat autism.”

Autism spectrum disorders (ASDs) are complex disorders defined by abnormalities in the development of language, social and repetitive behaviors. Hundreds of different genetic and environment factors are known to confer risk.  In this study, nearly a dozen UC San Diego scientists from different disciplines collaborated to find a unifying mechanism that explains autism.  Their work is the result of one of just three international “Trailblazer” awards given by the group Autism Speaks in 2011.

Describing a completely new theory for the origin and treatment of autism using APT, Naviaux and colleagues introduce the concept that a large majority of both genetic and environmental causes for autism act by producing a sustained cell danger response – the metabolic state underlying innate immunity and inflammation.

“When cells are exposed to classical forms of dangers, such as a virus, infection or toxic environmental substance, a defense mechanism is activated,” Naviaux explained.  “This results in changes to metabolism and gene expression, and reduces the communication between neighboring cells. Simply put, when cells stop talking to each other, children stop talking.”

Since mitochondria – the so-called “power plants” of the cell – play a central role in both infectious and non-infectious cellular stress, innate immunity and inflammation, Naviaux and colleagues searched for a signaling system in the body that was both linked to mitochondria and critical for innate immunity.  They found it in extracellular nucleotides like adenosine triphosphate (ATP) and other mitokines – signaling molecules made by distressed mitochondria. These mitokines have separate metabolic functions outside of the cell where they bind to and regulate receptors present on every cell of the body.  Fifteen types of purinergic receptors are known to be stimulated by these extracellular nucleotides, and the receptors are known to control a broad range of biological characteristics with relevance to autism.

The researchers tested suramin – a well-known inhibitor of purinergic signaling used medically for the treatment of African sleeping sickness since shortly after it was synthesized in 1916 – in mice.  They found that this APT mediator corrected autism-like symptoms in the animal model, even if the treatment was started well after the onset of symptoms.  The drug restored 17 types of multi-symptom abnormalities including normalizing brain synapse structure, cell-to-cell signaling, social behavior, motor coordination and normalizing mitochondrial metabolism.

“The striking effectiveness shown in this study using APT to ‘reprogram’ the cell danger response and reduce inflammation showcases an opportunity to develop a completely new class of anti-inflammatory drugs to treat autism and several other disorders,” Naviaux said. 

Additional contributors to the study include Zarazuela Zolkipli, Lin Wang, Tomohiro Nakayama, Jane C. Naviaux, Thuy P. Le, Michael Schuchbauer, Mihael Rogac, Qingbo Tang, Laura L. Dugan, and Susan B. Powell.

Funding for the project was provided by Autism Speaks, the UCSD Christini Fund, the Jane Botsford-Johnson Foundation, the Wright Family Foundation, the Lennox Foundation, the Larry L. Hillblom Foundation, the Gerber Foundation, and Hailey’s Wish Foundation.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

UC San Diego Moores Cancer Center, Salk Institute for Biological Studies and Sanford-Burnham Medical Research Institute come together in novel collaboration 

San Diego is a powerhouse for cancer research, home to the University of California, San Diego Moores Cancer Center – the region’s only National Cancer Institute (NCI)-designated comprehensive cancer center – and two NCI-designated centers for basic research: the Salk Institute Cancer Center and the Cancer Center at Sanford-Burnham Medical Research Institute.

These singular enterprises have now formed a novel collaboration – the San Diego National Cancer Institute Cancer Centers Council, or C3 – to leverage their distinct and combined resources and talents.

The NCI designation means these three cancer centers are already among the best in the nation. They are moving forward with a formalized structure to facilitate collaborations in key areas. This new partnership will allow San Diego’s cancer researchers to accelerate the understanding of and innovative treatments for cancer, the nation’s second leading cause of death.

“San Diego’s cancer centers are rapidly unlocking the genetic and molecular mechanisms involved in cancer and are in the vanguard of a new era in cancer science,” said Tony Hunter, PhD, director of the Salk Institute Cancer Center and American Cancer Society Professor. “The C3 partnership will allow us to build on the city’s foundation of groundbreaking cancer research and harness our collective strengths to produce the next generation of therapies.”

“The mission of C3 is to both exploit and create collaborative opportunities that can only happen in a place like San Diego, with so many exceptional cancer scientists and physicians,” said Scott Lippman, MD, director of UC San Diego Moores Cancer Center and Chugai Pharmaceutical Chair in Cancer Research. “Our goal is to build a structure for increased interaction among the cancer center faculties, leading to a deeper understanding of cancer and, ultimately, more and better treatments.”

“We are in the midst of a transformative decade in cancer research – one in which we have tools like whole-genome sequencing, high-throughput drug screening and nanotechnology to personalize cancer treatments, delivering medicines where they’ll do the most good and the least harm. This new partnership will better position all San Diego cancer researchers to get there faster,” said Kristiina Vuori, MD, PhD, Sanford-Burnham’s president, interim CEO and Cancer Center director.

Among C3’s goals:

• Greater interaction between the cancer centers—clinical, translational, basic science and educational—with increased joint faculty appointments.
• Enhanced collaborative research efforts, with members sharing resources in such areas as bioinformatics, genomics, clinical trials (at UC San Diego Moores Cancer Center) and data storage.
• Organized initiatives, such as symposia, conferences and forums, that expand and deepen scientific and public understanding of cancer and advance the field.

Voting members of C3 are:

• Scott Lippman, MD, director and Chugai Pharmaceutical Chair, UC San Diego Moores Cancer Center; senior associate dean and assistant vice chancellor for Cancer Research and Care, UC San Diego
• Tony Hunter, PhD, director, Salk Institute Cancer Center, American Cancer Society professor, Renato Dulbecco Chair
  Kristiina Vuori, MD, PhD, president and interim Chief Executive Officer, Sanford-Burnham Medical Research Institute; professor and director, NCI-designated Cancer Center
• Barbara Parker, MD, professor of clinical medicine, UCSD School of Medicine; deputy director for Clinical Affairs, UCSD Moores Cancer Center
• David Cheresh, PhD, Distinguished Professor of Pathology, UCSD School of Medicine; associate director for Innovation and Industry Relations, UCSD Moores Cancer Center
• Geoffrey Wahl, PhD, professor and Daniel and Martina Lewis Chair, Salk Institute for Biological Studies
• Ze’ev Ronai, PhD, professor and associate director, NCI-designated Cancer Center, Scientific Director at La Jolla, Sanford-Burnham Medical Research Institute

C3 will host regular meetings, with council chairmanship rotating every two years among the three cancer centers. Two previously established symposia—the Mahajani Symposium and the Preuss Foundation Seminar —will be sponsored by C3, as well as an annual retreat and an awards program to honor the best in local cancer science.

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Media contacts:
Scott LaFee, UC San Diego, 619-543-6163, slafee@ucsd.edu
Chris Emery, Salk, 858-453-4100 ext. 1395, cemery@salk.edu
Heather Buschman, Sanford-Burnham, 858-796-5343, hbuschman@sanfordburnham.org

What is an NCI-designated cancer center?

There are two types:

A “comprehensive cancer center” demonstrates depth and breadth of research in three major areas: laboratory, clinical and population-based research, plus substantial transdisciplinary research that bridges these scientific areas. In addition, it demonstrates professional and public education and outreach capabilities, including the dissemination of clinical and public health advances in the communities it serves.

A “cancer center” demonstrates scientific leadership, resources and capabilities in laboratory, clinical or population science, or some combination of these three components. It also demonstrates depth and breadth of research in the scientific areas it chooses and transdisciplinary research across these areas.

There are 41 NCI-designated comprehensive cancer centers and 7 NCI-designated basic science cancer centers in the nation.

Nationally recognized orthopedic surgeon Christopher Wahl, MD, has joined the University of California, San Diego Health System as the new chief of Sports Medicine.  Recognized for his specialty in treating complex, high-energy traumatic sports injuries, Wahl will further elevate UC San Diego Health System’s reputation for offering compassionate and innovative surgical care that dramatically improves patients’ lives.

Christopher Wahl, MD, chief of Sports Medicine at UC San Diego Health System.

“Wahl is passionate about treating elite and recreational athletes and is one of the nation’s most distinguished surgeons in the treatment of complex knee ligament injuries and dislocations,” said Steven Garfin, MD, professor and chair of the Department of Orthopedic Surgery at UC San Diego School of Medicine.  “We are honored to have Dr. Wahl join us and bring new approaches and treatment philosophies to our patients.”

Wahl’s practice will also focus on cartilage restoration and transplantation, repair of the knee and shoulder, rotator cuff pathology, shoulder stabilization and treatment of fractures. 

“As the new chief of UC San Diego Sports Medicine, I am enthusiastic to build on UC San Diego Health System’s exceptional resources to cultivate something unique for our patients,” said Wahl, associate professor of surgery, UC San Diego School of Medicine.  “I'm honored to bring some new ideas and expertise to UC San Diego Health System, to work with my regional orthopedic colleagues and become a valuable part of the active San Diego community.”

Wahl, named repeatedly as a U.S. News & World Report “Top Doctor” in orthopedics and sports medicine surgery, said he recognizes that a single medical issue can have many different solutions and that there is no “one-size-fits-all” approach to treating injures.

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“Whether working with elite athletes or not, my treatment philosophy has always been to try to act on my patients behalf as their advocate and educator and to be an exceptional physician and surgeon.  I try to learn about my patients as individuals, understand their goals and work toward these goals in the greater context of what the state-of-the-art orthopedic science has to offer,” said Wahl.  “This quality of care takes the kind of time and effort that is rarely seen in today’s medical climate.” 

Prior to joining UC San Diego Health System, Wahl served as associate professor and team physician for the University of Washington in Seattle, where he was the orthopedic surgeon for the Huskies' athletic teams, including football, men's basketball, volleyball, softball, gymnastics and tennis. 

Wahl is also an academician who has lectured and published extensively on sports medicine and surgery, including: the anatomic factors predisposing to anterior cruciate ligament tears, the treatment of recurrent shoulder dislocations associated with bone loss and the diagnosis and management of knee dislocations and multiple-ligament knee injuries.  In addition, he has developed several innovative surgical techniques for the treatment of cartilage repair, shoulder instability and revision surgery for failed procedures.

Wahl attended medical school and completed his residency training at Yale University.  He completed a sports medicine and shoulder surgery fellowship at the Hospital for Special Surgery in New York.  He continued his professional education studying trauma surgery in Germany and Switzerland before starting his clinical practice.  In 2011, Wahl was awarded the American Orthopedic Society Traveling Sports Medicine Fellowship and traveled throughout the countries of South America to visit sports medicine clinics, hospitals and institutes. 

The specialty trained orthopedic surgeons and nonsurgical sports medicine specialists at UC San Diego Health System are on the leading edge of innovation, with access to the latest technological advances, diagnostic techniques and treatment strategies. UC San Diego Sports Medicine specialists include primary care physicians, specializing in sports medicine, as well as orthopedic surgeons trained in advanced, minimally-invasive surgical techniques. Patients benefit from a multi-disciplinary team approach geared toward making the correct diagnosis, treating the injury and identifying and minimizing underlying causative factors. 

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

Mindfulness in Clinical Practice: Our Patients, Ourselves on May 11

On Saturday, May 11, the Center for Mindfulness at University of California, San Diego School of Medicine is hosting a workshop to help physicians and clinicians increase job satisfaction and prevent burnout. The program will show participants how to incorporate the concept of mindfulness into their daily clinical practice with the long-term goal of enhancing patient-centered care and physician well-being through compassionate communication.

Steven Hickman, PsyD, director, UCSD Center for Mindfulness

“This is a unique opportunity for clinicians to learn to take better care of themselves and their patients through attentive and mindful interactions in every moment,” said Steven Hickman, PsyD, director, UC San Diego Center for Mindfulness. “Practicing medicine mindfully can increase a clinician’s sense of well-being and the ability to empathize with each patient they encounter. This may result in fewer medical errors, greater self-awareness, and the ability to see a situation from multiple perspectives before reacting.”

The day-long course is designed to introduce participants to the components of mindfulness practice, how awareness of interpersonal communication can improve office dynamics, and how to avoid mental and physical burnout. Experiential exercises will help attendees better respond to the suffering of patients by exploring common reactions to chronic illness and pain and an analysis of personal reactions to it.

“This course is ideal for physicians who feel stressed or compassion fatigued or who think they are headed there. Embracing these techniques can bring joy back into the practice of medicine,” said Adele Josepho, MD, psychiatrist and UCSD Center For Mindfulness instructor. “Each time a physician opens a door to see a patient, she or he needs to be fully aware and present and to focus solely on the patient’s needs. This course can help doctors get back in touch with these skills.”

Offered on the UC San Diego campus in La Jolla, the interactive workshop is led by Mick Krasner, MD, associate professor of clinical medicine at the University of Rochester School of Medicine and Dentistry. He has taught mindfulness to patients, medical students, and health professionals for more than 10 years. Krasner is engaged in a variety of research projects including the investigation of the effects of mindfulness practices on the immune system in the elderly, on chronic psoriasis, and on medical student well-being.

General registration before April 11 is $200. Discounts are available to students, UC San Diego Health Sciences residents and faculty, and members of the San Diego County Medical Society. Lunch and parking are included in the fees. Six hours of medical education credits are offered with the American Psychological Association, California Board of Behavioral Sciences, and the California Board of Registered Nursing. The course is from 9 a.m. – 5 p.m. on the UC San Diego campus at the Medical Education and Telemedicine (MET) Building.

Mindfulness is most often formally taught in the west through the 8-week Mindfulness-Based Stress Reduction (MBSR) program developed by Jon Kabat-Zinn, PhD, and his colleagues at the University of Massachusetts. The UC San Diego Center for Mindfulness has offered MBSR programs to the general public for over 12 years. These classes are open to anyone who might be seeking to reduce stress, facilitate well-being or contend with distress, pain or illness, and are offered throughout the year. More information can be found at http://mindfulness.ucsd.edu

To learn more or to register for this conference, call 858-334-4636 or visit: http://cme.ucsd.edu/mindfulness/mcp_workshop_051113_home.html

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

After four years of confinement to a wheelchair, Rick Constantine, 58, is now walking again after undergoing an unconventional surgery at University of California, San Diego Heath System to restore the use of his leg. Neurosurgeon Justin Brown, MD, performed the novel 3-hour procedure.

Justin Brown, MD, neurosurgeon, specializes in a procedure to reverse musle paralysis.

“Following a car crash, Mr. Constantine had a brain stem stroke that caused paralysis on the right side of his body.  His leg muscles became so severely spastic that he could not walk,” said Brown, director of the Neurosurgery Peripheral Nerve Program at UC San Diego Health System. “Our team performed a delicate surgery to reduce input from the nerves that were causing the muscles to over contract to the point of disability.”

“After my injury, I was told I would never walk again. All I could to was move from my wheelchair to my bed or a chair,” said Constantine, a former NASCAR crew member. “After surgery with Dr. Brown, I could put my foot flat on the ground to walk. With physical therapy, everything just gets better and better. I'm a firm believer in never giving up.”

Prior to surgery, Constantine underwent botox treatments and physical therapy in an attempt to restore the use of his leg. The results were positive but minimal. An additional nerve conduction study, called an electromyogram (EMG), identified the muscles causing the dysfunction.

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“When all other options did not produce satisfying results, we opted for surgery,” said Brown. “With the EMG, we identified the over-excited nerves that needed to be downgraded. Mr. Constantine had surgery on a Friday and within days was in physical rehabilitation. Two weeks later he was walking without a walker and has even completed a 1-mile race without assistance.”

The surgery, called a selective peripheral neurotomy, is a procedure performed under a microscope.  Brown makes an incision behind the knee to reach the tibial nerve. He then selectively trims back the troublesome nerve branches by up to 80 percent.  Cutting the nerve reduces the “noise” being relayed back to the spinal cord which causes the spasticity.

Brown, who also serves as co-director of the Center for Neurophysiology and Restorative Neurology at UC San Diego Health System, said the advantage to this approach is that the muscle is preserved and there is no need to cut or lengthen the tendon.

“Depending on the specific patient and their medical history, selective peripheral neurotomy may be appropriate for patients with brain and spinal cord injury from strokes or tumors, cerebral palsy, or multiple sclerosis.”

No special post-operative care is required as the sutures are absorbable. Rehabilitation can begin 72 hours after the procedure.

Constantine underwent physical therapy at VIP NeuroRehabilitation Center in San Diego.

The surgery, seldom performed in the United States, is more common in France and Japan. Brown has performed this surgery on six patients. Patients requiring information on this procedure should call 858-657-7000.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

University of California, San Diego Medical Center has been named one of the nation’s 100 Top Hospitals^® for the second time by Truven Health Analytics, formerly the health care business of Thomson Reuters. Truven Health Analytics is a leading provider of information and solutions to improve the cost and quality of health care.

The Truven Health 100 Top Hospitals^® study evaluates performance in 10 areas: mortality; medical complications; patient safety; average patient stay; expenses; profitability; patient satisfaction; adherence to clinical standards of care; post-discharge mortality; and readmission rates for acute myocardial infarction, heart failure, and pneumonia. The study is celebrating its 20^th year, and has been conducted annually since 1993.

UC San Diego Medical Center has been named one of the nation's 100 Top Hospitals.

“With more than 6,000 hospitals in the United States, to be distinguished as one of the nation’s top 100 hospitals is an honor that reflects the devotion, hard work and commitment of our staff and faculty,” said Paul Viviano, CEO, UC San Diego Health System. “As the region’s only academic health system, we strive to demonstrate superior clinical outcomes and improved patient safety based on new science and new medicine, in an environment where our patients always come first.”

To conduct the 100 Top Hospitals study, Truven Health researchers evaluated 2,922 short-term, acute care, non-federal hospitals. They used public information — Medicare cost reports, Medicare Provider Analysis and Review (MedPAR) data, and core measures and patient satisfaction data from the Centers for Medicare and Medicaid Services (CMS) Hospital Compare website. Hospitals do not apply, and winners do not pay to market this honor.

“We are committed to providing safe patient-centered care and achieving optimal clinical outcomes through the practice of evidence-based medicine, teamwork and multi-disciplinary care,” said Angela Scioscia, MD, CMO, UC San Diego Health System.  “We have leveraged our electronic medical record to provide best practice alerts, standardized care and enhanced patient communication.  Recent efforts have focused on improving transitions in care, medication management and preventive health care.”

Last year, UC San Diego was also recognized as an Everest Award winner, which honors hospitals that have achieved both the highest current performance and the fastest long-term improvement over a five-year period. This year’s winning hospitals were announced in the February 25^th edition of Modern Healthcare magazine.

“This year’s winners have brought even higher value to their local communities - better quality, higher efficiency and high patient perceptions of care, while confronting the challenges of massive industry-wide transformation to implement healthcare reform,“ said Jean Chenoweth, senior vice president at Truven Health Analytics.  “The key to success in a tumultuous environment is visionary leadership that develops and maintains a hospital-wide culture of excellence that cuts across everything, from patient care to housekeeping to administration, and the refusal to rest on laurels when it comes to adopting new technologies and techniques.  I congratulate this year’s winners for their persistent drive for excellence.”

If all Medicare inpatients received the same level of care as those treated in the award-winning facilities:

• More than 164,000 additional lives could be saved.
• Approximately 82,000 additional patients could be complication free.
• $6 billion could be saved.
• The average patient stay would decrease by nearly half a day.

In operation since 1966, UC San Diego Health System’s mission is to deliver outstanding patient care through commitment to the community, groundbreaking research and inspired teaching.  The health system comprises UC San Diego Medical Center in Hillcrest, and UC San Diego Thornton Hospital, Moores Cancer Center, Shiley Eye Center, Sulpizio Cardiovascular Center in La Jolla, as well as other primary and specialty practices of UC San Diego Medical Group. UC San Diego Jacobs Medical Center, the second largest hospital construction project in California, is slated to open in La Jolla in 2016.

More information on this study and other 100 Top Hospitals research is available at www.100tophospitals.com

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu  

A study published February 21st in the New England Journal of Medicine (NEJM) provides clinical evidence of the safety and effectiveness of a new magnetic medical device to treat gastroesophageal reflux disease (GERD). Santiago Horgan, MD, professor of surgery at the University of California, San Diego School of Medicine and study co-author, was the first surgeon in the United States to implant the FDA-approved device.

Santiago Horgan, MD, surgeon, UC San Diego Health System

“What we found is that the LINX magnetic device can solve GERD’s underlying problem, a weak spincter,” said Horgan, chief of minimally invasive surgery, UC San Diego Health System. “The device corrects an anatomical defect that allows acids to move up the throat. For my patients this has been an effective way to permanently treat this painful condition, improve their quality of life, and end the need for over-the-counter medications.”

The LINX system is composed of a series of titanium beads, each with a magnetic core, that are connected to form a ring shape. It is implanted at the lower esophageal sphincter (LES), a circular band of muscle that closes the last few centimeters of the esophagus and prevents the backward flow of stomach contents.

Horgan has studied the LINX device since 2009.

As reported in the study, after sphincter augmentation with the LINX System, the majority of patients were able to substantially reduce or resolve their reflux symptoms, while eliminating use of their reflux medications such as proton pump inhibitors. Severe regurgitation was eliminated in 100 percent of patients, and nearly all patients (93 percent) reported a significant decrease in the need for medication. More than 9 in 10 patients (94 percent) reported satisfaction with their overall condition after having the LINX System, compared to 13 percent before treatment while taking medication.

Horgan said the device is an alternative to Nissen fundoplication which involves irreversibly wrapping the stomach around the esophagus. The LINX System allows surgeons to leave the stomach intact and support the weak sphincter with a small device that can be removed.

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More than 20 percent of the U.S. population experiences the painful burning symptoms of GERD. For these 20 million Americans, the first line of defense is medication. GERD can cause both pain and injury to the esophageal lining and may lead to a precancerous condition called Barrett’s esophagus. Symptoms of GERD include heartburn and regurgitation, often associated with the inability to sleep and dietary constraints.

The LINX system was studied in a controlled, prospective, multicenter trial involving 14 U.S. and European medical centers as part of the FDA approval process. The patients in the study reported suffering from reflux symptoms for a median of 10 years and taking reflux medications for a median of five years.

The LINX^® Reflux Management System is manufactured by Torax Medical which funded the study.

To learn more about the LINX device, call 858-657-8860.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Napoleone Ferrara one of 11 winners of inaugural Breakthrough Prize
 
Napoleone Ferrara, MD, PhD, the molecular biologist credited with helping decipher how tumors grow and now senior deputy director for basic sciences at the University of California, San Diego Moores Cancer Center, was today named one of 11 recipients of the inaugural Breakthrough Prize in Life Sciences, which comes with a $3 million cash award.

Napoleone Ferrara, MD, PhD

The prize is the collaborative creation of Mark Zuckerberg, founder of Facebook, and his wife, Priscilla Chan; Sergey Brin, co-founder of Google and his wife, Anne Wojcicki, founder of the genetics company 23andMe; and Yuri Milner, a Russian businessman and philanthropist who established a similar prize in fundamental physics last year, when $3 million each was awarded to nine researchers.

The Breakthrough Prize honors life scientists who have ambitiously pushed the boundaries of their disciplines, taken risks and impacted lives and society.

Ferrara, who is also a distinguished professor of pathology in the UC San Diego School of Medicine’s Department of Pathology, was recognized for his work identifying the role of the human VEGF gene in promoting angiogenesis – the formation of new blood vessels that can feed tumor growth – and subsequent development of two major monoclonal antibody drugs: Bevacizumab (marketed as Avastin), which is used to treat multiple forms of cancer, including breast, brain and colorectal, and ranibizumab (marketed as Lucentis), which treats wet age-related macular degeneration, a leading cause of blindness in the elderly.

"Napoleone's work has profoundly advanced our basic understanding of how cancer develops and grows," said David Brenner, MD, vice chancellor for Health Sciences and dean of the UC San Diego School of Medicine. "More importantly, he helped create brand new drugs and therapies based upon that research to effectively treat a broad range of cancers and other conditions. He continues with those efforts today, pushing himself and colleagues to find better answers to cancer."   

Ferrara, 56, came to UC San Diego last year after a long career at Genentech, the San Francisco-based biotechnology company where he did much of his ground-breaking work. He said that when Breakthrough Prize Foundation president Arthur D. Levinson, chairman of Apple and a former Genentech chief executive, called to tell him he had won, he was “very much astonished. I didn’t know the award existed.”

“The thing I am most proud of,” said Ferrara, “is that we’ve advanced the understanding of basic mechanisms of cancer and we’ve been able to help people, both in fighting cancer and restoring visual acuity. It’s that kind of work that I’m continuing at Moores Cancer Center, where I’ll be able to work closely with clinicians and develop new clinical trials.”

Scott Lippman, MD, director of the UC San Diego Moores Cancer Center, said the Breakthrough Prize justly recognizes Ferrara’s seminal research and how it “has changed therapy for cancer and eye diseases.”

“His work epitomizes our overall effort at Moores Cancer Center: high-risk, high-gain, high-impact achievement and innovation in taking basic-science discovery to the clinic and transforming cancer care.”

Joining Ferrara among the first winners of the Breakthrough Prize are:

• Cornelia I. Bargmann, Rockefeller University, who studies the nervous system and human behavior
• David Botstein, Princeton University, who uses the human genome to map disease biomarkers
• Lewis C. Cantley, Weill Cornell Medical College, who discovered a family of enzymes related to cell and cancer growth
  Hans Clevers, Hubrecht Institute in the Netherlands, who has parsed how stem cell processes go awry, resulting in cancer
• Eric S. Lander, Harvard University and the Massachusetts Institute of Technology (MIT), a leader in the Human Genome Project
• Titia de Lange, Rockefeller University, who studies the protective tips of chromosomes called telomeres
• Charles L. Sawyer, Memorial Sloan-Kettering Cancer Center, who has investigated the signals that prompt a cell to become cancerous
• Bert Vogelstein, Johns Hopkins University, who developed a model for how colon cancer progresses and discovered a protein that suppresses tumor growth
• Robert A. Weinberg, MIT, who discovered the first human oncogene
• Shinya Yamanaka, Kyoto University and Gladstone Institutes in San Francisco, for his fundamental research of stem cells

The founders of the Breakthrough Prize intend their awards – which will consist of five honorees in subsequent years, each receiving $3 million – to boost public attention and awareness of the major players and advances in the life sciences.

There are few limitations on who can win: Anyone can be nominated online at the Breakthrough Prize in Life Sciences Foundation’s website (www.breakthroughprizeinlifesciences.org). There are no restrictions on age or the number of people who can share the award. The cash prize comes with no constraints on how it can be spent. And individuals can win multiple times. This year’s 11 recipients will form a committee to select future winners.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Synaptic molecule works differently than thought; may mean new therapeutic targets for treating Alzheimer’s disease

In a pair of new papers, researchers at the University of California, San Diego School of Medicine and the Royal Netherlands Academy of Arts and Sciences upend a long-held view about the basic functioning of a key receptor molecule involved in signaling between neurons, and describe how a compound linked to Alzheimer’s disease impacts that receptor and weakens synaptic connections between brain cells.

The findings are published in the Feb. 18 early edition of the Proceedings of the National Academy of Sciences.

Long the object of study, the NMDA receptor is located at neuronal synapses – the multitudinous junctions where brain cells trade electrical and chemical messages. In particular, NMDA receptors are ion channels activated by glutamate, a major “excitatory” neurotransmitter associated with cognition, learning and memory.

“NMDA receptors are well known to allow the passage of calcium ions into cells and thereby trigger biochemical signaling,” said principal investigator Roberto Malinow, MD, PhD, professor of neurosciences at UC San Diego School of Medicine.

The new research, however, indicates that NMDA receptors can also operate independent of calcium ions. “It turns upside down a view held for decades regarding how NMDA receptors function,” said Malinow, who holds the Shiley-Marcos Endowed Chair in Alzheimer’s Disease Research in Honor of Dr. Leon Thal (a renowned UC San Diego Alzheimer’s disease researcher who died in a single-engine airplane crash in 2007).

Specifically, Malinow and colleagues found that glutamate binding to the NMDA receptor caused conformational changes in the receptor that ultimately resulted in a weakened synapse and impaired brain function.

They also found that beta amyloid – a peptide that comprises the neuron-killing plaques associated with Alzheimer’s disease – causes the NMDA receptor to undergo conformational changes that also lead to the weakening of synapses.

“These new findings overturn commonly held views regarding synapses and potentially identify new targets in the treatment of Alzheimer’s disease,” said Malinow.

Co-authors on both papers are Helmut W. Kessels, Center for Neural Circuits and Behavior, Departments of Neuroscience and Biology, UCSD and Netherlands Institute for Neuroscience, Royal Academy of Arts and Sciences; and Sadegh Nabavi, Center for Neural Circuits and Behavior, Departments of Neuroscience and Biology, UC San Diego.

The research was funded in part by the National Institutes of Health (grants MH049159 and AG032132), the Shiley-Marcos Foundation, the Cure Alzheimer’s Foundation, and the Internationale Stichting Alzheimer Onderzoek.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Accumulation appears to progressively disrupt neuronal function and viability

Researchers at the University of California, San Diego School of Medicine say overexpression of a protein called alpha-synuclein appears to disrupt vital recycling processes in neurons, starting with the terminal extensions of neurons and working its way back to the cells’ center, with the potential consequence of progressive degeneration and eventual cell death.

The findings, published in the February 6, 2013 issue of The Journal of Neuroscience, have major implications for more fully understanding the causes and mechanisms of Parkinson’s disease (PD), a neurodegenerative movement disorder that affects an estimated one million Americans.

“This is an important new insight. I don’t think anybody realized just how big a role alpha-synuclein played in managing the retrieval of worn-out proteins from synapses and the role of alterations in this process in development of PD,” said principal investigator Mark H. Ellisman, PhD, professor of neurosciences and bioengineering and director of the National Center for Microscopy and Imaging Research (NCMIR), based at UC San Diego.

Using serial block face scanning electron microscopy and other technologies, researchers created three-dimensional images of the neocortex of transgenic mice engineered to over-express the human protein, alpha-synuclein, and noted massively enlarged nerve terminals. In this image, an over-sized terminal (green) forms a synapse (red) with a dendritic spine (golden). A normal and smaller terminal (blue) forms a synapse with an adjacent spine on the same dendrite. Image courtesy of the National Center for Microscopy and Imaging Research, UC San Diego.

Parkinson’s disease is characterized by the gradual destruction of select brain cells that produce dopamine, a neurotransmitter involved in regulating movement and emotion. Symptoms include increasing loss of muscle and movement control. While most cases are sporadic – that is, their causes are unknown – there are also inherited forms of PD linked to specific gene mutations and modifications.

The UC San Diego researchers, with colleagues at the University of Illinois, Urbana, focused upon one of those gene products: alpha-synuclein. Using a variety of leading-edge imaging technologies, including a new fluorescent tagging technique developed for electron microscopy by UC San Diego Nobel laureate Roger Tsien’s lab and colleagues at NCMIR, the scientists created three-dimensional maps of alpha-synuclein distribution both in cultured neurons and in the neurons of mice engineered to over-express the human protein.

They found that excess levels of alpha-synuclein accumulated in the presynaptic terminal – part of the junction where axons and dendrites of brain cells meet to exchange chemical signals.

“The over-expression of alpha-synuclein caused hypertrophy in these terminals,” said Daniela Boassa, PhD, a research scientist at NCMIR and the study’s first author. “The terminals were enlarged, filled with structures we normally don’t see.”

Boassa said that as alpha-synuclein accumulates in the terminals, it appears to hinder normal degradation and recycling processes in neurons. This would progressively impair the release of neurotransmitters. In time, the neurons might simply stop functioning and die.

“Other studies have noted that PD is characterized by progressive loss of vesicle traffic, and neurotransmitter release,” Boassa said. “Our study provides a structural and mechanistic explanation for why that happens.”

Boassa said the findings shed greater light upon how PD is caused, at least in some heritable forms. Researchers plan to now probe more deeply into how the disease is propagated and how dysfunctional alpha-synuclein proteins spread from one neuron to another, hastening the advance of the disorder.

“The better we understand the mechanisms of PD, the easier it will be to develop clinical interventions,” she said.

Co-authors are Monica L. Berlanga, Masako Terada, Junru Hu, Eric A. Bushong and Minju Hwang, National Center for Microscopy and Imaging Research and Center for Research on Biological Systems; Mary Ann Yang and Julia M. George, Department of Cell and Developmental Biology, University of Illinois, Urbana; and Eliezer Masliah, Department of Neurosciences, UCSD.

Funding for this research came, in part, from the NIH National Center for Research Resources (5P41RR004050-24), the National Institute of General Medical Sciences (8 P41 GM103412-24), National Institutes of Health grants R01 GM086197-05, AG184440 and AG022074, as well as support from the Branfman Family Foundation and the Institute for Systems Biology, as part of the activities of a consortium of researchers linked to the Luxembourg Center for Systems Biomedicine’s research program on neurodegenerative disease.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

5-year grant totals $3.4 million

The National Institute of Mental Health has awarded a $3.4 million grant to a team of researchers at the University of California, San Diego School of Medicine to study successful aging in HIV-infected adults. HIV is a serious, chronic, medical disease that affects the lives of more than one million Americans. 

Since the advent of antiretroviral therapy (ART) to treat HIV, life expectancy of HIV+ adults has been increasing progressively. By 2015, nearly half of HIV+ individuals in the United States will be over age 50, and this number is expected to continue to rise. The newly funded study will be the first large-scale investigation of successful aging in HIV-infected individuals between the ages of 36 and 65 years.

The goals of the UC San Diego study are to examine the positive psychosocial factors such as resilience, hardiness, optimism, and social engagement that determine self-perceived successful aging, according to principal investigator Dilip Jeste, MD, Distinguished Professor of Psychiatry and Neurosciences, and director of UC San Diego’s Stein Institute for Research on Aging. The study will also look at biomarkers of both physical and cognitive aging, comparing these factors in individuals who are HIV-infected with non-infected adults.

“Our hope is that understanding factors that promote successful aging at an individual level may lead to the development of new preventive and therapeutic interventions aimed at improving quality of life and well-being in adults living with HIV,” said co-principal investigator David J. Moore, PhD, associate professor of psychiatry at UC San Diego School of Medicine.

Patients who are interested in enrolling in this study should call 619-543-5000. 

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Only 15 Percent of Joint Replacement Specialists in Nation Capable of Muscle-Sparing Approach
 
University of California, San Diego Health System is one of only a few hospitals in the nation to offer computer-assisted navigation technology with the direct anterior hip replacement technique, potentially resulting in less pain, faster recovery and fewer dislocations for patients with osteoarthritis and other forms of degenerative joint disease.  

Francis Gonzales, MD

Only 15 percent of the top joint centers in the United States have the expertise and technological capability to perform an anterior hip replacement, where the incision is made in the front (anterior) of the hip as opposed to the side (lateral) or back (posterior).  The anterior approach allows the surgeon to work in between a natural muscle plane without detaching muscles or tendons from the hip or thigh bone, avoiding undue trauma to the muscle and surrounding tissue.

“With traditional hip replacements, we have to cut muscle to do the surgery, which affects the recovery process and may limit immediate hip movement in the early post-operative period,” said Francis Gonzales, MD, orthopedic surgeon specializing in adult joint reconstruction at UC San Diego Health System.  “The muscle-sparing approach is performed in between muscle groups, gently pushing the muscle aside during the hip replacement instead of cutting through it.”

UC San Diego Health System performs a high volume of anterior hip replacements annually, making it a leader in the region on the technique. 

Gonzales, who is fellowship-trained in anterior hip replacements, is the only surgeon in San Diego performing the technique using computer-assisted navigation on a specialized surgical table from Mizuh OSI, which allows for live imaging guidance and manipulation in real time to confirm the hip replacement implants are precisely placed. 

“The specialized surgical table used during an anterior hip replacement is a vital instrument used during the procedure.  It enables the surgeon to perform the surgery with ease and decreases the complication rate,” said Gonzales.  “The table allows for safe leg placement not possible with a traditional surgery table.”

The anterior hip replacement approach means faster recovery, no limitations with hip movement, and increased stability with potentially fewer dislocations for the patient. 

Most patients are candidates for the anterior hip replacement.  Previous surgery, revision surgery or certain deformities may make an anterior approach not feasible.  Gonzales said his team sees a significant difference in the first year of recovery in patients who receive an anterior hip replacement. 

“Shortly after surgery, patients are back to their active lifestyles and hobbies they are passionate about,” said Gonzales, who is a leading authority on anterior hip replacement and trains other surgeons nationally on the technique.  “The results of this approach motivate our team to continue exploring new, leading edge techniques that will enhance the overall patient experience with joint replacements.”

The specialty trained orthopedic surgeons and nonsurgical sports medicine specialists at UC San Diego Health System are on the cutting edge of innovation, with access to the latest technological advances, diagnostic techniques and treatment strategies.  UC San Diego Sports Medicine specialists include primary care physicians, specializing in sports medicine, as well as orthopedic surgeons trained in advanced, minimally-invasive surgical techniques. Patients benefit from a multi-disciplinary team approach geared toward making the correct diagnosis, treating the injury and identifying and minimizing underlying causative factors. 

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

A new study, to be published in the Feb. 7, 2013 issue of the American Journal of Human Genetics, expands and deepens the biological and genetic links between cardiovascular disease and schizophrenia. Cardiovascular disease (CVD) is the leading cause of premature death among schizophrenia patients, who die from heart and blood vessel disorders at a rate double that of persons without the mental disorder.

“These results have important clinical implications, adding to our growing awareness that cardiovascular disease is under-recognized and under-treated in mentally ill individuals,” said study first author Ole Andreassen, MD, PhD, an adjunct professor at the University of California, San Diego School of Medicine and professor of psychiatry at the University of Oslo. “Its presence in schizophrenia is not solely due to lifestyle or medication side effects. Clinicians must recognize that individuals with schizophrenia are at risk for cardiovascular disease independent of these factors.”

Led by principal investigator Anders M. Dale, PhD, professor of radiology, neurosciences, psychiatry and cognitive science at UC San Diego School of Medicine, an international team of researchers used a novel statistical model to magnify the analytical powers of genome-wide association studies or GWAS.

These are studies in which differing bits of sequential DNA – called single nucleotide polymorphisms or SNPs – in persons and groups are compared to find common genetic variants that might be linked to a trait or disease. The researchers boosted the power of GWAS by adding information based on genetic pleiotropy, the concept that at least some genes influence multiple traits or phenotypes.

“Our approach is different in that we use all available genetic information for multiple traits and diseases, not just SNPs below a given statistical threshold,” said Dale. “This significantly increases the power to discover new genes by leveraging the combined power across multiple GWAS of pleiotropic traits and diseases.”

The scientists confirmed nine SNPs linked to schizophrenia in prior studies, but also identified 16 new loci – some of which are also associated with CVD. Among these shared risk factors: triglyceride and lipoprotein levels, waist-hip ratio, systolic blood pressure and body mass index.

“Our findings suggest that shared biological and genetic mechanisms can help explain why schizophrenia patients have a greater risk of cardiovascular disease,” said study co-author Rahul S. Desikan, MD, PhD, research fellow and radiology resident at the UC San Diego School of Medicine.

“In addition to schizophrenia, this new analysis method can be used to examine the genetic overlap between a number of diseases and traits,” Desikan said. “Examining overlap in common variants can shed insight into disease mechanisms and help identify potential therapeutic targets for common diseases.”

Co-authors include Srdjan Djurovic, University of Oslo and Oslo University Hospital, Norway; Wesley K. Thompson, Andrew J. Schork, J. Cooper Roddey and Linda K. McEvoy, UC San Diego; Kenneth S. Kendler, Virginia Commonwealth University; Michael C. O’Donovan, Cardiff University; Dan Rujescu, University of Halle-Wittenberg, Germany; Thomas Werge, University of Copenhagen; Martijn van de Bunt, Andrew P. Morris and Mark I. McCarthy, University of Oxford; The International Consortium for Blood Pressure GWAS; the DIAGRAM Consortium and the Psychiatric Genomics Consortium Schizophrenia Working Group.

Funding for this research came, in part, from the National Institutes of Health (grants RC2DA029475, R01HD061414 and T32 EB005970), the Research Council of Norway, the South East Norway Health Authority, the Unger-Vetlesen Medical Fund and the Robert J. Glushko and Pamela Samuelson Graduate Fellowship.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

A prospective study led by researchers from the University of California, San Diego School of Medicine has found that low serum vitamin D levels in the months preceding diagnosis may predict a high risk of premenopausal breast cancer. 

The study of blood levels of 1,200 healthy women found that women whose serum vitamin D level was low during the three-month period just before diagnosis had approximately three times the risk of breast cancer as women in the highest vitamin D group.  The study is currently published online in advance of the print edition of the journal Cancer Causes and Control.

Several previous studies have shown that low serum levels of vitamin D are associated with a higher risk of premenopausal breast cancer.  “While the mechanisms by which vitamin D could prevent breast cancer are not fully understood, this study suggests that the association with low vitamin D in the blood is strongest late in the development of the cancer, “said principal investigator Cedric Garland, DrPH, FACE, professor in the Department of Family and Preventive Medicine at UC San Diego. 

Analyses of vitamin D levels measured more than 90 days before diagnosis have not conclusively established a relationship between serum levels and risk of premenopausal breast cancer in the present cohort. However, this new study points to the possibility of a relevant window of time for cancer prevention in the last three months preceding tumor diagnosis –a time physiologically critical to the growth of the tumor.

According to Garland, this is likely to be the point at which the tumor may be most actively recruiting blood vessels required for tumor growth.  “Based on these data, further investigation of the role of vitamin D in reducing incidence of premenopausal breast cancer, particularly during the late phases of its development, is warranted,” he said.

The new study drew upon 9 million blood serum specimens frozen by the Department of Defense Serum Repository for routine disease surveillance.  The researchers thawed and analyzed pre-diagnostic samples of serum from 1,200 women whose blood was drawn in the same time frame – samples from 600 women who later developed breast cancer, and from 600 women who remained healthy. 

A 2011 meta-analysis by Garland and colleagues estimated that a serum level of 50 ng/ml is associated with 50 percent lower risk of breast cancer.  While there are some variations in absorption, those who consume 4000 IU per day of vitamin D from food or a supplement normally would reach a serum level of 50 ng/ml.

Garland added that a consensus of all available data has shown no known risk associated with this concentration of vitamin D, which is measured as serum 25-hydroxyvitamin D.  But he urges patients to ask their health care provider to measure their serum 25(OH)D before substantially increasing vitamin D intake.

“Reliance should not be placed on different forms of vitamin D, such as vitamin D2, and megadoses should be avoided except those ordered by a doctor for short-term use,” Garland added.

Contributors to this study include first author Sharif B. Mohr, PhD, and  Edward Gorham, PhD, Naval Health Research Center and UC San Diego; Christopher Kane, MD, J. Kellogg Parsons, MD, and Deborah L. Wingard, PhD, UC San Diego;  John E. Alcaraz, PhD and Carolyn Macera, PhD, San Diego State University; and Ronald Horst, PhD, Heartland Assays, Ames, Iowa.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Researchers at the University of California, San Diego School of Medicine have discovered that hard-to-reach, drug-resistant leukemia stem cells (LSCs) that overexpress multiple pro-survival protein forms are sensitive – and thus vulnerable – to a novel cancer stem cell-targeting drug currently under development.

The findings, published in the January 17 online issue of Cell Stem Cell, open the possibility that diseases like chronic myeloid leukemia (CML) and some solid tumor cancers might – in  combination with other therapies – be more effectively treated  with this drug, and with a lower chance of relapse.

Chronic myeloid leukemia leads to production of many abnormal white blood cells, which do not fight infection as well as normal white blood cells. As these abnormal cells accumulate in blood and bone marrow, they crowd out healthy white blood cells, red blood cells and platelets, impairing normal functions.

Led by principal investigator Catriona H. M. Jamieson, MD, PhD, associate professor of medicine and director of stem cell research at UC San Diego Moores Cancer Center, the researchers found that a compound called sabutoclax appears to selectively target LSCs that express particular protein isoforms through alternatively splicing, a fundamental process in which a gene is able to code for multiple proteins.

An emerging class of drugs called tyrosine kinase inhibitors (TKI) – such as imitinib (Gleevec), gifitinib (Iressa) and sunitinib (Sutent) – has become a popular anti-cancer treatment. However, current TKIs are not 100 percent effective. In cases of CML, for example, some LSCs tucked protectively within bone marrow elude destruction, develop resistance to therapy, self-renew and eventually cause the leukemia to dramatically return.

Jamieson and colleagues found that alternative splicing of BCL2 genes, which code for proteins involved in apoptosis or programmed cell death, specifically promoted malignant transformation of dormant white blood cell precursors into “blast crisis” LSCs. The blast crisis is the final phase of CML when overabundant, abnormal white blood cells crowd out healthy cells, causing serious dysfunction.

Of clinical importance, they noted that sabutoclax, which suppresses all BCL2 anti-apoptotic proteins, renders these marrow-dwelling blast crisis LSCs sensitive – and more susceptible – to TKI-based therapeutics at doses that do not harm normal progenitor cells.    

“Our findings show that pan-BCL2 inhibition will be critical for the eradication of cancer stem cells in CML and that there is an essential link between cancer stem cell dormancy, pro-survival BCL2 isoform expression and therapeutic resistance,” Jamieson said. “By using a novel pan-BCL2 inhibitor, we may be able to prevent therapeutic resistance by sensitizing malignant stem cell clones to TKIs.”

The findings may have implications for treating solid tumor cancers, such as colon, prostate, breast, and brain cancers, noted Daniel J. Goff, the study’s first author.
“With many of these tumor types being shown to harbor cancer stem cells, it raises the question of whether BCL2 family expression as well as isoform-switching may be crucial for the maintenance of cancer stem cells in these diseases as well,” he said. “If so, they may also be candidates for treatment with a BCL2 inhibitor like sabutoclax.”

Co-authors are Angela Court Recart, Anil Sadarangani, Heather Leu, Janine Low-Marchelli, Wenxue Ma, Alice Y. Shih, Ifat Geron, Minya Pu, Lei Bao, Ryan Chuang, Larisa Balaian, Peggy Wentworth, Kristen M. Smith, Christina A.M. Jamieson, Sheldon R. Rorris and Karen Messer, UCSD Department of Medicine and UCSD Moores Cancer Center; Hye-Jung Chun and Marco Marra, Michael Smith Genome Sciences Center, Vancouver, BC, Canada; Christian L. Barrett and Kelly A. Frazer, UCSD Department of Pediatrics; Maryla Krajewska, Jun Wei, Dayong Zhai, Maurizio Pellecchia and John C. Reed, Sanford-Burnham Medical Research Institute; Jason Gotlib, Stanford Medical Center; Mark Minden, Princess Margaret Hospital, Toronto, Canada; Giovanni Martinelli, Institute of Hematology and Medical Oncology, University of Bologna, Italy; Jessica Rusert and Lawrence S.B. Goldstein, UCSD Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute; Kim-Hien Dao, Oregon Health and Science University, Portland; Kamran Shazand and Thomas J. Hudson, Ontario Institute for Cancer Research, Toronto, Canada.

Funding for this research was provided by a California Institute for Regenerative Medicine (CIRM) early Translational II grant (TR2-1789), a CIRM HALT leukemia disease team grant (DR1-01430), the UCSD CIRM Training Grant (TG2-01154), the Ratner Family Foundation, the National Cancer Institute (CA-55164), the National Institutes of Health (CA-149668), the Ontario Institute for Cancer Research, Genome Canada, Ontario Genomics Institute and the Canadian Institute of Health Research.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Researchers at the University of California, San Diego School of Medicine have identified a molecular mechanism regulating autophagy, a fundamental stress response used by cells to help ensure their survival in adverse conditions.

The findings are published online in the January 17 issue of Cell.

Senior author Kun-Liang Guan, PhD, a professor of pharmacology at UC San Diego Moores Cancer Center, and colleagues report that an enzyme called AMPK, typically involved in sensing and modulating energy use in cells, also regulates autophagic enzymes.

An electron microscope image of a mammalian cell with organelles depicted. In autophagy, some elements of a cell are degraded and recycled to generate nutrients and energy to sustain and preserve the whole cell.

Autophagy, which derives from the Greek words for “self” and “eat,” is triggered to protect cells when times are tough, such as when cells are starved for nutrients, infected or suffering from damaged organelles, such as ribosomes and mitochondria. Much like the human body in freezing conditions will reduce operations in extremities to preserve core temperatures and organ functions, cellular autophagy involves the degradation and synthesis of some internal cellular elements to ensure survival of the whole.

The scientists found that AMPK regulates different complexes of an enzyme class called Vps34 kinase in different ways. Some Vps34 enzymes are involved in normal cellular vesicle trafficking – the vital movement of molecules inside a cell. Other Vps34 complexes are involved in autophagy. Guan and colleagues say AMPK inhibits some non-autophagy enzymes, but activates autophagous ones. 

The study more fully illuminates a process essential to healthy cell function and survival. “Autophagy is an important way for cells to clear damaged parts that could be harmful to them and to digest parts for nutrients when cells are experiencing starvation conditions,” Guan said.

More broadly, he noted that “defects in autophagy have been associated with human disease, such as cancer and neurodegenerative disorders.” Failure of normal autophagy has also been associated with accumulated cell damage and aging.

Co-authors are Joungmok Kim, Department of Oral Biochemistry and Molecular Biology, Kyung Hee University and UCSD Department of Pharmacology and UCSD Moores Cancer Center; Young Chul Kim, Chong Fang and Ryan C. Russell, UCSD Department of Pharmacology and UCSD Moores Cancer Center; Jeong Hee Kim, Department of Oral Biochemistry and Molecular Biology, Kyung Hee University; and Weiliang Fan, Rong Liu and Qing Zhong, UC Berkeley Division of Biochemistry, Biophysics and Structural Biology, Department of Molecular and Cell Biology.

Funding for this research came, in part, from grants from the National Institutes of Health (R01CA108941; R01GM51586) and U.S. Department of Defense and the Bio&Medical Technology Development Program of the National Research Foundation of Korea.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

One of the greatest challenges faced by cancer surgeons is to know exactly which tissue to remove, or not, while the patient is under anesthesia. A team of surgeons and scientists at University of California, San Diego School of Medicine have developed a new technique that will allow surgeons to identify during surgery which lymph nodes are cancerous so that healthy tissue can be saved. The findings will be published in the January 15 print edition of Cancer Research.

Quyen T. Nguyen, MD, PhD, associate professor of head and neck surgery, UC san Diego School of Medicine.

“This research is significant because it shows real-time intraoperative detection of cancer metastases in mice,” said Quyen T. Nguyen, MD, PhD, associate professor of Head and Neck Surgery at UC San Diego School of Medicine. “In the future, surgeons will be better able to detect and stage cancer that has spread to the patient’s lymph nodes using molecules that were designed and developed at UC San Diego.”

Lymph nodes, located throughout the body, serve as filters that contain immune cells to fight infection and clean the blood. When cancer cells break away from a tumor, the cells can travel through the lymph system and hide in these tiny organs. Surgeons remove the nodes to determine if a cancer has spread. However, human nodes, only half a centimeter in size, are difficult to discern among the surrounding tissue during surgery. Furthermore, even when surgeons are able to map the location of the nodes, there is no current technique that indicates whether or not the lymph nodes contain cancer, requiring removal of more lymph nodes than necessary.

“With molecular-targeted imaging, surgeons can avoid unnecessary removal of healthy lymph nodes which is better long-term for patients,” said Nguyen, director of the facial nerve clinic at UC San Diego Health System. “The range of the surgeon’s visual field is greatly enhanced by a molecular tool that can help achieve accurate surgical margins and detection of metastases so that no tumor is left behind.”

The fluorescently labeled molecules, known as ratiometric activatable cell-penetrating peptides (RACPP), are injectable. When used in mouse models, surgeons could see where the cancer had spread with high sensitivity and specificity even when the metastatic sites were only a few millimeters in size.

This form of instant pathology is an improvement over traditional sentinel node mapping, whereby only the location of the lymph node is detected without gleaning any information on actual cancer involvement.

Current methods for managing prostate cancer and neck squamous cell carcinoma only reveal the extent of cancer involvement after the patient has undergone surgical removal of all susceptible lymph nodes.

This new technique will decrease OR time because the surgical team need not wait for pathology reports, decrease time under anesthesia, and decrease unnecessary surgery on noncancerous lymph nodes. 

Nyguyen’s earlier research with Nobel Prize winner Roger Tsien, PhD, professor of pharmacology at UC San Diego School of Medicine, showed in animal models how injectable fluorescent peptides could be used to highlight hard-to-see peripheral nerves, allowing surgeons to avoid them when removing or repairing other tissues.

Contributors to this research paper include Elamprakash N. Savariar, Csilla Felsen, Nadia Nashi, Tao Jiang, Lesley G. Ellies, Paul Steinbach, and Roger Tsien from UC San Diego.

This work was supported by the Howard Hughes Medical Institute and ICMIC NCIP50-CA128346 career development grant, the Burroughs Wellcome Fund (CAMS) and NIH grants 5K08EB008122 and R01 CA158448.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu  

Repression of a single protein in ordinary fibroblasts is sufficient to directly convert the cells – abundantly found in connective tissues – into functional neurons. The findings, which could have far-reaching implications for the development of new treatments for neurodegenerative diseases like Huntington’s, Parkinson’s and Alzheimer’s, will be published online in advance of the January 17 issue of the journal Cell.

In recent years, scientists have dramatically advanced the ability to induce pluripotent stem cells to become almost any type of cell, a major step in many diverse therapeutic efforts.  The new study focuses upon the surprising and singular role of PTB, an RNA-binding protein long known for its role in the regulation of alternative RNA splicing.

Confocal micrograph of a primary human fibroblast cell grown in culture stained blue for actin, a highly abundant protein that makes up the cytoskeleton of cells. Energy-producing mitochondria are shown in green. Image courtesy of Matthew Daniels, University of Oxford and Wellcome Images.

In in vitro experiments, scientists at University of California, San Diego School of Medicine and Wuhan University in China describe the protein’s notable regulatory role in a feedback loop that also involves microRNA – a class of small molecules that modulate the expression of up to 60 percent of genes in humans. Approximately 800 miRNAs have been identified and characterized to various degrees.

One of these miRNAs, known as miR-124, specifically modulates levels of PTB during brain development. The researchers found that when diverse cell types were depleted of PTB, they became neuronal-like cells or even functional neurons – an unexpected effect. The protein, they determined, functions in a complicated loop that involves a group of transcription factors dubbed REST that silences the expression of neuronal genes in non-neuronal cells.

According to principal investigator Xiang-Dong Fu, PhD, professor of cellular and molecular medicine at UC San Diego, it’s not known which neuronal signal or signals turn on the loop, which in principle can happen at any point in the circle. But the ability to artificially manipulate PTB levels in cells, inducing them to become neurons, offers tantalizing possibilities for scientists seeking new treatments for an array of neurodegenerative diseases.

It is estimated that over a lifetime, one in four Americans will suffer from a neurodegenerative disease, from Alzheimer’s and Parkinson’s to multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig’s disease).

“All of these diseases are currently incurable. Existing therapies focus on simply trying to preserve neurons or slow the rate of degeneration,” said Fu. “People are working with the idea of replacing lost neurons using embryonic stem cells, but there are a lot of challenges, including issues like the use of foreign DNA and the fact that it’s a very complex process with low efficiency.”

Fu explained that REST is expressed in cells everywhere except in neurons. PTB is itself a target of miR-124, but also acts as a break for this microRNA to attack other cellular targets that include REST, which is responsible for repressing miR-124. 

In non-neuronal cells, REST keeps miR-124 down and PTB enforces this negative feedback loop, but during neural induction, miR-124 is induced, which diminishes PTB, and without PTB as a break, REST is dismantled, and without REST, additional miR-124 is produced.  This loop therefore becomes a positive feed forward, which turns non-neuronal cells into neurons.

“If we learn how to manipulate PTB, which appears to be a kind of master regulator, we might eventually be able to avoid some of these problems by creating new neurons in patients using their own cells adjacent deteriorating neurons,” said Fu.

Co-authors are Yuanchao Xue and Yu Zhou, Wuhan University, China and UCSD Department of Cellular and Molecular Medicine; Kunfu Ouyang, Gang Wang and Ju Cheng, UCSD Department of Medicine; Jie Huang, Qijia Wu, Yanzhen Bi, Li Jiang, Zhiqiang Cai, Hui Sun, UCSD Department of Cellular and Molecular Medicine; Hong Ouyang and Kang Zhang, UCSD Institute of Genomic Medicine; Hairi Li and Chaoliang Wei, UCSD Department of Cellular and Molecular Medicine; and Yi Zhang, Wuhan University, China and Center for Genome Analysis, Wuhan, China.

Funding for this research came, in part, from National Institutes of Health grants (GM049369, GM052872 and HG004659) and the China 973 programs.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu  

UC San Diego-based study looks at differentiation of hESCs in endocrine cell progression

Type 1 and type 2 diabetes results when beta cells in the pancreas fail to produce enough insulin, the hormone that regulates blood sugar.  One approach to treating diabetes is to stimulate regeneration of new beta cells. 

There are currently two ways of generating endocrine cells (cell types, such as beta cells, that secrete hormones) from human embryonic stem cells, or hESCs: either generating the cells in vitro in culture or transplanting immature endocrine cell precursors into mice.

Maike Sander, MD

Researchers from the University of California, San Diego School of Medicine, collaborating with scientists from San Diego-based biotech company ViaCyte, Inc., looked at the differences and similarities between these two types of hESC-derived endocrine cell populations and primary human endocrine cells, with the longer-term goal of developing new stem cell therapies for diabetes.

The results of their study will be published on line January 10, in advance of the February 7 print edition of the journal Cell Stem Cell.

The scientists compared gene expression and chromatin architecture – the structure of combined DNA and proteins that make up the nucleus of the cell, in which dynamic remodeling occurs at various stages of differentiation – in both primary human endocrine cells and hESC-derived cells.

“We found that the endocrine cells retrieved from transplanted mice are remarkably similar to primary human endocrine cells,” said principal investigator Maike Sander, MD, professor of pediatrics and cellular and molecular medicine, and director of UC San Diego’s Pediatric Diabetes Research Center. “This shows that hESCs can differentiate into endocrine cells that are almost indistinguishable from their primary human counterparts.”

However, the researchers observed that endocrine cells produced in vitro lack features of primary endocrine cells and fail to express the majority of genes that are critical for endocrine cell function. Consistent with this finding, these cells are not able to reverse diabetes in diabetic animal models.

Sander explained that one way to move forward with cell replacement therapies for diabetes is to transplant the endocrine precursor cells into humans and let the cells mature in the patient as they do in mice. “However, we don’t currently know whether the maturation process will occur in humans in the same way.”

She added that an alternative approach is to generate fully functional endocrine cells in the culture dish and to then transplant these cells into humans. While such a method of generating functional endocrine cells in the dish does not yet exist, this study provides hints about the steps currently missing in in vitro differentiation protocols. 

Sander and colleagues identified a key mechanism for the induction of developmental regulators –removal of a family of proteins that can remodel chromatin called the Polycomb group (PcG). Reinstating PcG-dependent repression silenced the expression of genes that are only temporarily activated, and need to be turned off in order for cells to progress to their final differentiated endocrine state. When endocrine cells were produced in the culture dish, the researchers found that PcG-mediated repression was not fully eliminated, probably contributing to the cells’ malfunction.

“This information will help devise protocols to generate functional insulin-producing beta cells in vitro,” said Sander. “This will be important not only for cell therapies, but also for identifying disease mechanisms that underlie the pathogenesis of diabetes.”

Additional contributors to the study include first author Ruiyu Xie, Nisha A. Patel and Allen Wang, UC San Diego; Logan J. Everett, Hee-Woong Lim, Jonathan Schug, Kyoung-Jae Won and Klaus H. Kaestner, Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania; and Evert Kroon, Olivia G. Kelly, Kevin A. D'Amour and Allan J. Robins, ViaCyte Inc., San Diego.

This work was supported by National Institutes of Health grants U01-DK089567, R01-DK07243, U01-DK089529, R01-DK088383 and P30-DK19525.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

The Sulpizio Cardiovascular Center located at University of California, San Diego Health System has been named among "100 Hospitals with Great Heart Programs" by Becker's Hospital Review, a business and legal news publication for hospital and health system leadership. 

UC San Diego Sulpizio Cardiovascular Center is among best in nation.

According to Becker’s editorial team, the hospitals chosen for this list “offer outstanding heart care” and were selected based on clinical accolades, recognition for quality care and contributions to the field of cardiology and cardiovascular surgery.

“It is a great honor to be recognized for the high quality of our patient care,” said Paul Viviano, CEO, UC San Diego Health System.  “Sulpizio Cardiovascular Center provides comprehensive cardiac and stroke care and is ranked among the most prestigious cardiac hospitals nationally.”

Becker’s editorial team also noted that these hospitals have been set apart for excellence in heart care and research by reputable healthcare rating resources, including U.S. News & World Report, HealthGrades, Thomson Reuters, and the American Nurses Credentialing Center. The Sulpizio Cardiovascular Center was specifically recognized as being San Diego’s first dedicated heart center and for its advanced surgical capabilities.

“At Sulpizio Cardiovascular Center, we provide our regional, national and international patients with a combination of advanced cardiac diagnostics, novel treatments, and access to a number of unique clinical programs,” said Kirk L. Peterson, MD, director, Sulpizio Cardiovascular Center and professor of Cardiology and Medicine at UC San Diego School of Medicine.  “This recognition speaks to the dedication of our multi-disciplinary team members toward providing the very best care possible.” 

The Sulpizio Cardiovascular Center is the first hospital-based project in the region to receive LEED Gold certification from the United States Green Building Council (USGBC).  Sulpizio Cardiovascular Center has also received Modern Healthcare’s highest design honor, the 2012 Modern Healthcare Design Award, and was ranked #10 on Soliant Health Care's annual list of top 20 most beautiful hospitals in the United States.  In October 2012, Truven Health Analytics named Sulpizio Cardiovascular Center one of the nation’s 50 Top Cardiovascular Hospitals. 

To view an alphabetical listing of “100 Hospitals with Great Heart Programs,” please visit:
http://www.beckershospitalreview.com/great-heart-programs-2013/100-hospitals-with-great-heart-programs.html

About Becker's Hospital Review
Becker's Hospital Review features up-to-date business and legal news and analysis relating to hospitals and health systems. The content is geared toward high-level hospital leaders and works to provide valuable content, including hospital and health system news, best practices and legal guidance specifically for decision-makers. Each of the nine annual issues of Becker's Hospital Review reaches approximately 18,500 people, primarily acute-care hospital CEOs and CFOs.  More available at: www.BeckersHospitalReview.com

About UC San Diego Sulpizio Cardiovascular Center
UC San Diego Sulpizio Cardiovascular Center is dedicated to innovative care and the prevention, diagnosis and treatment of cardiovascular disease. The state-of-the-art facility, which opened in La Jolla in 2011, is the region’s first academic-based facility to combine all heart and vascular-related services, programs and technology under one roof. For more information, visit www.heartcenter.ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

For the sixth consecutive year, the Training, Research and Education for Driving Safety (TREDS) program at the University of California, San Diego School of Medicine has been awarded a grant from the California Office of Traffic Safety to promote driving safety in older adults.  This team of experts, part of UCSD’s Injury Epidemiology, Prevention and Research Center, has been working to keep Southern California’s highways and senior drivers safe.

Linda Hill, MD, MPH, leader of the TREDS program, shares valuable driving tips with the 10 News crew.

TREDS training for health care professionals and law enforcement increases awareness of impairments common with aging that can impact driving ability.  The health-related training focuses on screening guidelines recommended by the American Medical Association (AMA), rehabilitation options, and counseling techniques; while the law enforcement-related training offers visual representations of medical impairments behind the wheel, effective intervention approaches, and referral options.

“A multidisciplinary approach between the community, health professionals and law enforcement, is needed to keep older adults driving for as long as safely possible,” said Linda Hill, MD, MPH, clinical professor in the Department of Family and Preventive Medicine at UC San Diego School of Medicine. “It is very important for older adults to maintain a healthy lifestyle, to ensure driving fitness. At any age, abstaining from alcohol, wearing seatbelts and refraining from distractions is crucial to driving safety.”

More than 1500 health professionals and 1200 law enforcement officers in Southern California have received TREDS training. Health professionals and students of health sciences throughout the state can receive the training through an interactive online curriculum. The training of health professionals and law enforcement can assist with the early identification of conditions that can put drivers at risk. If impairments are identified, there are new technologies and vehicle adaptations that can be utilized to help a driver compensate for certain deficiencies.

“Many older adults begin to self-restrict and avoid demanding driving situations, but some continue to drive,” Raul Coimbra, MD, PhD, FACS, chief of the Division of Trauma at UC San Diego Health System and founder of the UCSD Injury Epidemiology, Prevention and Research Center.  “Older adults who can no longer safely drive put themselves and their often frail passengers at risk.  Older adults are four times more likely to die in crashes of similar intensity than 20 year olds.”

“Getting older does not mean the end of a person’s driving days,” said CHP Chief Jim Abele, commander of CHP’s Border Division.  “It’s the perfect time to evaluate, improve and maintain the safety and mobility of California’s senior drivers.”

Additional Data
TRIP, a national transportation research group, estimates that the population of Americans 65 and older will grow by 60 percent over the next 15 years. Currently, California is the state with the greatest number of licensed older drivers with 3,146,256 drivers 65 and older.

The National Highway Traffic Safety Administration (NHTSA) estimates that by the year 2020, there will be more than 40 million licensed drivers over the age of 65, and six million drivers over 65 in California by the year 2030.

As the “baby boom” generation reaches retirement at a rate of nearly 10,000 people per day for the next 20 years, Hill’s team says more focus has to be given to things that can be done to prolong safe driving: Families must begin talking about driving before a problem is suspected and any concerns should be openly discussed.  Physicians should be included in these conversations, as they can advise on appropriate screening, nutrition, and physical activity guidelines.  Medications should be reviewed routinely to identify any that could affect driving and to insure all are at the lowest effective dosage.  Several organizations also offer mature driver courses to mitigate any bad habits that have developed over the years.

Funding for this program is provided by a grant from the California Office of Traffic Safety (OTS), through the National Highway Traffic Safety Administration (NHTSA).  The grant team, led by Hill, includes Raul Coimbra, MD, PhD; Kathy Fischer, MD, MPH; Jill Rybar, MPH, project manager; and Tara Styer, MPH, training coordinator. For additional information or to schedule trainings, email TREDS@ucsd.edu or call 858-534-9330.

Additional resources to promote safe driving for older adults can be found on the TREDS website at: http://treds.ucsd.edu

The Injury Epidemiology, Prevention and Research Center
The UCSD Injury Epidemiology, Prevention and Research Center is a combined effort of the Division of Trauma, Surgical Critical Care, and Burns with its Level-1 Trauma Center and the Regional Burn Center and the UCSD Department of Preventive Medicine to make our communities safer and to decrease the burden of injuries to our society.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Researchers exploit gene position to test “histone code”

In a novel use of gene knockout technology, researchers at the University of California, San Diego School of Medicine tested the same gene inserted into 90 different locations in a yeast chromosome – and discovered that while the inserted gene never altered its surrounding chromatin landscape, differences in that immediate landscape measurably affected gene activity. 

The findings, published online in the Jan. 3 issue of Cell Reports, demonstrate that regulation of chromatin – the combination of DNA and proteins that comprise a cell’s nucleus – is not governed by a uniform “histone code” but by specific interactions between chromatin and genetic factors.

An x-ray micrograph of a yeast cell, Saccharomyces cerevisiae, as it buds before dividing. Courtesy of Carolyn Larabell, UC San Francisco, Lawrence Berkeley National Laboratory and the National Institute of General Medical Sciences.

“One of the main challenges of epigenetics has been to get a handle on how the position of a gene in chromatin affects its expression,” said senior author Trey Ideker, PhD, chief of the Division of Genetics in the School of Medicine and professor of bioengineering in UC San Diego’s Jacobs School of Engineering. “And one of the major elements of that research has been to look for a histone code, a general set of rules by which histones (proteins that fold and structure DNA inside the nucleus) bind to and affect genes.”

The Cell Reports findings indicate that there is no singular universal code, according to Ideker. Rather, the effect of epigenetics on gene expression or activity depends not only on the particular mix of histones and other epigenetic material, but also on the identity of the gene being expressed.

To show this, the researchers exploited an overlooked feature of an existing resource. The widely-used gene knockout library for yeast, originally created to see what happens when a particular gene is missing, was built by systematically inserting the same reporter gene into different locations. Ideker and colleagues focused on this reporter gene and observed what happens to gene expression at different locations along yeast chromosome 1.

“If epigenetics didn’t matter – the state of histones and DNA surrounding the gene – the expression of a gene would be the same regardless of where on the chromosome that gene is positioned,” said Ideker. But in every case, gene expression was measurably influenced by interaction with nearby epigenetic players.

Ideker said the work provides a new tool for more deeply exploring how and why genes function, particularly in relation to their location.

Co-authors are first author Menzies Chen, UCSD Department of Bioengineering; Katherine Licon, UCSD Department of Medicine and UCSD Institute for Genomic Medicine; Rei Otsuka and Lorraine Pillus, UCSD Department of Molecular Biology and UCSD Moores Cancer Center.

Funding for this research came, in part, from NIH grants R21HG005232, R01GM084279, P50GM085764 and P30CA023100.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

An international team, headed by researchers at the University of California, San Diego School of Medicine, has identified a key enzyme in the reprogramming process that promotes malignant stem cell cloning and the growth of chronic myeloid leukemia (CML), a cancer of the blood and marrow that experts say is increasing in prevalence.

The findings are published in the Dec. 24 online early edition of the Proceedings of the National Academy of Sciences (PNAS).

Chronic myeloid leukemia blood cells.

Despite the emergence of new therapies, such as tyrosine kinase inhibitors, CML and other leukemias remain problematic because some cancer stem cells avoid destruction and eventually regenerate themselves, a stem cell process known as self-renewal that can result in a return and spread (metastasis) of the disease.

In the PNAS paper, principal investigator Catriona H. M. Jamieson, MD, PhD, associate professor of medicine at UC San Diego, with colleagues in the United States, Canada and Italy, report that inflammation – long associated with the development of cancer – boosts activity of  an enzyme called adenosine deaminase or ADAR1.

Expressed during embryogenesis to help blood cell development, ADAR1 subsequently turns off and is triggered by viral infections where it protects normal hematopoietic stem cells from attack. In leukemia stem cells, however, overexpression of ADAR1 enhances the missplicing of RNA, which leads to greater self-renewal and therapeutic resistance of malignant stem cells.

The findings build upon previous studies by Jamieson and others that elucidate the effects of RNA missplicing and instability. “People normally think about DNA instability in cancer, but in this case, it’s how the RNA is edited by enzymes that really matters in terms of cancer stem cell generation and resistance to conventional therapy.”

The described RNA editing process, which occurs in the context of human and other primate specific sequences, also underscores the importance of addressing inflammation as “an essential driver of cancer relapse and therapeutic resistance,” Jamieson said. It also presents a new target for future therapies.

“ADAR1 is an enzyme that we may be able to specifically target with a small molecule inhibitor, an approach we have already used effectively with other inhibitors,” said Jamieson. “If we can block the capacity of leukemia stem cells to use ADAR1, if we can knock down that pathway, maybe we can put stem cells back on the right track and stop malignant cloning.”

CML is a cancer initiated by a mutant gene called BCR-ABL in blood forming stem cells that leads to an expansion of white blood cells and their precursors. It is typically slow-growing and often not diagnosed until its later stages when there can be a sudden, dramatic increase in malignant cells, known as blast crisis. Median age of diagnosis is 66 years; incidence of the disease increases with age.  Despite tremendous advances in BCR-ABL tyrosine kinase inhibitor therapies, the majority of patients relapse if therapy is discontinued, in part as a result of dormant cancer stem cell resistance.  This work suggests a novel mechanism for overcoming cancer stem cell resistance to therapy that may prevent relapse and progression.

The estimated prevalence of CML in the United States is 70,000 persons with the disease, projected to steadily increase to approximately 181,000 by 2050. CML is initiated by the mutant BCR-ABL gene, but scientists have not yet identified the cause of the mutation.

Co-authors are Qingfei Jiang, Leslie A. Crews, Angela C. Court, David J. Goff, Anil Sadarangani and Sheldon R. Morris, Stem Cell Program, UCSD Department of Medicine and UCSD Moores Cancer Center; Christian L. Barrett, UCSD Division of Genome Information Sciences, Departments of Pediatrics; Hye-Jung Chun, Michael Smith Genome Sciences Centre, Vancouver; Jane M. Isquith, Stem Cell Program, UCSD Department of Medicine, UCSD Moores Cancer Center and Department of Animal Science, California Polytechnic State University; Maria A. Zipeto, UCSD Department of Medicine, UCSD Moores Cancer Center and Department of Experimental Medicine, University of Milano-Biocca, Italy; Mark Minden, Princess Margaret Hospital, Toronto, Canada; Jessica M. Rusert and Lawrence S.B. Goldstein, UCSD Department of Cellular and Molecular Medicine and Howard Hughes Medical Institute; Kim-Hien T. Dao, Oregon Health and Science University Knight Cancer Institute; Marco A. Marra, Michael Smith Genome Sciences Centre, Vancouver; and Kelly A. Frazer, UCSD Division of Genome Information Sciences, Departments of Pediatrics.

Funding for this research came, in part, from California Institute for Regenerative Medicine grants RN2-00910-1 and DR1-01430, CIRM training grant TG2-01154, CIRM SEED grant RS1-00228-1, the Government of Canada through Genome Canada and the Ontario Genomics Institute and the Canadian Institute of Health Research and the Ratner family foundation.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Johnathan Sebat, PhD

An international team, led by researchers from the University of California, San Diego School of Medicine, has discovered that “random” mutations in the genome are not quite so random after all. Their study, to be published in the journal Cell on December 21, shows that the DNA sequence in some regions of the human genome is quite volatile and can mutate ten times more frequently than the rest of the genome. Genes that are linked to autism and a variety of other disorders have a particularly strong tendency to mutate.

Clusters of mutations or “hotspots” are not unique to the autism genome but instead are an intrinsic characteristic of the human genome, according to principal investigator Jonathan Sebat, PhD, professor of psychiatry and cellular and molecule medicine, and chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at UC San Diego.

“Our findings provide some insights into the underlying basis of autism—that, surprisingly, the genome is not shy about tinkering with its important genes” said Sebat.  “To the contrary, disease-causing genes tend to be hypermutable.”

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Sebat and collaborators from Rady Children’s Hospital-San Diego and BGI genome center in China sequenced the complete genomes of identical twins with autism spectrum disorder and their parents.  When they compared the genomes of the twins to the genomes of their parents, the scientists identified many “germline” mutations (genetic variants that were present in both twins but not present in their mother or father).

Nearly 600 germline mutations – out of a total of 6 billion base pairs – were detected in the 10 pairs of identical twins sequenced in the study. An average of 60 mutations was detected in each child.

“The total number of mutations that we found was not surprising,” said Sebat, “it’s exactly what we would expect based on the normal human mutation rate.”  What the authors did find surprising was that mutations tended to cluster in certain regions of the genome. When the scientists looked carefully at the sites of mutation, they were able to determine the reasons why some genomic regions are “hot” while other regions are cold.

“Mutability could be explained by intrinsic properties of the genome,” said UC San Diego postdoctoral researcher Jacob Michaelson, lead author of the study.  “We could accurately predict the mutation rate of a gene based on the local DNA sequence and its chromatin structure, meaning the way that the DNA is packaged.”

The researchers also observed some remarkable examples of mutation clustering in an individual child, where a shower of mutations occurred all at once.   “When multiple mutations occur in the same place, such an event has a greater chance of disrupting a gene,” said Michaelson.

The researchers surmised that hypermutable genes could be relevant to disease. When they predicted the mutation rates for genes, the authors found that genes that have been linked to autism were more mutable than the average gene, suggesting that some of the genetic culprits that contribute to autism are mutation hotspots.

The authors observed a similar trend for other disease genes. Genes associated with dominant disorders tended to be highly mutable, while mutation rates were lower for genes associated with complex traits.

“We plan to focus on these mutation hotspots in our future studies,” said Sebat. “Sequencing these regions in larger numbers of patients could enable us to identify more of the genetic risk factors for autism.”

The researchers at UC San Diego and Rady Children’s Hospital are actively recruiting families through a genetic study called “REACH,” that is funded by the Simons Foundation. For more information about this study or to get involved in autism research at UC San Diego, visit http://reachproject.ucsd.edu

Additional contributors to the published study include co-first authors Yujian Shi and Hancheng Zheng, BGI-Shenzhen, China, and Madhusudan Gujral and Dheeraj Malhotra, UC San Diego; Douglas Greer, Abhishek Bhandari, Wenting Wu, Roser Corominas, Shuli Kang, Guan Ning Lin, Jasper Estabillo, Therese Gadomski, Balvindar Singh, Natacha Akshoomoff, and Lilia M. Iakoucheva, UC San Diego School of Medicine; Xin Jin, BGI-Shenzhen and South China University of Technology, Guangzhou, China; Jian Minghan and Yingrui Li, BGI-Shenzhen; Guangming Liu, National University of Defense Technology, Changsha, Hunan, China and National Supercomputer Center, Tianjim, China;  Áine Peoples, UC San Diego and Trinity College, Dublin, Ireland; Amnon Koren and Steven McCarroll, Harvard Medical School;  Athurva Gore and Kun Zhang, Department of Bioengineering, UC San Diego;  Christina Corsello, Rady Children’s Hospital-San Diego; and Jun Wang, BGI-Shenzhen, University of Copenhagen, and the Novo Nordisk Foundation Center for Basic Metabolic Research, Copenhagen, Denmark.

The study was funded in part by grants from the National Institutes of Health (MH076431 and HG005725), the Simons Foundation Autism Research Initiative (SFARI 178088), and NIH RO1 HD065288 and NIH RO1 MH091350.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Researchers at the University of California, San Diego School of Medicine report that tumor cells use stress signals to subvert responding immune cells, exploiting them to actually boost conditions beneficial to cancer growth.

The findings are published in the December 18 online issue of the journal PLOS ONE.

Lead author Navin R. Mahadevan, a graduate student in the Laboratory of Immunology at the UC San Diego Moores Cancer Center, and colleagues found that tumor cells manipulate a fundamental cellular mechanism called unfolded protein response (UPR). In all cells, UPR is used to maintain homeostasis, or equilibrium, in the endoplasmic reticulum (ER) – the cell’s protein-making factory. When, for a variety of reasons, a cell is subjected to overwork, ER stress occurs and a compensatory UPR is triggered. 

“The goal is to understand how ER stress is transmitted and how this is amplified by receiver cells to attack vulnerable aspects of the immune system,” said principal investigator Maurizio Zanetti, MD, who heads the Laboratory of Immunology and is director of Tumor Immunology at the Center for Immunity, Infection and Inflammation at UC San Diego.

The cartoon represents the consequences of tumor ER stress on components of the adaptive anti-tumor immune response.  Under ideal circumstances (left panel), tumor cells and their antigens are picked up by immune cells such as dendritic cells (DC), which in turn instruct T cells (T) to proliferate and eliminate the tumor cells. A different scenario (center panel and right insert) occurs in the growing tumor where tumor micro-environmental factors such as nutrient deprivation or hypoxia create ER stress in tumor cells (TmC). These stressors induce an unfolded protein response (UPR) in tumor cells, which is then transmitted to nearby DC and brainwashes them. Affected dendritic cells no longer coordinate T cells, and impaired T cells no longer proliferate. This inappropriate T cell education hinders the effect of the body’s anti-tumor immune response and allows for unrestrained tumor growth.

“These findings suggest that the tumor UPR should be a target of therapy, not only for its intrinsic function in promoting tumor adaption and survival, but now for its external role in subverting the anti-tumor immune response.”

When a UPR response is triggered, one of two things can happen. Either UPR restores homeostasis by slowing cellular processes and synthesizing chaperone molecules to ease the burden on the endoplasmic reticulum or it decides homeostasis can’t be restored and the cell is better off dying. The latter is called apoptosis, or programmed cell death.

In research published last year, Zanetti and colleagues found that the UPR is transmissible: It can travel from one cell to another. In normal cells, ER stress is transient with the UPR usually restoring normal function. But cancer cells thrive in an environment in which low oxygen and scarce nutrients, such as glucose, induce continuous ER stress. For them, a sustained ER stress response “offers a survival advantage by promoting cancer cell adaptation, continued growth, and inflammation that is more damaging than healing,” Zanetti said.

In the latest study, the scientists found that the transmissible ER stress response (TERS), which emanates from tumor cells experiencing ER stress, alters immune cells in such a way that they no longer function to help fight off cancer. Normally dendritic cells – the sentinels and information couriers of the immune system – train T cells (the immune system’s enforcers) to specifically kill foreign entities. In the case of cancer, however, T cells are unable to properly eliminate tumor cells – confounding efforts to develop more effective cancer treatments. The new findings implicate TERS as cancer’s siren call. It brainwashes dendritic cells so that they ineffectively communicate with T cells, reducing anti-tumor immunity while increasing tumor growth.  

“This is one of the hot topics of contemporary immunology,” said Mahadevan. “Our paper shows that TERS – and by inference ER stress in tumor cells – has the ability to negatively affect the sanctuary of the immune response.”

Zanetti said the research further elucidates the fundamental processes that tumor cells use – or abuse – to manipulate their local microenvironment to promote their survival and growth. And it points to an area of drug development the pharmaceutical industry will likely focus on over the next decade.

Targeting the UPR, he said, may also help improve efficacy of long-sought cancer vaccines which have thus far been hampered by the ability of cancer cells to subvert the immune response, perhaps through mechanisms like TERS.

Co-authors are Veronika Anufreichik, Jeffrey J. Rodvold and Kevin T. Chiu, UCSD; and Homero Sepulveda, BD Biosciences, San Diego.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

2net™ Platform provides physicians with state-of-the-art patient monitoring platform

UC San Diego Health System is collaborating with Qualcomm Life, a wholly owned subsidiary of Qualcomm Technologies, Inc. to pilot the 2net™ Platform and Hub for remote patient monitoring.  Qualcomm Life’s innovative 2net technology collects patients’ clinical information from wireless medical devices and transmits it to UC San Diego Health System physicians, to supplement information already available.  This system provides a rapid, automated way to collect patient data in near real-time, analyze the readings, and suggest follow up actions with the patient, if needed.

“This collaboration is a perfect example of UC San Diego Health System’s dedication to integrating advanced information technology into patient care,” said Ed Babakanian, CIO, UC San Diego Health System.  “Our physicians have access to the most comprehensive and up-to-date clinical information – specific to each one of their patients.  This allows our teams to provide the highest quality of care, across all care settings.” 

UC San Diego Health System is one of the first health system locations to implement this unique pilot program.  Patients who volunteer for the pilot program will be given specific kits comprised of medical devices such as a weight scale, a blood pressure cuff and a blood glucose meter.  When, for example, the patient steps on the weight scale or takes a blood glucose reading, the data is collected via the 2net Hub, a plug-and-play gateway device, sent through Qualcomm’s 2net Platform and into Entra Health System’s MyHealthPoint solution to be accessed by the physician’s office for review and follow up.

“We are leveraging technology to create a two-way exchange of important clinical information no matter where the patient may be,” said Marlene Millen, MD, assistant clinical professor, UC San Diego School of Medicine.  “This system is also a service to the community in that we are helping our patients manage their care in a timely way – and we proactively are able to help patients who need help monitoring their care but do not have family nearby.”

“We are delighted to be working with UC San Diego Health System, an internationally recognized academic medical center ranked number one in San Diego area,” said Rick Valencia, vice president and general manager, Qualcomm Life.  “Our award winning 2net technology is increasingly seen as a viable solution for extending care outside of the hospital while helping to decrease readmissions in high risk, diabetic patient populations.”

About UC San Diego Health System

Launched in 1966, UC San Diego Health System is the region’s only academic health system, with a mission of providing excellent and compassionate patient care, advancing medical discoveries and educating future health care professionals. It comprises UC San Diego Medical Center in Hillcrest, and UC San Diego Thornton Hospital, Moores Cancer Center, Shiley Eye Center, Sulpizio Cardiovascular Center and Jacobs Medical Center (slated to open in 2016) in La Jolla, as well as other primary and specialty practices of UC San Diego Medical Group. For more information, visit http://health.ucsd.edu.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

A $50,000 research prize to promote active health has been awarded to James Sallis, PhD, Distinguished Professor of Family and Preventive Medicine at the University of California, San Diego School of Medicine.  Sallis is a noted academic who is on a mission to use research to promote health, fitness, and active lifestyles.

James Sallis, PhD,/p>

The 2012 Bloomberg Manulife Prize for the Promotion of Active Health – the world's largest prize devoted to physical activity – is awarded annually by McGill University in Montreal, Canada, in association with Lawrence S. Bloomberg and Manulife Financial.  The prize is given to a researcher “whose work promises to broaden our understanding of how physical activity, nutrition or psychosocial factors influence personal health and well-being.”  Sallis will accept the award at special ceremonies in Toronto on January 21, 2013 and on January 23 on the McGill campus in Montreal.

Widely regarded as a leading expert in the field of policy and environmental influences on fitness, nutrition and obesity, Sallis has dedicated his career to health promotion through physical activity, and has been recognized with numerous honors and awards, including a Distinguished Service Award from the Society of Behavioral Medicine, the Vice Presidency of the American College of Sports Medicine, and a Lifetime Achievement Award from the President’s Council on Fitness, Sports, and Nutrition.

He is an outspoken advocate of evidence-based interventions, and to that end has led many large-scale research projects, including the Neighborhood Quality of Life Study, a study of neighborhood walkability and physical activity, which is the model for studies conducted around the world. He is also co-founder of SPARK (Sports, Play, and Active Recreation for Kids), which resulted in the development and implementation of highly effective physical activity programs for youth across North America.

Sallis is also the director of the Active Living Research Program, which aims to build the evidence base about how environments and policies shape physical activity, and subsequently use the evidence to inform policy change.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Moores Cancer Center Cookbook Offers Tips for Delicious and Healthy Holiday Eating

What's round, red, full of holiday cheer, and (dare we say it) good for you?  It's the cranberry.  Its powerful goodness, coupled with cruciferous vegetables- such as broccoli, bok choy, and kale- and festive seasonal fruits like persimmons, can change attitudes about "healthy" eating during the holidays.  Gain some flavorful food insights in Food for Thought: Healing Foods to Savor, authored by nutritional experts at University of California, San Diego Moores Cancer Center. All proceeds benefit the UCSD Healthy Eating Program

Healthy Enhancing Cranberries

Cranberry Salsa: one of the many healthy recipes freatured in Food for Thought: Healing Foods to Savor, authored by nutritional experts at UC San Diego Moores Cancer Center.

"Evidence of the health benefits of cranberries is mounting," said Vicky Newman,  RD, MS, who is one of the cookbook authors and also director of Nutrition Services, Cancer Prevention & Control Program at UC San Diego Moores Cancer Center.  "Like other berries, cranberries are rich in antioxidant and anti­-inflammatory compounds reported to enhance immune function, improve urinary tract health, reduce cardiovascular and periodontal disease, and potentially inhibit cancer growth."  One of Newman's favorite recipes for the holiday season is a Cranberry Salsa she serves with goat cheese and whole-grain crackers.  "This pungent mixture of cranberries, jalapeno peppers, and ginger is an appetizer that will please the palate, while also providing plentiful amounts of health enhancing  'plant protectors'."

Detoxifying  Veggies

Cruciferous vegetables, like arugula, bok choy, broccoli, cabbage, cauliflower,  and kale, contain sulfur compounds  that support the body's detoxification system and may help reduce cancer risk.  For example, dithiolthiones and isothiocyanates  seem to increase the activity of enzymes involved in detoxifying carcinogens.   lndoles, another cruciferous compound,  appear to alter the metabolism of hormones in ways that might help prevent or reduce the growth of hormone sensitive tumors.  Newman suggests surprising your holiday guests with a cruciferous vegetable-rich salad  featuring holiday colors made with crunchy bok choy, red peppers, shredded carrots, green onions, and peanuts.

Persimmons Rich in Protective Carotenoids

This seasonal bright orange fruit is a good source of beta-carotene and provides a substantial amount of vitamin C and potassium. Newman says, "Fuyu persimmons are firm when ripe and you can eat them like an apple. But the most widely available variety of persimmon is the Hachiya (or Japanese persimmon), which has a smooth, creamy texture. Unripe Hachiyas are extremely bitter until fully soft and ripe.  Since it can be messy, try cutting a Hachiya in half and and eating it from the skin with a spoon. Hachiya persimmons are also great in baked goods and persimmon pudding cakes that starts out a luscious bright orange and come out of the oven a rich deep brown.  Reminiscent of holiday plum pudding, this dessert is best served warm right from the oven.”

For more information on health eating, or to purchase a copy of the cookbook, visit http://cancer.ucsd.edu/coping/diet-nutrition/healthy-eating-program/Pages/cookbook.aspx 

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Everything You Always Wanted to Know About Genes

Turning vast amounts of genomic data into meaningful information about the cell is the great challenge of bioinformatics, with major implications for human biology and medicine. Researchers at the University of California, San Diego School of Medicine and colleagues have proposed a new method that creates a computational model of the cell from large networks of gene and protein interactions, discovering how genes and proteins connect to form higher-level cellular machinery.

The findings are published in the December 16 advance online publication of Nature Biotechnology.

A hierarchical ontology of genes, cellular components and processes derived from large genomic datasets.

“Our method creates ontology, or a specification of all the major players in the cell and the relationships between them,” said first author Janusz Dutkowski, PhD, postdoctoral researcher in the UC San Diego Department of Medicine. It uses knowledge about how genes and proteins interact with each other and automatically organizes this information to form a comprehensive catalog of gene functions, cellular components, and processes.

“What’s new about our ontology is that it is created automatically from large datasets. In this way, we see not only what is already known, but also potentially new biological components and processes – the bases for new hypotheses,” said Dutkowski.

Originally devised by philosophers attempting to explain the nature of existence, ontologies are now broadly used to encapsulate everything known about a subject in a hierarchy of terms and relationships. Intelligent information systems, such as iPhone’s Siri, are built on ontologies to enable reasoning about the real world. Ontologies are also used by scientists to structure knowledge about subjects like taxonomy, anatomy and development, bioactive compounds, disease and clinical diagnosis.

A Gene Ontology (GO) exists as well, constructed over the last decade through a joint effort of hundreds of scientists. It is considered the gold standard for understanding cell structure and gene function, containing 34,765 terms and 64,635 hierarchical relations annotating genes from more than 80 species.

“GO is very influential in biology and bioinformatics, but it is also incomplete and hard to update based on new data,” said senior author Trey Ideker, PhD, chief of the Division of Genetics in the School of Medicine and professor of bioengineering in UC San Diego’s Jacobs School of Engineering.

“This is expert knowledge based upon the work of many people over many, many years,” said Ideker, who is also principal investigator of the National Resource for Network Biology, based at UC San Diego. “A fundamental problem is consistency. People do things in different ways, and that impacts what findings are incorporated into GO and how they relate to other findings. The approach we have proposed is a more objective way to determine what’s known and uncover what’s new.”

In their paper, Dutkowski, Ideker and colleagues capitalized upon the growing power and utility of new technologies like high-throughput assays and bioinformatics to create elaborately detailed datasets describing complex biological networks. To test the approach, the scientists pulled together multiple such datasets, applied their method, and then compared the resulting “network-extracted ontology” to the existing GO.

They found that their ontology captured the majority of known cellular components, plus many additional terms and relationships, which subsequently triggered updates of the existing GO.

Neither Ideker nor Dutkowski say the new approach is intended to replace the current GO. Rather, they envision it as complementary high-tech model that identifies both known and uncharacterized biological components derived directly from data, something the current GO does not do well. Moreover, they note a network-extracted ontology can be continuously updated and refined with every new dataset, moving scientists closer to the complete model of the cell.

Co-authors are Michael Kramer, UCSD Departments of Medicine and Bioengineering; Michal A. Surma, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany and UCSF Department of Cellular and Molecular Pharmacology; Rama Balakrishnan and J. Michael Cherry, Department of Genetics, Stanford University; and Nevan J. Krogan, UCSF Department of Cellular and Molecular Pharmacology and J. David Gladstone Institutes, San Francisco.

Funding for this research came, in part, from National Institutes of Health grants (P41-GM103504, P50-GM085764, R01-GM084448 and P50-GM081879).

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Pregnancy complication is primary cause of induced premature deliveries

Mana Parast, MD, PhD, an assistant professor of pathology at the University of California, San Diego School of Medicine, has been awarded a $3 million grant to continue her research into new therapies for preeclampsia, a pregnancy complication that often results in additional neonatal complications. The grant was part of more than $36 million awarded today to 12 researchers by the California Institute for Regenerative Medicine or CIRM, the state’s stem cell agency.

Preeclampsia is characterized by high blood pressure and abnormal kidney function and affects roughly 5 to 8 percent of all pregnancies. It’s responsible for a significant proportion of maternal deaths and growth-restricted babies, and is the primary reason for inducing delivery prematurely.

The condition involves the placenta, the temporary organ that connects mother and unborn baby. Parast’s work focuses upon the stem cells that give rise to the placenta, which are called trophoblast stem cells. Her lab has created a human trophoblast stem cell model – a first – that can be used to study stages of placental development. The CIRM grant will fund continuation of this work and be used to identify potential stem cell-based therapies for treating preeclampsia without resorting to premature delivery.

Parast’s funding is part of the third round of CIRM’s New Faculty Physician Scientist Translational Research Awards program, which supports promising young researchers in the early stages of their career. Parast is the fifth researcher from UC San Diego to receive such funding.

CIRM was established in November 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The statewide ballot measure provided $3 billion in funding for stem cell research at California universities and research institutions and called for the establishment of an entity to make grants and provide loans for stem cell research, research facilities, and other vital research opportunities.

The latest award brings the total value of UC San Diego’s CIRM grants to more than $115 million since the first awards in 2006.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

For years Alzheimer’s researchers have focused on testing experimental drugs on patients who already have a diagnosis of Alzheimer’s and significant changes in cognition, memory and behavior. It has now become quite clear that researchers have been trying to treat the disease at too late a stage. They agree that they need to be focusing on the very earliest stage, what is called “prodromal AD,” when patients suffer little or no cognitive or memory loss but scans show that their brains contain beta amyloid, the sticky plaques that are the hallmark of the disease that destroy healthy neurons.

“In the past people with prodromal Alzheimer’s disease would not have been considered to have the disease,” says Michael Rafii, MD, PhD, director of the UC San Diego Health System Memory Disorders Clinic.  “Now, we recognize it as a condition where we may be able to intervene and possibly prevent it from progressing to full blown Alzheimer’s disease.”

Rafii compares the early intervention to heart disease. “Until cholesterol was discovered as the culprit that caused plaques in the arteries that ultimately blocked blood flow and caused heart attacks, heart disease was being treated only after someone suffered a heart attack, which people often did not survive,” he said, adding that once cholesterol was identified and drugs were developed to keep arteries free of cholesterol and dangerous plaques, heart disease rates and death from heart attacks plummeted.  The same, he says, can be said for Alzheimer’s disease.  “We’ve been attacking the problem too late.”

More studies are studying the disease at this early prodromal phase. The Scarlet Road Study, currently enrolling patients at UC San Diego Health System, is one such innovative study.

Scarlet Road, Rafii says, is a double-blind, placebo-controlled study that will test the effect of injections of an experimental drug, gantenerumab, or placebo on people who have prodromal Alzheimer’s disease. Gantenerumab is a new experimental drug made from human antibodies, a type of protein produced by the human immune system in response to a foreign substance such as a virus or bacteria. Antibodies protect the body from disease by attacking these substances and destroying them. Gantenerumab has been developed to attack the beta-amyloid plaques in the brain. In animal tests, antibodies like gantenerumab have been shown to remove plaques from the brain. In some cases, there has been improvement of the animals’ ability to think, make decisions, concentrate or remember, called “cognitive function.”

The UC San Diego study will run over a two and a half year period. One third of study participants will receive a low drug dose, one third will receive a moderate drug dose and the remaining group will receive the placebo. Most studies follow a 50/50 drug to placebo formula; in this study participants have a two in three chance of receiving the actual experimental drug. Neither the participants nor study staff will know who is receiving the study drug and who is receiving the placebo.

For further information on the Scarlet Road Study call 858-246-1300 or email CAPmemory@ucsd.edu

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Media Contacts: Jeffree Itrich, 858-246-1317, jitrich@ucsd.edu; Debra Kain, 619-543-6163, ddkain@ucsd.edu

Presently, there are about 40 million Americans over the age of 65, with the fastest-growing segment of the population over 80 years old.  Traditionally, aging has been viewed as a period of progressive decline in physical, cognitive and psychosocial functioning, and aging is viewed by many as the “number one public health problem” facing Americans today.

But this negative view of aging contrasts with results of a comprehensive study of 1,006 older adults in San Diego by researchers from the University of California, San Diego School of Medicine and Stanford University.  Results of the Successful Aging Evaluation (SAGE) study – comprising a 25-minute phone interview, followed by a comprehensive mail-in survey – will be published in the December 7 online issue of the American Journal of Psychiatry. 

“While there is a growing public health interest in understanding and promoting successful aging, until now little published research has combined measures of physical health with cognitive and psychological assessments, in a large and randomly selected  sample,” said principal investigator Dilip V. Jeste, MD, Estelle and Edgar Levi Chair in Aging, Distinguished Professor of Psychiatry and Neurosciences, and director of UC San Diego’s Stein Institute for Research on Aging, and the current President of the American Psychiatric Association (which was not involved in this study).  

The SAGE study included adults between the ages of 50 and 99 years, with a mean age of just over 77 years.  In addition to measures which assessed rates of chronic disease and disability, the survey looked at more subjective criteria such as social engagement and participants’ self-assessment of their overall health.

“Sometimes the most relevant outcomes are from the perspective of the subjects themselves,” said Jeste. 

The study concludes that resilience and depression have significant bearing on how individuals self-rate successful aging, with effects that are comparable to that of physical health. “Even though older age was closely associated with worse physical and cognitive functioning, it was also related to better mental functioning,“ said co-author Colin Depp, PhD, associate professor of psychiatry at UC San Diego School of Medicine.  

After adjusting  for age, a higher self-rating of successful aging was associated with higher education, better cognitive function, better perceived physical and mental health, less depression, and greater optimism and resilience. 

Participants were asked to rate the extent to which they thought they had “successfully aged,” using a 10-point scale and using their own concept of the term.  The study found that  people with low physical functioning but high resilience, had self-ratings of successful aging similar to those of physical healthy people with low resilience.  Likewise, the self-ratings of individuals with low physical functioning but no or minimal depression had scores comparable to those of physically healthy people with moderate to severe depression.

“It was clear to us that, even in the midst of physical or cognitive decline, individuals in our study reported feeling that their well-being had improved with age,” Jeste said.  This counterintuitive increase in well-being with aging persisted even after accounting for variables like income, education and marriage.

Jeste suggests there’s a take-away message for clinicians, which is that an optimistic approach to the care of seniors may help reduce societal ageism. “There is considerable discussion In public forums about the financial drain on the society due to rising costs of healthcare for older adults – what some people disparagingly label the ‘silver tsunami.’ But, successfully aging older adults can be a great resource for younger generations,” he said.

The findings point to an important role for psychiatry in enhancing successful aging in older adults. “Perfect physical health is neither necessary nor sufficient,” Jeste said. “There is potential for enhancing successful aging by fostering resilience and treating or preventing depression.”  

Additional contributors to this study include Gauri N. Savla, PhD, Wesley K. Thompson, PhD, Ipsit V. Vahia, MD, Danielle K. Glorioso, MSW, A’verria Sirkin Martin, PhD, Barton W. Palmer, PhD, David Rock, BA, and Shahrokh Golshan, PhD, UC San Diego; and Helena C. Kraemer, PhD, professor of biostatistics in psychiatry at Stanford University.

This work was supported, in part, by NIMH grants T32 MH-019934 and P30 MH-066248, by NIH National Center for Research Support grant UL1 RR-031980, by the John A. Hartford Foundation, and by the Sam and Rose Stein Institute for Research on Aging.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Rigorous requirements highlight significant difference in the treatment of complex stroke cases

UC San Diego Medical Center-Hillcrest is one of the first five facilities in the country, and the only center in San Diego County, to be certified as a Comprehensive Stroke Center (CSC), the newest level of certification for advanced stroke care awarded by The Joint Commission.  This certification recognizes the significant differences in resources, staff and training that are necessary for the treatment of complex stroke cases.

“This Comprehensive Stroke Center certification is vital to UC San Diego Health System’s position as a leader in the San Diego community in providing the most advanced and state-of-the-art medical and surgical care for all patients who suffer a stroke in our region,” said Paul Viviano, CEO, UC San Diego Health System.  “This expert care is provided not only to patients directly admitted to UC San Diego Medical Center but also to those patients transferred from other care centers that cannot offer the comprehensive stroke level of care.”

For two days in September, a team of Joint Commission expert surveyors evaluated the Stroke Center in Hillcrest for compliance with the new comprehensive stroke center standards and requirements.  Joint Commission experts reviewed UC San Diego Medical Center’s compliance with the requirements for The Joint Commission’s Comprehensive Stroke Certification program in addition to the primary stroke center requirements, such as collecting Joint Commission core measure data and using it for performance improvement activities.

“UC San Diego Medical Center offers the region’s only truly multidisciplinary stroke team.  This means all stroke patients have access to the best care for their individual needs, be it surgical, medical or endovascular,” said Thomas Hemmen, MD, PhD, director of the Stroke Center at UC San Diego Health System and associate professor of medicine at UC San Diego School of Medicine.  “We know that patients admitted to a facility such as ours have better outcomes and a better chance for meaningful recovery.”

"By achieving this advanced certification, UC San Diego Medical Center – Hillcrest has thoroughly demonstrated the greatest level of commitment to the care of its patients with a complex stroke condition,” says Mark R. Chassin, MD, FACP, MPP, MPH, president, The Joint Commission. “Certification is a voluntary process and The Joint Commission commends UC San Diego Medical Center – Hillcrest for successfully undertaking this challenge to elevate the standard of its care for the community it serves.”

The higher standards of the CSC certification indicates that UC San Diego Medical Center can assist all stroke patients and is better prepared – with state-of-the-art equipment, infrastructure, staff and training – to diagnose and treat patients with the most complex strokes.

“The best stroke care is team based and comprehensive,” said Bob Carter, MD, PhD, chief of Neurosurgery at UC San Diego Health System and professor of neurosurgery at UC San Diego School of Medicine.  “This certification recognizes UC San Diego Health System’s investment to provide round-the-clock availability – of stroke neurologists, neurosurgeons, neurocritical care specialists, and specially trained stroke nurses – to treat patients any hour of the day, seven days a week, every day of the year for stroke from any cause, whether a blocked artery, a ruptured aneurysm, or brain hemorrhage.”
 


Carter also commented that UC San Diego Health System is home to many firsts in neurosurgical therapy for stroke including the use of minimally invasive endovascular neurosurgery, a program now led by Alexander Khalessi, MD, MS.  “UC San Diego Health System is a national leader in the development and use of advanced neurovascular procedures including endovascular clot retrieval for stroke, treatment of brain aneurysms and arteriovenous malformations, and endoscopic brain hemorrhage removal.  These technologies have helped put UC San Diego at the forefront of stroke care.”

Comprehensive Stroke Center Certification was developed in collaboration with the American Heart Association/American Stroke Association and derived from the Brain Attack Coalition’s “Recommendations for Comprehensive Stroke Centers,” (Stroke, 2005), and “Metrics for Measuring Quality of Care in Comprehensive Stroke Centers,” (Stroke, 2011), and on recommendations from a multidisciplinary advisory panel of experts in complex stroke care.

“The American Heart Association/American Stroke Association congratulates UC San Diego Medical Center – Hillcrest on its Comprehensive Stroke Center Certification,” commented Mark J. Alberts, MD, FAHA, American Heart Association/American Stroke Association spokesperson and incoming vice-chair of Neurology and Neurotherapeutics at UT Southwestern Medical Center. “Comprehensive Stroke Centers offer a high level of care for patients with the most severe and challenging types of strokes and cerebrovascular disease.”

Every year, over 5,000 San Diegans are brought to a local hospital via EMS with an acute and often fatal stroke. The CSC will offer these patients with arterial blood clots or brain hemorrhages a multidisciplinary treatment approach guaranteeing the best possible outcomes in each individual case.

Nearly 1 million people in the United States were hospitalized by stroke in 2009, according to the Centers for Disease Control and Prevention. An estimated 7 million Americans have had some form of stroke, which was the fourth-leading cause of death in the United States in 2010.
The Stroke Center at UC San Diego Health System became the first primary stroke center in San Diego County recognized by The Joint Commission and has also earned the Joint Commission's Gold Seal of Approval.™

For more information about the Stroke Center at UC San Diego Health System, visit http://health.ucsd.edu/stroke 

For more information on The Joint Commission and American Heart Association’s Advanced Certification for Comprehensive Stroke Center visit http://www.jointcommission.org/ or www.heart.org/myhospital

About UC San Diego Health System:
Launched in 1966, UC San Diego Health System is the region’s only academic health system, with a mission of providing excellent and compassionate patient care, advancing medical discoveries and educating future health care professionals. It comprises UC San Diego Medical Center in Hillcrest, and UC San Diego Thornton Hospital, Moores Cancer Center, Shiley Eye Center, Sulpizio Cardiovascular Center and Jacobs Medical Center (slated to open in 2016) in La Jolla, as well as other primary and specialty practices of UC San Diego Medical Group. For more information, visit http://health.ucsd.edu

About The Joint Commission:
Founded in 1951, The Joint Commission seeks to continuously improve health care for the public, in collaboration with other stakeholders, by evaluating health care organizations and inspiring them to excel in providing safe and effective care of the highest quality and value. The Joint Commission evaluates and accredits more than 19,000 health care organizations and programs in the United States, including more than 10,300 hospitals and home care organizations, and more than 6,500 other health care organizations that provide long term care, behavioral health care, laboratory and ambulatory care services. The Joint Commission currently certifies more than 2,000 disease-specific care programs, focused on the care of patients with chronic illnesses such as stroke, joint replacement, stroke rehabilitation, heart failure and many others. The Joint Commission also provides health care staffing services certification for more than 750 staffing offices. An independent, not-for-profit organization, The Joint Commission is the nation's oldest and largest standards-setting and accrediting body in health care. Learn more about The Joint Commission at www.jointcommission.org

About the American Heart Association/American Stroke Association:
The American Heart Association/American Stroke Association is devoted to saving people from heart disease and stroke – America’s No. 1 and No. 3 killers. We team with millions of volunteers to fund innovative research, fight for stronger public health policies, and provide lifesaving tools and information to prevent and treat these diseases. The Dallas-based association is the nation’s oldest and largest voluntary organization dedicated to fighting heart disease and stroke. To learn more or to get involved, call 1-800-AHA-USA1, visit www.heart.org or call any of our offices around the country.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Verizon Foundation to provide grant, in-kind technology solutions to scale up novel approach to TB treatment

As part of an innovative philanthropic health care program targeting reduction of health care disparities in diverse communities around the United States, the Verizon Foundation has provided the University of California, San Diego School of Medicine with a $300,000 grant, as well as important in-kind health information technology solutions.

The support from Verizon will allow researchers from the University to more quickly scale-up a mobile phone-based solution that they developed to overcome the high cost and other barriers to monitoring tuberculosis patients throughout their treatment.  The approach, called “video directly observed therapy,” or VDOT, is headed by Richard Garfein, PhD, MPH, professor in the Division of Global Public Health, Department of Medicine at UC San Diego.

“Based on the results of a successful pilot study involving patients with tuberculosis in San Diego and Tijuana, Mexico, we plan to scale-up this technology so that tuberculosis care providers elsewhere can use the VDOT system,” said Garfein, adding that the hope is to eventually offer this novel way of monitoring TB treatment to patients across the United States and eventually in countries hard-hit by the contagious disease, such as India.

TB is one of the world’s deadliest infectious diseases, currently affecting more than 11 million people worldwide.  Each year, there are approximately 8.8 million new cases reported, resulting in 1.5 million deaths.

“TB can be cured with an antibiotic regimen,” Garfein explained.  “But the biggest problem care givers face, especially in developing countries, is making sure patients are compliant with treatment that takes six months or longer to complete.”

Adherence is critical to ensure that the treatment succeeds, and the patient doesn’t relapse or develop a drug-resistant strain of TB.  Traditionally, health care providers personally observe patients taking their medication – an approach with many barriers, including high cost, human resources and transportation challenges, particularly in rural areas, and making patients feel patronized.

With VDOT, patients are observed for treatment adherence via videos sent on mobile phones.  UC San Diego’s pilot study of 50 patients in San Diego and Tijuana, supported by the National Institutes of Health, resulted in “high adherence and patient satisfaction,” according to Garfein, as well as significant cost and time savings.

The technologies that underlie the VDOT system were developed under the direction of Kevin Patrick, MD, MS, professor of Family and Preventive Medicine and a researcher at the California Institute for Telecommunications and Information Technology (Calit2) at UC San Diego. In addition to the novel video app, VDOT incorporates a customizable patient management system, text messaging and a HIPAA-compliant server environment. With help from the Verizon grant, Garfein, Patrick and colleagues will spend the next six months customizing the software used to record, encrypt, transfer, store and observe patient videos – making it functional for multiple health departments and care providers simultaneously.

“Once we scale up the software, we initially plan to demonstrate that it works with 100 patients in two California health departments,” said Garfein.  Verizon’s in-kind support will include mobile phones, monthly phone service as well as secure IT storage of this health information, using Enterprise Cloud technology provided by Verizon affiliate Terremark Cloud Computing.

If proven successful, this approach could be a cheap and effective way to assure medication adherence in remote areas of India and other countries, where in-person monitoring is very difficult and labor-intensive.

“We are grateful for Verizon’s support in this critical next stage of development,” Garfein said.  “The potential for VDOT to save lives as well as resources domestically and abroad is tremendous.”

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Researchers at the University of California, San Diego School of Medicine and the VA San Diego Healthcare System have found that deficiencies in the neural processing of simple auditory tones can evolve into a cascade of dysfunctional information processing across wide swaths of the brain in patients with schizophrenia.

The findings are published in the current online edition of the journal Neuroimage.

Schizophrenia is a mental disorder characterized by disturbed thought processes and difficulty in discerning real from unreal perceptions. Common symptoms include auditory hallucinations and unfounded suspicious ideas. The disorder affects about 1 percent of the U.S. population, or roughly 3 million people. 

In this schematic, reduced activation in discrete medial prefrontal brain regions is depicted (in blue) in schizophrenia patients, occurring 0.2 seconds after sound changes (top panel), cascading forward to widespread brain regions associated with the automatic activation of attentional networks 0.1 second later (bottom panel).

“Impairments in the early stages of sensory information processing are associated with a constellation of abnormalities in schizophrenia patients,” said Gregory Light, PhD, associate professor of psychiatry at UC San Diego and senior author of the study. 

These impairments, according to Light, may explain how schizophrenia patients develop clinical symptoms such as hearing voices that others cannot hear and difficulty with cognitive tasks involving attention, learning and recalling information. “If someone’s brain is unable to efficiently detect subtle changes in sounds despite normal hearing, they may not be able to automatically direct their attention and rapidly encode new information as it is being presented.”

Light and colleagues used electroencephalography – a technique that records patterns of electrical brain activity using electrodes positioned on the scalp – on 410 schizophrenia patients and 247 nonpsychiatric comparison subjects. The researchers employed novel computational imaging approaches to deconstruct the brain dynamics that underlie two leading neurobiological markers used in schizophrenia research: mismatch negativity (MMN) and P3a event-related potentials.

In healthy volunteers, a specific pattern of EEG responses across a complex network of brain structures is elicited within a fraction of a second in response to changes in auditory tones. In patients with schizophrenia, the researchers found that this normal process is disrupted. Reduced activity in specific areas of the medial frontal lobe quickly propagated to other regions of the brain that support activation of attentional networks.

“Changes in the tone of speech convey complex information including nuances of emotional meaning and content,” said Light, who is also associate director of the VISN-22 Mental Illness, Research, Education and Clinical Center (MIRECC) at the San Diego VA Medical Center. “If a patient’s brain is not processing auditory information optimally, he or she may miss out on important-but-subtle social cues and other critical information.  They may not properly recognize sarcasm or humor that is carried by pitch changes in speech. This can be a major barrier to achieving better functioning in social relationships, school or job performance, and ultimately limit their overall quality of life.” 

In research published earlier this year, Light and colleagues established that MMN and P3a showed promise for unlocking the elusive brain and molecular dysfunctions of schizophrenia patients.  “These brain-based biomarkers may eventually prove to be useful for assisting clinicians with diagnosis, guiding treatment decisions, and tracking therapeutic response over time.  These measures may also predict which individuals are at risk for developing a serious mental illness and are most likely to benefit from course-altering early interventions.” 

According to Stephen R. Marder, MD, VISN-22 MIRECC director and a professor at UCLA’s Semel Institute for Neuroscience and Human Behavior, “this study makes a valuable contribution to our understanding of how impairments in the very early processing of sensory information in schizophrenia can explain the complex symptoms of the illness. This new knowledge may also be useful in developing better pharmacological and non-pharmacological treatments for schizophrenia.” 

Co-authors of this study are Hidetoshi Takahashi, UCSD Department of Psychiatry and National Center of Neurology and Psychiatry, Japan; Anthony J. Rissling, Kenji Kirihara, Marlena Pela, and Joyce Sprock, UCSD Department of Psychiatry; Robert Pascual-Marqui, Key Institute for Brain-Mind Research, University Hospital of Psychiatry, Switzerland; and David Braff, UCSD Schizophrenia Research Program. 

Funding for this research came, in part, from the National Institute of Mental Health (grants MH079777, MH042228 and MH065571), the Department of Veteran Affairs and the Mitsubishi Pharma Research Foundation.

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Media Contacts: Scott LaFee, UC San Diego Health Sciences, 619-543-6163, slafee@ucsd.edu; Cindy Butler, VA San Diego Healthcare System, 858-552-4373, cynthia.butler@va.gov

A multidisciplinary team from the Sulpizio Cardiovascular Center at University of California, San Diego Health System has performed its 100th lead (pronounced “leed”) extraction surgery, a delicate procedure to replace the thin wiring of lifesaving heart devices such as pacemakers or implantable defibrillators (ICDs). The collaborative program, pioneered at UC San Diego Health System, has a 100 percent success rate.

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Animation of pocket and prep for lead extraction.

The 100th patient, JenyLyn Carpio, was 22 years old when she experienced a total heart blockage and was diagnosed with a genetic heart disorder that makes her prone to sudden death events. After seven years, she needed a lead extraction procedure.

“Without the quick action of the UC San Diego cardiac team, I would not be alive.  They keep me going, even today,” said Carpio who is now 29, a full-time mom, wife and active 5k runner.

“We have a specialized cardiac team dedicated to entire sequence of this procedure,” said Green.  “These are high-risk procedures where complications can occur quickly. At the Sulpizio Cardiovascular Center we perform our extractions in a hybrid operating room – the only hybrid operating room in the San Diego Region – so if necessary we can instantly switch to a full-blown operating suite.”

“From anesthesiology, to surgery to electrophysiology and the after-care coordinators, every member plays a significant role in the care of the patient,” explained Victor Pretorius, MD, cardiothoracic surgeon, Sulpizio Cardiovascular Center, and assistant clinical professor of surgery, UCSD School of Medicine.  “There is a big variance in the patients we see, but for the most part, these patients are very complex with heart tissues that are challenging to manage. Our approach is customized for each patient.”

About UC San Diego Sulpizio Cardiovascular Center
UC San Diego Sulpizio Cardiovascular Center is dedicated to innovative care and the prevention, diagnosis and treatment of cardiovascular disease. The state-of-the-art facility, which opened in La Jolla in 2011, is the region’s first academic-based facility to combine all heart and vascular-related services, programs and technology under one roof. For more information, visit www.heartcenter.ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

A team of scientists, led by researchers at the University of California, San Diego School of Medicine, has shown for the first time how cancer cells control the ON/OFF switch of a program used by developing embryos to effectively metastasize in vivo, breaking free and spreading to other parts of the body, where they can proliferate and grow into secondary tumors.

The findings are published in the December 11 issue of the journal Cancer Cell.

A cluster of malignant breast cancer cells (stained brown) metastasized to the liver. Image courtesy of the National Cancer Institute.

In 90 percent of cancer deaths, it is the spreading of cancer, known as metastasis, which ultimately kills the patient by impacting ever-more tissues and functions until the body fails. Ten years ago, a French cancer researcher named Jean Paul Thiery hypothesized that tumor cells metastasized by exploiting a developmental process known as epithelial-to-mesenchymal transition or EMT.

EMT is seen in developing embryos whose cells transform from stationary epithelial cells into more mobile mesenchymal cells, the latter able to migrate to new locations and create new types of tissue and organs. Thiery proposed that cancer cells also switch “ON” EMT, temporarily changing attributes so that they can detach from primary tumors, enter the bloodstream and seed new tumors elsewhere. After arriving at a new location, the cancer cells then turn “OFF” the EMT program and grow into carcinoma metastases or tumors.

Thiery’s hypothesis was controversial because researchers haven’t been able to find supporting evidential proof in vivo. “Although this model was proposed in 2002, there have been no experiments done to attest to it in a spontaneous tumor model,” said Jing Yang, PhD, associate professor of pharmacology and pediatrics and senior author of the Cancer Cell paper. “Our new study provides an in vivo demonstration of the reversible EMT in metastasis and helps to resolve the controversy on this leading theory in metastasis.”

Using a mouse squamous cell carcinoma model, Jeff Tsai, PhD, a postdoctoral fellow in Yang’s lab and first author of the study, with help from collaborators at the Whitehead Institute for Biomedical Research in Cambridge, MA and The Sanford-Burnham Medical Research Institute in La Jolla, showed that activation of an EMT-inducing gene called Twist1 is sufficient to turn “ON” the EMT switch and promote carcinoma cells to disseminate into blood circulation.  Equally importantly, the researchers found that turning “OFF” the EMT switch at distant sites is essential for disseminated tumor cells to proliferate and form metastases.  Their findings indicate that reversible EMT likely represents a key driving force in human carcinoma metastasis. 

“There are many similarities between developmental EMT and EMT in metastasis,” Yang said.  “Both processes seem to use the same cellular machineries and signaling pathways to activate the EMT program. During embryogenesis, the EMT program tends to be more permanent and epithelial cells commit to a mesenchymal fate.  Our study shows that carcinoma cells need a reversible EMT to achieve efficient metastasis. It suggests that EMT reversion could be a critical step to wake up tumor cells from dormancy, a phenomenon in which cancer patients develop metastasis years after the initial primary tumor diagnosis and removal.”

It’s not entirely known how Twist1 becomes active in primary tumors, though previous studies have pointed to factors like hypoxia and inflammation in the tumor microenvironment. Researchers do not know exactly how Twist1 is “turned off at distant organs.” Yang said these are subjects of current experiments.

More broadly, the published findings suggest that more research is needed to determine how to target EMT to combat cancer metastasis. Several pharmaceuticals and research institutes are already pursuing EMT inhibitors as possible cancer treatments. 

“Since reversion of EMT promotes colonization and growth of metastases, this study actually cautions that therapies inhibiting EMT could be counterproductive in preventing distant metastases when patients already present circulating tumor cells. Instead, blocking EMT reversion may prevent dormant tumor cells from establishing metastases.”

Co-authors of the paper include Sandra Chau, Department of Pharmacology, UCSD School of Medicine; Joana Liu Donaher, Whitehead Institute for Biomedical Research; and Danielle A. Murphy, The Sanford-Burnham Medical Research Institute.

Funding came, in part, from the American Cancer Society, the National Institutes of Health, the Sidney Kimmel Foundation for Cancer Research, California Breast Cancer Research program, University of California Cancer Research Coordinating Committee, UCSD Cancer Center Training Program in Drug Development and UCSD Cancer Center Specialized Support Grant.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

A diagnosis of pancreatic cancer is particularly devastating since the prognosis for recovery is usually poor, with the cancer most often not detected until late stages. 

Research led by scientists at the University of California, San Diego and UC San Francisco Schools of Medicine examined the tumor-initiating events leading to pancreatic cancer (also called pancreatic ductal adenocarcinoma or PDA) in mice. Their work, published on line November 29 in the journal Cancer Cell, may help in the search for earlier detection methods and treatments.

Maike Sander, MD

“Previously, it was believed that this cancer arises from the epithelial cells in pancreatic ducts,” said Maike Sander, MD, professor of pediatrics and cellular and molecular medicine and director of UC San Diego’s Pediatric Diabetes Research Center, co-principal investigator of the study along with Matthias Hebrok, PhD, director of the UCSF Diabetes Center. “But in this study, we show that ducts have almost no response to oncogenic mutations – mutations that give rise to cancerous tumors.”

The study revealed that another pancreatic cell type, called the acinar cell, converts into a duct-like cell that initiates tumors. The researchers also showed that inflammation of the pancreas, which is a significant risk factor for pancreatic cancer, promotes the conversion of acinar cells into duct-like tumor precursors.

Kras is a gene that may cause cancer when it is mutated.  It makes the Kras protein, which is involved in cell signaling pathways, cell growth and apoptosis, or cell death. Agents that block the activity of the mutated Kras gene or its protein may stop the growth of cancer.

Tracing specific cell populations in the presence and absence of tissue injury in mice, the research team demonstrated that oncogenic Kras can readily induce PDA precursor – or premalignant – lesions called PanIN, from adult pancreatic acinar cells, but not from ductal cells. 

Accounting for the fact that acinar cells are more abundant than ductal cells in the adult pancreas of mice, the difference in the ability of the acinar cells to generate PanIN premalignant lesions remained more than a 100 times greater than the ability of ductal or so-called centroacinar cells.  In addition, the study demonstrated that, when PanIN lesions originate in acinar cells, they activate the ductal transcription factor Sox9. The scientists show that activation of Sox9 is necessary to convert the acinar cells into premalignant lesions.  Overexpression of the Sox9 gene enhances both abnormal, pancreatitis-associated changes in adult tissue cells and Kras-induced PanIN formation.

Ductal and centroacinar cells already expressing Sox9 are dramatically resistant to Kras-induced neoplastic transformation, which is the conversion of a tissue with a normal growth pattern into a malignant tumor.   The findings demonstrate a key role for acinar cells in the beginning stages of pancreatic cancer, and point to Sox9 as a potential target for preventing early tumor-initiating events.

Additional contributors include co-first authors Janel L. Kopp, UC San Diego, and Guido von Figura, UCSF; Erin Mayes, Fen-Fen Liu and Claire L. Dubois, UC San Diego; John P. Morris IV, UCSF; Fong Cheng Pan and Christopher V.E. Wright, Vanderbilt University; Haruhiko Akiyama, Kyoto University; and Kristin Jensen, Veteran Affairs Palo Alto Health Care System and Stanford University Hospital. 

This work was supported by grants from the National Institutes of Health grants R01DK078803, R01CA112537, F32CA136124 and DFG-FI1719/1-1.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

UC San Diego Health System was honored with two separate “A” Hospital Safety Scores by The Leapfrog Group, an independent national nonprofit run by employers and other large purchasers of health benefits.  The A scores were awarded in the latest update to the Hospital Safety Score^SM, the A, B, C, D or F scores assigned to US hospitals based on preventable medical errors, injuries accidents, and infections.

UC San Diego Health System was honored with two "A" grades for patient safety.

“These A scores – awarded to two hospital campuses – reflect our deep commitment to patient safety, placing us among the most safe hospitals in the United States,” said Paul Viviano, CEO, UC San Diego Health System. “Our A scores were achieved through diligent systemwide initiatives across inpatient services as well as throughout the organization to optimize safety, every day, with each patient interaction. I thank our staff and faculty for their thoughtful work and lifesaving care to make this happen.”

The Hospital Safety Score was compiled under the guidance of the nation’s leading experts on patient safety and is designed to give the public information they can use to protect themselves and their families.

“UC San Diego Health System’s Quality and Patient Safety program has continuously pursued the goals of achieving outstanding clinical outcomes and preventing patient harm through teamwork and a thoughtful, evidenced-based approach to care,” said Angela Scioscia, MD, CMO, UC San Diego Health System.

“These scores capture the enterprise-wide focus on improving patient safety, which includes continued improvements in resuscitation practices, health care associated infection prevention, and medication safety. Significant investments have been made in information technology to help clinicians provide safe and reliable care to our patients,” said Andrea Snyder, RN, quality officer, UC San Diego Health System.

To see UC San Diego Health System’s scores as they compare nationally and locally, visit the Hospital Safety Score website at www.hospitalsafetyscore.org, which also provides information on how the public can protect themselves and loved ones during a hospital stay. People can also check their local hospital’s score on the free mobile app, available at www.hospitalsafetyscore.org.

Calculated under the guidance of The Leapfrog Group’s nine-member Blue Ribbon Expert Panel, the Hospital Safety Score uses 26 measures of publicly available hospital safety data to produce a single score representing a hospital’s overall capacity to keep patients safe from infections, injuries, and medical and medication errors. The panel includes: John Birkmeyer (University of Michigan), Ashish Jha (Harvard University), Lucian Leape (Harvard University), Arnold Millstein (Stanford University), Peter Pronovost (Johns Hopkins University), Patrick Romano (University of California, Davis), Sara Singer (Harvard University), Tim Vogus (Vanderbilt University), and Robert Wachter (University of California, San Francisco). 

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Media Conact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

In older adults, antipsychotic drugs are commonly prescribed off-label for a number of disorders outside of their Food and Drug Administration (FDA)-approved indications – schizophrenia and bipolar disorder. The largest number of antipsychotic prescriptions in older adults is for behavioral disturbances associated with dementia, some of which carry FDA warnings on prescription information for these drugs.

In a new study – led by researchers at the University of California, San Diego School of Medicine, Stanford University and the University of Iowa, and funded by the National Institute of Mental Health – four of the antipsychotics most commonly prescribed off label for use in patients over 40 were found to lack both safety and effectiveness. The results will be published November 27 in The Journal of Clinical Psychiatry.

The study looked at four atypical antipsychotics (AAPs) – aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), and risperidone (Risperdal) – in 332 patients over the age of 40 diagnosed with psychosis associated with schizophrenia, mood disorders, PTSD, or dementia.

“Our study suggests that off-label use of these drugs in older people should be short-term, and undertaken with caution,” said Dilip V. Jeste, MD, Estelle and Edgar Levi Chair in Aging, Distinguished Professor of Psychiatry and Neurosciences, and director of the Stein Institute for Research on Aging at UC San Diego.

Results of the five-year study led by Jeste, who is also current president of the American Psychiatric Association (which was not involved in this research), showed that within one year of treatment, one-third of the patients enrolled in the study developed metabolic syndrome (medical disorders that can increase the risk of cardiovascular disease or diabetes). Within two years, nearly a quarter of the patients developed serious adverse effects and just over half developed non-serious adverse effects.

Because the patients enrolled in the study were all diagnosed with conditions with psychotic symptoms that required antipsychotic drug treatment according to their treating physicians, no placebo was used in the trial.  Instead, the researchers used a technique called “equipoise stratified randomization” which is a hybrid of complete randomization and a clinician’s choice method. 

“Our goal was to ensure clinical relevance,” said Jeste.  Patients had to agree to be randomized to 2, 3 or 4 of the study drugs, as they or their physicians were allowed to exclude one or two of the study AAPs, due to past experience or anticipated risk of the particular drug.   Treating clinicians could determine the optimal dosage.  “We attempted to make the study as ‘user-friendly’ as possible, to allow the drugs the best chance of success, while seeking to minimize the amount of bias,” he explained.

While the researchers’ intent was to continue the patients on the randomized medications for two years, the average length turned out to be only six months, after which the medications were halted or switched because they didn’t work and/or had side effects. 

Because of a notably high incidence of serious adverse events, quetiapine had to be discontinued midway through the trial.  The researchers  found that there were significant differences among patients willing to be randomized to different AAPs – thus, treating clinicians tended to exclude olanzapine and prefer aripiprazole as one of the possible choices in patients with existing metabolic problems. Yet, the different AAP groups did not appreciably differ in most outcome measures.

Using a common scale called the Brief Psychiatric Rating Scale (BPRS), to measure symptoms such as delusions, hallucinations, unusual behavior, depression, and anxiety, assessments were made at 6 weeks, 12 weeks, and then every 12 weeks.   Results using “blind” raters showed no significant improvement in BPRS over a six-month period.

“While there were a few significant differences among the four drugs, the overall risk-benefit ratio for the AAPs in patients over age 40 was not favorable, irrespective of diagnosis and drug,” said Jeste.

Jeste points out that clinicians, patients, and caregivers are often left with difficult and unclear choices for treatment for older persons with psychosis, such as that associated with dementia.   Not only are psychosis and agitation common in persons with dementia but they also frequently cause considerable caregiver distress and hasten institutionalization of patients. At the same time, there are no FDA-approved alternatives to antipsychotics for this population, and the high cost of newer AAPs also makes their use problematic.

While the researchers say their findings do not suggest that these AAPs should be banned in older patients with psychiatric disorders, they do indicate that considerable caution is warranted in off-label, long-term use of the drugs in older persons.

“When these medications are used off-label, they should be given in low dosages and for short durations, and their side effects monitored closely,” said Jeste. “Clearly, there is also a critical need to develop and test new interventions that are safe and effective in older people with psychotic disorders.” 

Other authors of this paper are Hua Jin, MD, Pei-an Betty Shih, PhD, Shahrokh Golshan, PhD, Sunder Mudaliar, MD, Robert Henry, MD, and Danielle K. Glorioso, MSW, from University of California, San Diego; Helena C. Kraemer, PhD, emerita professor of biostatistics in psychiatry at Stanford University, and Stephan Arndt, PhD, professor of psychiatry and biostatistics at the University of Iowa.

The study was supported in part by National Institutes of Health grants MH071536, P30 MH080002-01, 1K01DK087813-01, NCRS UL1RR031980 and by the Department of Veteran Affairs. 

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Methylome modifications offer new measure of our “biological” age

Women live longer than men. Individuals can appear or feel years younger – or older – than their chronological age. Diseases can affect our aging process. When it comes to biology, our clocks clearly tick differently.

In a new study, researchers at the University of California, San Diego School of Medicine, with colleagues elsewhere, describe markers and a model that quantify how aging occurs at the level of genes and molecules, providing not just a more precise way to determine how old someone is, but also perhaps anticipate or treat ailments and diseases that come with the passage of time.

The findings are published in the November 21 online issue of the journal Molecular Cell.

“It’s well known that people age at different rates,” said Kang Zhang, MD, PhD, professor of ophthalmology and human genetics at the Shiley Eye Center and director of the Institute for Genomic Medicine, both at UC San Diego. “Some people in their 70s look like they’re in their 50s, while others in their 50s look like they’re in their 70s.”

However, identifying markers and precisely quantifying the actual rate of aging in individuals has been challenging. For example, researchers have looked at telomeres – repeating nucleotide sequences that cap the ends of chromosomes and which shorten with age – but have found that other factors like stress can affect them as well.

In the new Molecular Cell paper, Zhang and colleagues focus on DNA methylation, a fundamental, life-long process in which a methyl group is added or removed from the cytosine molecule in DNA to promote or suppress gene activity and expression. The researchers measured more than 485,000 genome-wide methylation markers in blood samples of 656 persons ranging in age from 19 to 101.

“It’s a very robust way of predicting aging,” said Zhang, one that was subsequently validated on a second sampling of several hundred blood samples from another cohort of human individuals.

The scientists found that an individual’s “methylome” – the entire set of human methylation markers and changes across a whole genome – predictably varies over time, providing a way to determine a person’s actual biological age from just a blood sample.

“It’s the majority of the methylome that accurately predicts age, not just a few key genes,” said co-senior author Trey Ideker, PhD, a professor of medicine and chief of the Division of Medical Genetics in the UC San Diego School of Medicine and professor of bioengineering in the Jacobs School of Engineering. “The methylation state decays over time along the entire genome. You look in the body, into the cells, of young people and methylation occurs very distinctly in some spots and not in others. It’s very structured. Over time, though, methylation sites get fuzzier; the boundaries blur.”

They do not, however, blur at the same rate in everybody. At the molecular level of the methylome, the researchers said it was clear that individual bodies age at varying rates, and even within the same body, different organs age differently. Moreover, cancer cells age differently than their surrounding normal cells.  The findings, according to the study authors, have broad practical implications. Most immediately, they could be used in forensics to determine a person’s age based only upon a blood or tissue sample.

More profoundly, said Zhang, the methylome provides a measure of biological age – how quickly or slowly a person is experiencing the passage of time. That information has potentially huge medical import. “For example, you could serially profile patients to compare therapies, to see if a treatment is making people healthier and ‘younger.’ You could screen compounds to see if they retard the aging process at the tissue or cellular level.”

Ideker said assessing an individual’s methylome state could improve preventive medicine by identifying lifestyle changes that might slow molecular aging. He noted, however, that much more research remains to be done.

“The next step is to look to see whether methylation can predict specific health factors, and whether this kind of molecular diagnosis is better than existing clinical or physical markers. We think it’s very promising,” Ideker said. 

Co-authors of this study include Gregory Hannum and Menzies Chen, UCSD Department of Bioengineering; Justin Guinney and Stephen Friend, Sage Bionetworks, Seattle, WA; Ling Zhao, UCSD Institute for Genomic Medicine and UCSD Department of Ophthalmology; Li Zhang, Sichuan University, UCSD Institute for Genomic Medicine, UCSD Department of Ophthalmology and Guangzhou iGenomics Co., China; Guy Hughes, UCSD Institute for Genomic Medicine and UCSD Department of Ophthalmology; SriniVas Sadda, University of Southern California; Brandy Klotzle, Marina Bibikova and Jian-Bing Fan, Illumina Inc, San Diego; Yuan Gao, Johns Hopkins University, Baltimore, MD; Rob Deconde, UCSD Department of Bioengineering and Department of Medicine; Indika Rajapakse, Fred Hutchinson Cancer Research Center, Seattle, WA.

Funding came, in part, from the National Institutes of Health (grants P50GM085764, R01E5014811, EY014428, EY018660, EY019270 and EY021374), the National Basic Research Program of China (973 Program, grant 2013CB967504), the Natural Science Foundation of China (grant 81130017), the National Eye Institute, a Veterans Administration Merit Award, the Research to Prevent Blindness and the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

American Cancer Society recognized Charles von Gunten, MD, PhD, at annual meeting

Charles F. von Gunten, MD, PhD, FACP, FAAHPM, provost and vice president of the Institute for Palliative Medicine at San Diego Hospice, a teaching affiliate of the UC San Diego School of Medicine, is this year’s American Cancer Society “Pathfinder in Palliative Care” honoree.  The award – which recognizes individuals who have demonstrated innovation and ingenuity in their contributions to the advancement of the field of palliative care – was presented today at the Society’s Nationwide Volunteer and Staff Leadership Summit in Atlanta.

“There is nothing more meaningful to a physician than to be recognized for having an impact on patients’ and families’ lives,” said von Gunten, who is also medical director of the Doris A. Howell Palliative Care Service at UC San Diego Moores Cancer Center. “To be recognized by ACS – a patient advocacy organization – is a pinnacle moment in my career.”

von Gunten holds an established investigator award from the National Cancer Institute and is the editor-in-chief of the Journal of Palliative Medicine.  He is a founding trustee and past chairman of the American Board of Hospice and Palliative Medicine, and immediate past president of the American Association for Cancer Education.

“The American Cancer Society is committed to both saving lives and improving the quality of life of individuals and families facing cancer,” said Vincent T. DeVita Jr., MD, president of the American Cancer Society. “Dr. von Gunten deserves to be recognized for his commitment to his field and for his pioneering efforts to improve palliative care in this country.”

Palliative care is a branch of medicine that specializes in symptom management and pain control while also addressing psychological, spiritual and social concerns. The goal is the best quality of life for patients with serious illnesses and their families Dr. von Gunten is one of very few internationally recognized palliative medicine educators.  Under his leadership, among the earliest palliative medicine graduate fellowship training programs were launched at Northwestern University, and he now leads the largest palliative medicine fellowship training program in the nation at San Diego Hospice and UC San Diego Health System. 

In 2011, von Gunten received the Lifetime Achievement Award from the American Academy of Hospice and Palliative Medicine (AAHPM), the professional organization for physicians who care for patients with serious illness. 

For more on the Doris A. Howell Palliative Care Service at Moores Cancer Center:
http://cancer.ucsd.edu/coping/support-services/Pages/palliative-care.aspx

About UC San Diego Moores Cancer Center
UC San Diego Moores Cancer Center is home to nearly 350 medical and radiation oncologists, cancer surgeons, and researchers. It is one of only 40 National Cancer Institute-designated comprehensive cancer centers in the country, a rare honor distinguishing exceptionally high achievement in research, clinical care, education and community outreach and partnerships. For more information, visit http://cancer.ucsd.edu

About the American Cancer Society
The American Cancer Society combines an unyielding passion with nearly a century of experience to save lives and end cancer for good. As a global grassroots force of three million volunteers, we fight for every birthday threatened by every cancer in every community. We save lives by helping you stay well by preventing cancer or detecting it early, helping you get well by being there for you during and after a diagnosis, by finding cures through groundbreaking discovery and fighting back through public policy. As the nation’s largest non-governmental investor in cancer research, contributing more than $3.8 billion, we turn what we know about cancer into what we do. As a result, an estimated 13.7 million people in America who have had cancer and countless more who have avoided it will be celebrating birthdays this year. To learn more about us or to get help, call us anytime, day or night, at 1-800-227-2345 or visit http://cancer.org.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Napoleone Ferrara, MD, PhD, the molecular biologist credited with helping decipher how tumors grow, and with development of new treatments for both cancer and age-related macular degeneration, has been named recipient of The Economist magazine’s 2012 Innovation Award for bioscience.

Napoleon Ferrara, MD, PhD

Ferrara, 56, joins the University of California, San Diego School of Medicine on December 1 as a professor of pathology and as senior deputy director for basic science at the UC San Diego Moores Cancer Center. He comes from Genentech, the San Francisco-based biotechnology company where he served as a long-time research fellow.

The Innovation prize in bioscience honors Ferrara’s work identifying the role of the human VEGF gene in promoting angiogenesis – the formation of new blood vessels that can feed tumor growth – and subsequent development of two major monoclonal antibody drugs: Bevacizumab (marketed as Avastin), which is used treat multiple forms of cancer, including breast, brain and colorectal, and ranibizumab (marketed as Lucentis), which treats wet age-related macular degeneration, a leading cause of blindness in the elderly.

“Not only did he help explain how tumors proliferate through angiogenesis,” said Scott Lippman, MD, director of the UC San Diego Moores Cancer Center. “He took this new knowledge and translated it into novel clinical treatments that benefit real patients. We’re thrilled to bring his vision, passion and commitment for truly collaborative scientific discovery and clinical progress to Moores.”

At UC San Diego Moores Cancer Center, Ferrara will continue his cancer drug development research targeting angiogenesis and oversee the center’s basic science operation.

In 2010, Ferrara received the highly regarded Lasker-DeBakey Clinical Medical Research award for his work. Winners of Lasker awards have also won Nobel Prizes, as have several Economist Innovation recipients. Previous Innovation award winners in bioscience include artificial skin inventor Robert Langer, Harald zur Hausen, the Nobel Laureate who discovered the viral cause of cervical cancer, and J. Craig Venter, a pioneer in human genome sequencing and president of the J. Craig Venter Institute in La Jolla.

Now in their 11th year, The Economist’s Innovation Awards celebrate individual innovators whose efforts have had great impact upon business and/or society. An international panel of 29 judges selected honorees in categories that include energy and the environment, computing and telecommunications, social and economic innovation and consumer products. The winners were announced at a London ceremony last night.

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Media contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

A study led by researchers from the University of California, San Diego School of Medicine has found a correlation between vitamin D3 serum levels and subsequent incidence of Type 1 diabetes.  The six-year study of blood levels of nearly 2,000 individuals suggests a preventive role for vitamin D3 in this disease.  The research appears the December issue of Diabetologia, a publication of the European Association for the Study of Diabetes (EASD).

“Previous studies proposed the existence of an association between vitamin D deficiency and risk of and Type 1 diabetes, but this is the first time that the theory has been tested in a way that provides the dose-response relationship,” said Cedric Garland, DrPH, FACE, professor in UCSD’s Department of Family and Preventive Medicine.

This study used samples from millions of blood serum specimens frozen by the Department of Defense Serum Registry for disease surveillance.  The researchers thawed and analyzed 1000 samples of serum from healthy people who later developed type 1 diabetes and 1000 healthy controls whose blood was drawn on or near the same date but who did not develop type 1 diabetes.  By comparing the serum concentrations of the predominant circulating form of vitamin D – 25-hydroxyvitamin D (25(OH)D) – investigators were able to determine the optimal serum level needed to lower an individual’s risk of developing type 1 diabetes. 

Based mainly on results of this study, Garland estimates that the level of 25(OH)D needed to prevent half the cases of type 1 diabetes is 50 ng/ml. A consensus of all available data indicates no known risk associated with this dosage.

“While there are a few conditions that influence vitamin D metabolism, for most people, 4000 IU per day of vitamin D3 will be needed to achieve the effective levels,” Garland suggested.  He urges interested patients to ask their health care provider to measure their serum 25(OH)D before increasing vitamin D3 intake. 

“This beneficial effect is present at these intakes only for vitamin D3,” cautioned Garland. “Reliance should not be placed on different forms of vitamin D and mega doses should be avoided, as most of the benefits for prevention of disease are for doses less than 10,000 IU/day.”

Garland’s co-authors from UC San Diego School of Medicine and the Naval Health Research Center include Edward Gorham, PhD; Sharif Mohr, PhD; and Heather Hofflich, DO; Alina Burgi and Kenneth Zeng of the Naval Health Research Center, and Camillo Ricordi MD, of the University of Miami  Diabetes Research Institute.

The study was supported by a Congressional allocation to the Diabetes Research Institute of the University of Miami through the Naval Health Research Center, San Diego, California.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Margarita Baggett, MSN, BSN, RN, chief nursing officer (CNO) and interim chief operating officer (COO) for UC San Diego Health System has been elected President of the Association of California Nurse Leaders (ACNL), a prestigious statewide organization that advances the art and profession of nursing.

Margarita Baggett, MSN, BSN, RN, CNO and interim COO for UC San Diego Health System elected President of the Association of California Nurse Leaders.

“I am deeply honored to accept the position of president of the Association of California Nurse Leaders,” said Baggett, who recently led UC San Diego Health System to MAGNET® designation. “My goal is to promote innovation in patient safety and quality of care, identify emerging nurse leaders who have a passion for advocacy, and to strategically appoint these leaders to community, regional, and state committees.” 

As CNO of UC San Diego Health System, Baggett provides leadership of the nursing staff and is responsible for planning, organizing, and directing all functions of Nursing Services, Pharmacy Services, Care Coordination and Volunteer Services. As interim COO, Baggett’s responsibilities include the day-to-day operations for a staff of more than 5,600 along with key participation in strategic planning for growth.

“UC San Diego Health System is proud of Margarita and supports her in this influential role,” said Paul Viviano, chief executive officer, UC San Diego Health System. “Margarita is a highly accomplished nurse leader who has had a transformative effect on nursing and patient care in San Diego. We know she will make an equal impact statewide.”

In 2009, under Baggett’s leadership, nurses surveyed by Nursing Professionals magazine gave UC San Diego Medical Center top ratings in job satisfaction.  UC San Diego Health System was one of only 10 hospitals in the entire state of California to make the highly competitive “Top 100 Hospitals to Work For” list.

Baggett has extensive experience in quality management, service excellence, patient throughput, staff recruitment and retention, and regulatory affairs. Before coming to UC San Diego Health System, she had more than 27 years of progressively responsible experience in the North Shore-Long Island Jewish Health System in Manhasset, N.Y., where she served as deputy executive director, nurse executive, and associate executive director for Patient Care Services and Care Coordination.

A graduate of the Johnson & Johnson Wharton Fellows Program in Management for Nurse Executives, Baggett earned her Master of Science from Adelphi University and a bachelor’s degree in nursing from Molloy College, both in New York. She is currently an active member of the California Institute for Nursing & Health Care, and Nursing Spectrum/NurseWeek Advisory Board Southern California. She is a presenter at national nursing conferences and has been published in the journal Nursing Management.

ACNL is a non-profit professional nursing organization that shapes the future of health care by developing California nurse leaders through mentoring, coaching, and education opportunities; promoting quality and patient safety; advancing professional practice; and providing a consistent advocacy message for health policy. More can be learned at: http://www.acnl.org/

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

UCSD Center for Mindfulness helps raise compassionate generation with Jon Kabat-Zinn

The Center for Mindfulness at University of California, San Diego School of Medicine announces early registration for the 2013 Bridging the Hearts and Minds of Youth Conference, February 1 – 3 in San Diego, California.  Mindfulness leader Jon Kabat-Zinn, PhD – along with his wife Myla and experts from across the U.S. – will show participants how to support and foster the growth of mindfulness and happiness, especially among youths.
 
“The topic of bringing mindfulness to youth has virtually exploded in recent years as people realize the toll that modern society and technology is putting on our kids and families,” said Steven D. Hickman, PsyD, clinical psychologist, director of the UC San Diego Center for Mindfulness.  “Our presenters practice mindfulness at home, in classrooms and therapy rooms. They will share their key findings, challenges and successes with each other to help raise a generation of healthier children and students.”

The 2013 program, hosted at the Catamaran Hotel in San Diego, California, will be headlined by noted mindfulness teacher, Kabat-Zinn, author of Wherever You Go There You Are, Coming to Our Senses and Full Catastrophe Living. His keynote lecture, "Befriending Your Mind, Befriending Your Life: Mindfulness and the Endless Adventure of Growing into Yourself," will benefit the UC San Diego Family & Child Programs.  Kabat-Zinn and his wife, Myla, will also host a 3-hour workshop on Mindful Parenting, based on their book Everyday Blessings.

“We are all born with the capacity to be mindful, to live in the moment, but our upbringing and experiences sometimes cause us to lose track of this capacity for long stretches,” said Allan Goldstein, associate director of the UCSD Center for Mindfulness. “The joy of bringing mindfulness to young people is that children instinctively 'know' how to be present and less reactive to life stress. Thus they can reconnect with the present moment sometimes more easily than those of us who been living reactively. We can learn from them.”

For the first time, this year’s program includes presentations on recent research related to mindfulness and youth, talks regarding implementing a variety of innovative, mindfulness-based programs such as Mindfulness for Urban and High-Risk Youth, based on the work of brothers, Ali and Atman Smith, who teach yoga in the inner city, where such healing practices are often needed most.

Additionally, optional workshops will offer learning specific programs and skills related to bringing mindfulness to youth.  For example, the “Still Quiet Place” curriculum teaches practices that can be used in work and play with children and adolescents geared toward an understanding of how observing thoughts and feelings from a place of stillness and quietness improves attention, decreases anxiety, supports healthy choices and enhances compassion for oneself and others.

“This is a community of professionals – educators, therapists, researchers, and administrators – who are just now realizing that they are a true community,” said Hickman, associate clinical professor in the departments of Psychiatry and Family & Preventive Medicine at UC San Diego School of Medicine.  “We are united around a common goal of helping our young people reach their potential to be happy, healthy, well-adjusted human beings who practice compassion, patience, equanimity and presence.”

For more information, please visit: http://cme.ucsd.edu/bridging/index.html

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Bariatric Program Accredited by ACS Bariatric Surgery Center Network

The Bariatric Metabolic Institute (BMI) at University of California, San Diego Health System has been accredited as a Level 1 facility by the Bariatric Surgery Center Network (BSCN) Accreditation Program of the American College of Surgeons (ACS).  This designation means that the institutional performance of UC San Diego BMI meets the rigorous requirements outlined by the ACS BSCN Accreditation Program.

Santiago Horgan, MD, internationally recognized weight-loss surgeon.

“This accreditation from the American College of Surgeons affirms our mission of providing safe and effective weight loss surgeries for all patients,” said Santiago Horgan, MD, director, UC San Diego Bariatric Metabolic Institute and chief of minimally invasive surgery, UC San Diego Health System. “We are dedicated to reversing the obesity epidemic by offering an array of customized surgical procedures that significantly reduce weight and produce less pain and scarring.”

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Willie De Pascale underwent gastric banding surgery after he had a heart attack at age 43. At 390 pounds, the retired chef found a good solution for him at UC San Diego Bariatric and Metabolic Institute.

In the United States, more than 11 million people suffer from severe obesity, a disease commonly associated with type II diabetes, hypertension, and cardiovascular disease.  Currently, weight-loss surgery provides the only effective, lasting relief from severe obesity. 

The UC San Diego Bariatric Metabolic Institute is dedicated to the science of developing and offering an array of surgical and non-surgical weight loss techniques that are customized to the patient’s individual needs. A team of internationally recognized surgeons and specialists including registered nurses, a program psychologist, registered dietitians, patient advocates and support staff provide patients with a comprehensive long-term plan to improve their health and lifestyle. Learn more at http://bmi.ucsd.edu   

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Pulmonary Thromboendarterectomy program honored as “Center of Excellence”

The physicians, surgeons and team members who pioneered the lifesaving pulmonary thromboendarterectomy (PTE) procedure at University of California, San Diego Health System are being honored for excellence at the annual CHEST conference, hosted by the American College of Chest Physicians, in Atlanta, October 20 to 25, 2012.  The PTE program based at the UC San Diego Sulpizio Cardiovascular Center is among 11 specially selected “Centers of Excellence” showcasing the defining characteristics and practices that make them unique among health-care providers.

Dr. Bill Auger speaks with a colleague at the 2012 CHEST conference, hosted by ACCP in Atlanta.

“To be nationally recognized by our ACCP colleagues as a Center of Excellence is an honor our entire team shares,” said William Auger, MD, Pulmonary PTE program, UC San Diego Health System and clinical professor at UC San Diego School of Medicine.  “This work is our passion.  We are a family of caregivers who truly believe in delivering the best possible care to patients with chronic pulmonary hypertension from first-contact through surgery to annual check-ups.” 

Dr. Bill Auger, Alicia Gormican, and Dr. Nick Kim: proud to lead the PTE Program at UC San Diego Sulpizio Cardiovascular Center.

Pulmonary thromboendarterectomy (PTE) is a surgical procedure to remove deadly clots from the pulmonary arteries, the large yet thin blood vessels that carry blood from the heart to the lungs. The delicate 8 to 10 hour surgery takes out part of the wall of the pulmonary artery and the thick scar-like clot material that causes the obstruction.  Developed by UCSD cardiothoracic surgeons and pulmonary-critical care medicine physicians, the team has led the way in the successful evaluation and treatment of patients of all ages.

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UC San Diego Sulpizio Cardiovascular Center physicians and surgeons pioneered the PTE program.

Surgeons at UC San Diego Health System have performed nearly 2,800 PTE procedures– the majority since 1990 – and experienced a 2.2 percent mortality rate between 2006 and 2010 and less than one percent rate for the past two years. This is the lowest known postoperative mortality rate worldwide.  The procedure can reverse heart failure and is considered more effective than lung transplantation.

“When we began this program, many people said it could not be done, that this was not a disease,” explained Stuart Jamieson, MD, FRCS, head of the Division of Cardiothoracic Surgery, UC San Diego Health System, and Endowed Chair and Distinguished Professor of Surgery at UC San Diego School of Medicine.  “Now, patients come from all over the world to receive this life-saving, curable treatment and we have trained the lion’s share of the surgeons who specialize in this procedure.”

“It used to be difficult just to walk a flight of stairs and now I snowboard and can do just about anything I want to do,” said Cassie Rodriguez, who had the life-saving PTE surgery at 13 and is now 22 years old.  “I call Dr. Auger every year on the anniversary of my surgery.  He was the first person, after my parents, who I called after I got engaged this year.”

About The American College of Chest Physicians
The American College of Chest Physicians is the global leader in clinical chest medicine, representing 18,500 members who provide patient care in the areas of pulmonary, critical care, and sleep medicine in the United States and throughout the world. The mission of the ACCP is to promote the prevention, diagnosis, and treatment of chest diseases through education, communication, and research. For more information about the ACCP, visit the ACCP website at www.chestnet.org or follow the ACCP on Facebook and Twitter.          

About UC San Diego Sulpizio Cardiovascular Center
UC San Diego Sulpizio Cardiovascular Center is dedicated to innovative care and the prevention, diagnosis and treatment of cardiovascular disease. The state-of-the-art facility, which opened in La Jolla in 2011, is the region’s first academic-based facility to combine all heart and vascular-related services, programs and technology under one roof. For more information, visit www.heartcenter.ucsd.edu

For more information on CHEST Centers Of Excellence:
http://2012.accpmeeting.org/clinical-resource-center/centers-of-excellence

For more information on UC San Diego Sulpizio Cardiovascular Center’s PTE program:
http://heartcenter.ucsd.edu/pte/Pages/default.aspx

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

East County Chamber of Commerce Honors Lisa Murphy for achievements in health care

Lisa Murphy, associate administrator for University of California, San Diego Health System and administrative director for Cardiovascular and Medicine Services, has been chosen “Woman of the Year” in the field of health care by the Women in Leadership program sponsored by the San Diego East County Chamber of Commerce.  Murphy is one of six women of achievement – in various categories, including business, non-profit, education, government, arts/culture/media and health care – honored at the 10th Annual Women in Leadership Luncheon at the Town & Country Hotel.

Lisa Murphy is San Diego East County Chamber of Commerce "Woman of the Year" in health care.

“Lisa brings focus and great enthusiasm to everything she does,” said Kirk Peterson, MD, director, UC San Diego Sulpizio Cardiovascular Center.  "Her dedication to our mission – providing excellent patient care within a hub of education, innovation and discovery – is obvious and heart felt.  We are very proud to see her efforts recognized in this way.”

Murphy was selected by the East County Chamber Board for her “demonstrated leadership abilities and outstanding achievements.”  Her responsibilities include leadership and oversight for clinical operations as well as financial performance and program growth for the cardiovascular service line.  Murphy was also actively engaged in planning, operationalizing and licensing the Sulpizio Cardiovascular Center from July 2005 through opening day on July 31, 2011.  Due to the success of that project, Murphy is now co-chair of the Transition Committee for UC San Diego Jacobs Medical Center (JMC), a $700 million,
240-bed tertiary care medical center scheduled to open in La Jolla in 2016.  

Among her contributions, Murphy is a major sponsor, fundraiser and team leader of the annual UC San Diego Sulpizio Cardiovascular Center Heart Walk.  She was San Diego’s regional chairwoman for the American Heart Association's "Go Red for Women" campaign in 2011 as well as a member of the LEAD Impact class of 2012. 

“I am honored to receive this recognition for doing what I love to do,” said Murphy.  “UC San Diego Health System’s cardiovascular program is recognized for excellence worldwide, and the Sulpizio Cardiovascular Center is the diamond in our crown.  I’m inspired everyday by the level of dedication our staff, nurses, physicians and surgeons give our patients.”

As part of the only academic health system in San Diego, the Sulpizio Cardiovascular Center is the only facility in San Diego providing all cardiovascular research, services and programs in one location. It was recently recognized by Truven Health Analytics as one of the nation's 2013 50 Top Cardiovascular Hospitals.

About UC San Diego Sulpizio Cardiovascular Center
UC San Diego Sulpizio Cardiovascular Center is dedicated to innovative care and the prevention, diagnosis and treatment of cardiovascular disease. The state-of-the-art facility, which opened in La Jolla in 2011, is the region’s first academic-based facility to combine all heart and vascular-related services, programs and technology under one roof. For more information, visit http://heartcenter.ucsd.edu.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

No Trick to Treating Children (and Adults) to a Safe Halloween

UC San Diego Health System offers tips for a fun and safe Halloween.

The Regional Burn Center and Emergency Departments at UC San Diego Health System - along with the California Poison Control System - San Diego Division located at UC San Diego Medical Center - offer the following safety precautions to help parents and guardians make Halloween safe this year.

Burn Prevention

• Keep an eye on Jack-O-Lanterns with burning candles inside. Make sure they’re placed where they cannot ignite a fire.
• Look for costumes, wigs and masks that are flame resistant and with enough room for a child to dress warmly underneath.  Flame resistant does not mean the fabric won't catch fire, only that it will resist burning and should extinguish quickly once removed from the ignition’s source.

Safe Eating

• Feed children before they go trick-or-treating.  Select a small amount of candy or other food to eat while trick-or-treating so they won’t be tempted to eat from the bag before their treats can be checked.
• Look carefully at all treats to detect signs of tampering.  Throw away unwrapped candy or treats not in the original wrapper, candy with faded or torn wrappers and candies that show signs of rewrapping.
• Parents with children of different ages should sort the candies to make sure that younger kids don't get hold of small hard candies, peanuts or other objects that may get lodged in a youngster's throat. 
• Remember, some treats, especially chocolate, can be poisonous to pets.

Costume Musts

• Face paints, glues and glitters should be made of non-toxic materials. Some children have allergic reactions to these products, such as a rash or itching.  If this occurs, remove the make-up immediately and thoroughly cleanse the skin with mild soap and water.
• If your child wears a mask, make sure it does not impair the child’s vision or breathing.
• Physicians recommend kids wear flat shoes with their costumes and make sure the costumes are short enough to prevent the child from tripping

Trick-or-Treating Tips

• Never let a child trick-or-treat alone. An adult should accompany young children in familiar neighborhoods, visiting known areas.
• Walk on the sidewalk and only stop by houses that have the front porch light on.
• Carry a flashlight after dusk and watch for cars.
  Make walkways and lawns safe by removing obstacles and leaving outside lights on.
• Stay away from barking dogs or other upset animals.
• Choose costumes with light or bright colors, which can be seen by drivers.
• Use reflective tape on costumes and trick-or-treat bags so that they are highly visible.
• Halloween also means parties for parents.  Make sure all alcohol and cigarette butts are cleaned up as these items can poison small children.

Parents who find any candy that has been tampered with should report the incident to the police department.  If children are experiencing any symptoms following ingestion of food or candy, parents should call the California Poison Control System - San Diego Division at 800-222-1222.  The Poison Center is open 24-hours a day, seven days a week.

Alcohol Consumption Warning

Emergency physicians in UC San Diego Health System’s emergency departments say they experience an upswing in alcohol-related incidents.  “Unfortunately, we can almost always count on an increase,” said Theodore Chan, MD, Medical Director of UC San Diego’s emergency department.  “Those numbers can be reduced if adult partiers take a moderate approach to alcohol consumption and designate a driver before the evening’s festivities begin.”

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

Kristin Bertell

Effective October 1, Kristin Bertell has assumed the position of associate vice chancellor for Health Sciences Development at the University of California, San Diego.  In this role, Bertell is responsible for all fund raising related to Health Sciences, including clinical, research and academic programs.  UC San Diego Health Sciences comprises UC San Diego Health System, the region’s only academic health system; UC San Diego School of Medicine, one of the nation’s top research-intensive schools of medicine; and Skaggs School of Pharmacy and Pharmaceutical Sciences.

Bertell came to UC San Diego Health Sciences in 2011 as executive director of development for principal gifts.  Prior to that, she was senior vice president for The Greenwood Company, a consulting firm headquartered in San Francisco.  There, she conducted campaign planning and management for such organizations as the Gladstone Institutes, Buck Institute for Age Research and Scripps Health.

From 2002 to 2007, Bertell served as vice president for Institute Relations at the Salk Institute for Biological Studies in La Jolla.  She is a graduate of UCLA and received a master’s degree in communications management from the Annenberg School for Communication at the University of Southern California.  A certified fund raising executive with the National Society of Fund Raising Executives, she is also a member of the Association of Fundraising Professionals, the Association of Healthcare Philanthropy and the Southern California Association of Healthcare Development.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Ustekinumab Induces, Sustains Clinical Response in Patients

Ustekinumab, an antibody proven to treat the skin condition psoriasis, has now shown positive results in decreasing the debilitating effects of Crohn’s Disease, according to researchers at the University of California San Diego, School of Medicine. The study will appear in the October 18, 2012 issue of the New England Journal of Medicine (NEJM).

Sandborn discusses latest potential drug therapy for Crohn's disease.

Results from the clinical trial showed ustekinumab (Stelara) increased clinical response and remission in patients suffering from moderate-to-severe Crohn’s Disease - a form of inflammatory bowel disease (IBD) that can lead to a variety of distressing symptoms, including diarrhea, intestinal bleeding and weight loss. Serious complications such as bowel obstruction and abscesses can also occur.

“Our biggest challenge in treating patients with Crohn’s Disease is managing patients whose bodies are resistant to tumor necrosis factor (TNF) inhibitors such as Remicade, Humira and Cimzia,” said Sanborn, MD, principal investigator and chief of the Division of Gastroenterology at the UC San Diego School of Medicine.  “Ustekinumab blocks two proteins that cause inflammation, interleukin 12 and 23.  This finding is a significant first step towards a new treatment option for these patients.”

One third of patients with moderate-to-severe Crohn’s Disease do not respond to current treatment with TNF inhibitors, which regulates the body’s immune system and inflammation.  Another one third of patients only have a temporary response.

Five hundred and twenty six patients were part of the randomized trial, which was conducted in 12 countries. Eligible patients were at least 18 years of age and had a confirmed diagnosis of Crohn’s Disease for at least three months.

The patients were treated for 36 weeks in the placebo-controlled study.  They were given an intravenous dose of ustekinumab at the beginning of the study and a subcutaneous dose every eight weeks. Benefits could be seen as early as six weeks of therapy. 

Among patients treated, serious infection was reported in five patients and a basal-cell carcinoma, a form of skin cancer, was reported in one patient.

“These promising initial results are now being followed up and confirmed with additional Phase 3 induction trials – UNITI-1 and UNITI-2.  A Phase 3 maintenance trial (IM-UNITI) will also be conducted in which the patients who respond to ustekinumab will receive additional treatment for one year,” said Sandborn, director of the Inflammatory Bowel Disease Center at UC San Diego Health System. “Our goal is to increase clinical response and put the disease in remission to improve the patient’s quality of life.”

Crohn’s Disease affects approximately 700,000 Americans. There is no cure for the disease, and severe flare ups can result in surgery where the large intestine is removed.

Researchers who also participated in this study include Christopher Gasink, MD, Long-Long Gao, PhD, Marion A. Blank, PhD, Jewel Johanns, PhD, Cynthia Guzzo, MD, all at Janssen Research & Development, Springhouse, PA; Bruce E. Sands, MD, and Simon Lichtiger, MD, Mount Sinai School of Medicine, New York; Stephen B. Hanauer, MD, University of Chicago; Stephan Targan, MD, Cedars Sinai Medical Center; Paul Rutgeerts, MD, PhD, University Hospital Gasthuisberg, Leuven, Belgium; Subrata Ghosh, MD, and Remo Panaccione, MD, University of Calgary; Gordon Greenberg, MD, Mount Sinai Hospital, University of Toronto; Willem J.S. de Villiers, MD, PhD, University of Kentucky Medical Center, Lexington; Stefan Schreiber, MD, Christian Albrechts University, University Hospital, Schleswig-Holstein, Kiel, Germany; and Brian G. Feagan, MD, Robarts Research Institute, London, ON.

The study was funded by Janssen Research & Development.

The Division of Gastroenterology at UC San Diego Health System is nationally recognized for its innovative and comprehensive care of patients by a multidisciplinary team of specialists in gastroenterology, endoscopy, oncology, surgery, transplantation and radiology. The Inflammatory Bowel Disease Center is dedicated to diagnosing and treating people with IBD from around the world.  The center’s leadership in IBD medical research means patient access to clinical trials for the newest therapies and advanced surgical techniques for the treatment of this challenging condition.

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

The Institute of Medicine (IOM) today announced the names of 70 new members and 10 foreign associates during its 42nd annual meeting.  Included are two new members from the University of California, San Diego School of Medicine: David A. Brenner, MD, vice chancellor for Health Sciences and dean of the UCSD School of Medicine, and Don W. Cleveland, PhD, chair of the UCSD Department of Cellular and Molecular Medicine, and professor of medicine, neurosciences, and cellular and molecular medicine at the Ludwig Institute for Cancer Research. 

Election to the IOM is considered one of the highest honors in the fields of health and medicine and recognizes individuals who have demonstrated outstanding professional achievement and commitment to service.

"The Institute of Medicine is greatly enriched by the addition of our newly elected colleagues, each of whom has significantly advanced health and medicine," said IOM President Harvey V. Fineberg. "Through their research, teaching, clinical work, and other contributions, these distinguished individuals have inspired and served as role models to others. We look forward to drawing on their knowledge and skills to improve health through the work of the IOM."

David A. Brenner, MD
Don W. Cleveland, PhD

As vice chancellor for Health Sciences, Brenner has oversight of more than 900 faculty physicians, pharmacists and scientists; 7,500 staff; more than 600 medical and pharmacy students, and the UC San Diego Health System, which cares for more than 125,000 patients annually.  Brenner is a leader in the field of gastroenterological research, specializing in diseases of the liver. He has focused on understanding the molecular pathogenesis of fibrotic liver disease and the genetic basis of liver disorders as the foundation for improving prevention and treatment of liver disease. For five years, Brenner was editor-in-chief of Gastroenterology, the premier journal in the field.  He is also a member of the American Society for Clinical Investigation, the Association of American Physicians, the American College of Physicians; the American Gastroenterological Association and the American Clinical and Climatological Association.

Cleveland heads the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research, based at UC San Diego.  He was elected to the American Academy of Arts and Sciences in 2006 for his pioneering discoveries of the mechanisms of chromosome movement and cell-cycle control during normal cellular division, as well as of the principles of neuronal cell growth during mammalian development – defects that lead to inherited human neurodegenerative disease.   He won the “Spirit of Lou Gehrig” award from the ALS Association in 2010 for his research on ALS (commonly called Lou Gehrig’s disease), a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement.

New members to IOM are elected by current active members through a selective process that recognizes individuals who have made major contributions to the advancement of the medical sciences, health care, and public health. The newly elected members raise IOM's total active membership to 1,732 and the number of foreign associates to 112. With an additional 84 members holding emeritus status, IOM's total membership is 1,928.

Established in 1970 by the National Academy of Sciences, IOM has become recognized as a national resource for independent, scientifically informed analysis and recommendations on health issues.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

According to the Centers for Disease Control (CDC), endometriosis, a gynecological disorder in which cells from the uterus lining grow in other areas of the body, is the number one reason for a hysterectomy in women ages 18-35.  Current treatment options for endometriosis are severely limited by side effects of existing medications and surgical options have more risks.  A nationwide clinical trial is testing an investigational drug as a potential new option for patients with moderate to severe pain from this disease. 

The Violet Petal Study, funded by Abbott and led at UC San Diego by Sanjay Agarwal, MD, FACOG, with the Department of Reproductive Medicine at UC San Diego School of Medicine, is currently recruiting patients to be part of the one to two year study to investigate the safety and effectiveness of the oral drug Elagolix. “Endometriosis can be an extremely painful disease, especially during a woman’s menstrual cycle.  Many women find themselves debilitated during these bouts, and the disease can also cause pain during intercourse and increase infertility,” said Agarwal, director of UC San Diego Health System’s Center for Endometriosis Research and Treatment (CERT), a one of a kind, multidisciplinary program in Southern California for women suffering from endometriosis.  

Common therapies include injections, which bring estrogen down to very low levels, resulting in side effects such as hot flashes, bone loss and mood swings.

“Many patients have to take a secondary medication to counteract the side effects from current treatment options,” said Agarwal.  “The hope with Elagolix, taken daily, is to suppress estrogen just enough to take away the pain associated with endometriosis but without the harsh side effects to the body.”

About five to 10 percent of women of reproductive age have endometriosis. The growths caused by the disease can cause tissue implants on the ovaries, bowel, rectum, bladder, and on the lining of the pelvic area. There is no cure for endometriosis and women usually need to be on treatment until menopause. 

As director of CERT, Agarwal brings together a broad team of clinical and scientific experts to work with endometriosis and look at different treatment options that will improve the quality of life for patients. 

“The Violet Petal Study will hopefully lead to a gentler treatment option for women living with endometriosis and advance our knowledge of this chronic disease,” said Agarwal.

Eligible patients for the study must be between the ages of 18-49 and have been surgically diagnosed with endometriosis in the last seven years.

For more information about the study, please contact Sanjay Agarwal at skagarwal@ucsd.edu or 858-543-8930 or please visit: https://www.violetpetalstudy.com/HomePage.aspx

For more information on CERT, please visit: http://cert.ucsd.edu

Research studies often involve volunteer participants, without whom the work would not be possible.  For more information on participating in clinical research studies at UC San Diego or in your region, visit http://participate.ucsd.edu and consider registering for ResearchMatch, a free Web-based registry that matches volunteers with researchers.

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

Chemical found in many plastics linked to multiple health threats
 
Bisphenol A or BPA is a synthetic chemical widely used in the making of plastic products ranging from bottles and food can linings to toys and water supply lines. When these plastics degrade, BPA is released into the environment and routinely ingested.

Contacts between the ends (red) of estradiol and the estrogen receptor are critical for biological activity. BPA is too short to have both contacts; MBP is longer and can mimic the sex hormone estradiol in the estrogen receptor.

New research, however, from the University of California, San Diego School of Medicine suggests it is the metabolic changes that take place once BPA is broken down inside the body that pose the greater health threat.

More than 90 percent of all Americans are believed to carry varying levels of BPA exposure. 

In recent years, numerous studies have reported alarming associations between BPA exposure and myriad adverse health and development effects, from cancer and neurological disorders to physiological defects and, perhaps, a cause of childhood obesity.

Of particular concern is that BPA exposure is correlated with disruption of estrogen signaling.  The chemical’s molecular structure is similar to that of estradiol, one of the human body’s three main estrogens, suggesting that BPA binds to estrogen receptors. The estrogen receptor is designed to grab and hold estradiol and related estrogens. Disparate chemicals, however, can share some structures found in estrogens, enabling them to bind to the estrogen receptor. When that happens, problems can occur.

In binding to the estrogen receptor, BPA can disrupt the body’s endocrine or hormone system, with consequences especially worrisome for fetuses, infants and young children. Earlier this year, the U.S. Food and Drug Administration banned BPA in baby bottles and sippy cups. Its use is more broadly banned elsewhere in the world.

In new research published in the October 4 online issue of the journal PLOS ONE,  two scientists at UC San Diego School of Medicine say three-dimensional modeling suggests a metabolite of BPA – a molecule produced when BPA is metabolized or broken down by the body – actually binds to the estrogen receptor much more strongly than BPA itself. The finding could point the way to development of a new class of drugs designed to specifically inhibit excessive estrogen activity linked to disease.

According to Michael E. Baker, PhD, UCSD professor of medicine, and Charlie Chandsawangbhuwana, a graduate student in the UCSD Department of Bioengineering, several research labs have reported that BPA binds weakly to the estrogen receptor, suggesting that something else is interacting with this receptor.

In 2004, Shin'ichi Yoshihara, PhD, and colleagues at Hiroshima International University, discovered that another compound, dubbed MBP, was produced when BPA was metabolized.  MBP has a 100-fold to 1,000-fold stronger bond to the estrogen receptor than BPA. However, the structural basis for MBP’s high affinity for the estrogen receptor was not investigated further.  

In their PLOS ONE study, Baker and Chandsawangbhuwana revived Yoshihara’s research by creating three-dimensional, molecular models of MBP and BPA in the estrogen receptor and matching it against the crystal structure of estradiol in the estrogen receptor. They found that MBP’s longer structure allows both ends of the chemical to interact with the estrogen receptor in a way similar to estradiol. The shorter BPA molecule contacts the receptor at just one end, resulting in a weaker connection, providing an explanation for BPA’s lower affinity for the estrogen receptor.

“In other words, MPB is basically grabbing onto the estrogen receptor with two hands compared to just one hand for BPA,” said Baker. “Two contact points makes a much stronger connection.”

Baker said the 3D modeling supports the idea “that BPA is not the endocrine disruptor culprit. Instead, MBP is one (of perhaps several BPA metabolites) that causes disruption of estrogen signaling in humans and other animals.”

He said the research points to the need to measure MBP levels in urine and blood of patients suspected of BPA-mediated health effects, and may fuel development of a new therapeutic treatment for conditions linked to excessive estrogen levels and activity, such as some forms of breast and prostate cancers.

“One could use MBP, which has a novel structure, as a template to develop a new class of chemicals that could bind to the estrogen receptor with high affinity,” Baker said. “The goal would be to have these chemicals inhibit the action of estradiol instead of activating the estrogen response. These chemicals could control unwanted growth of estrogen-dependent tumors.”

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

UC San Diego Sulpizio Cardiovascular Center has been named one of the nation’s 50 Top Cardiovascular Hospitals by Truven Health Analytics.  The Truven study examined the performance of more than 1,000 hospitals by analyzing outcomes for patients with heart failure and heart attacks and for those who received coronary bypass surgery and percutaneous coronary interventions such as angioplasties. This year’s winners were announced October 1 in Modern Healthcare magazine.

UC San Diego Sulpizio Cardiovascular Center is one of nation's top heart hospitals.

“This prestigious award recognizes UC San Diego Sulpizio Cardiovascular Center as one of the top heart hospitals in the United States based on the outstanding quality of our clinical care,” said Paul Viviano, CEO, UC San Diego Health System. “As the region’s only comprehensive cardiovascular center, we are dedicated to providing lifesaving cardiac care and research that makes a real difference in the lives of our patients locally and globally.”

UC San Diego Sulpizio Cardiovascular Center offers all the care you need, all in one place.

Truven Health Analytics researchers analyzed 2010 and 2011 Medicare Provider Analysis and Review (MedPAR) data, 2010 Medicare cost reports, and 2012 Centers for Medicare and Medicaid Services (CMS) Hospital Compare data. They scored hospitals in key performance areas: risk-adjusted mortality, risk-adjusted complications, core measures (a group of measures that assess process of care), percentage of coronary bypass patients with internal mammary artery use, 30-day mortality rates, 30-day readmission rates, severity-adjusted average length of stay, and wage- and severity-adjusted average cost. 

“This honor supports our mission of delivering to our patients, and exhibiting to our medical residents and fellows, the world’s best cardiovascular care,” said Kirk L. Peterson, MD, director, Sulpizio Cardiovascular Center and professor of Cardiology and Medicine at UC San Diego School of Medicine. “Led by highly accomplished cardiovascular experts and teachers, we offer a combination of advanced cardiac diagnostics, standard and novel treatments, and access to a number of clinical programs only available here.”

The study evaluated general and applicable specialty, short-term, acute care, non-federal U.S. hospitals treating a broad spectrum of cardiology patients.  Results show that cardiovascular outcomes in U.S. hospitals are improving nationwide. Across all U.S. hospitals, 96 percent of cardiovascular inpatients survive and remain complication-free. Among the 50 Top Hospitals, performance surpasses these high-water marks as indicated by:

• Better risk-adjusted survival rates (41 percent fewer deaths than expected, compared with 9 percent fewer than expected at peer hospitals) for bypass surgery patients.
• Lower complications indices (35 percent lower rate of heart failure complications than peers).
• Fewer patients readmitted to the hospital after 30 days.
• Shorter hospital stays. The typical winning hospital released their bypass patients a full day sooner, and their heart attack and heart failure patients about three-quarters of a day sooner than their peers. 
• Lower costs. Top hospitals spend $3,500 less per bypass case and $1,000 less per angioplasty than non-winners.

"This year’s 50 Top Cardiovascular Hospitals have proven that a commitment to deliver excellent care is still attainable in times of economic uncertainty," said Jean Chenoweth, senior vice president for performance improvement and the 100 Top Hospitals® program at Truven Health Analytics. “The hospitals in this study have achieved higher levels of care and efficiency than their peers, demonstrating incredibly strong focus by cardiologists, cardiovascular surgeons, and cardiovascular service administrators and staff on basic care and outcomes."

In February 2005, UC San Diego received a $10 million gift from Richard and Maria (Gaby) Sulpizio to help construct this state-of-the-art cardiovascular patient care and clinical research facility.  The $138 million project came in on budget and ahead of time.  The UC San Diego Sulpizio Cardiovascular Center is also the first hospital-based project in the region to receive LEED Gold certification from the United States Green Building Council (USGBC).  Sulpizio Cardiovascular Center has received Modern Healthcare’s highest design honor, the 2012 Modern Healthcare Design Award, and was ranked #10 on Soliant Health Care's annual list of top 20 most beautiful hospitals in the United States.

About UC San Diego Sulpizio Cardiovascular Center
UC San Diego Sulpizio Cardiovascular Center is dedicated to innovative care and the prevention, diagnosis and treatment of cardiovascular disease. The state-of-the-art facility, which opened in La Jolla in 2011, is the region’s first academic-based facility to combine all heart and vascular-related services, programs and technology under one roof. For more information, visit http://heartcenter.ucsd.edu

About Truven Health Analytics
Truven Health Analytics, formerly the Healthcare business of Thomson Reuters, delivers unbiased information, analytic tools, benchmarks, and services to the healthcare industry. Hospitals, government agencies, employers, health plans, clinicians, pharmaceutical, and medical device companies have relied on us for more than 30 years. We combine our deep clinical, financial, and healthcare management expertise with innovative technology platforms and information assets to make healthcare better by collaborating with our customers to uncover and realize opportunities for improving quality, efficiency, and outcomes. With more than 2,000 employees globally, we have major offices in Ann Arbor, Mich.; Chicago; and Denver. Advantage Suite, Micromedex, ActionOI, MarketScan, and 100 Top Hospitals are registered trademarks or trademarks of Truven Health Analytics.  For more information, please visit www.truvenhealth.com

How tumors exploit microflora and immune cells to fuel growth

Researchers at the University of California, San Diego School of Medicine report the discovery of microbial–dependent mechanisms through which some cancers mount an inflammatory response that fuels their development and growth.

The findings are published in the October 3, 2012 Advanced Online Edition of Nature.

Mouse colorectal tumors display inflammatory infiltration by macrophages (green) and activated stromal cells (red). The question of why and how tumors recruit immune cells remains unknown.

The association between chronic inflammation and tumor development has long been known from the early work of German pathologist Rudolph Virchow. Harvard University pathologist Harold Dvorak later compared tumors with “wounds that never heal,” noting the similarities between normal inflammation processes that characterize wound- healing and tumorigenesis or tumor-formation.

Indeed, 15 to 20 percent of all cancers are preceded by chronic inflammation – a persistent immune response that can target both diseased and healthy tissues. Chronic hepatitis, for example, may result in hepatocellular carcinoma (liver cancer) and inflammatory bowel disease can eventually cause a form of colon cancer, known as colitis-associated cancer.

Still, most cancers are not preceded by chronic inflammation. On the other hand, they exploit ubiquitous, infiltrating immune cells to unduly provoke and hijack the host inflammatory reaction. Until now, the mechanism of so-called “tumor-elicited inflammation,” which is detected in most solid malignancies, was poorly explained.

“The tumor-associated inflammatory reaction is an emerging and vibrant field for biomedical studies. It may hold the keys for future preventive and therapeutic measures,” said first author Sergei Grivennikov, PhD, noting that studies of long-term users of non-steroidal anti-inflammatory drugs, such as aspirin, have revealed that general inhibition of inflammation reduces the risk of cancer death by up to 45 percent, depending on the type of cancer. “So inhibition of inflammation during cancer development may be beneficial.”

Studying early colonic tumors in humans and in animal models, the researchers, led by principal investigator Michael Karin, PhD, Distinguished Professor of Pharmacology and head of the Laboratory of Gene Regulation and Signal Transduction at UC San Diego, found that developing tumors disrupt tissue homeostasis (the normal, healthy functioning of tissues), in part because they lack a particular protective protein coating and a tight seal between their epithelial cells – a basic cell type that covers most internal surfaces and organs. Without that coating and the cellular seal, ordinarily benign, commensal bacteria present in the colon can enter the tumor to be recognized by immune cells as invaders, launching an inflammatory reaction.

In addition, said Grivennikov, who is a scientist in Karin’s lab, “cell-to-cell contacts are defective in tumors, further allowing entry of microbial products from the intestinal lumen into the tumor. These microbial products are recognized by tumor-associated macrophages and dendritic cells, which are normally isolated from commensal microflora by the intestinal barrier.”

In response, the immune cells produce signaling proteins called cytokines that further spur the inflammatory process. Chief among these is a cytokine called Interleukin-23, which regulates tumor-elicited inflammation and triggers the production of other inflammatory cytokines that promote tumor development and progression.

Grivennikov said that when researchers reduced the presence of commensal microflora through a combination of broad spectrum antibiotics, tumor-elicited inflammation and tumor growth were dampened.

“This is a very nice demonstration of how tumor-elicited inflammation in cancers that arise in the absence of underlying chronic inflammatory disease can be induced,” he said. “The next step is to look for the upregulation of Interleukin-23 and related cytokines in colon cancer patients, inhibit these cytokines and determine whether these impact cancer progression and response to therapy.”

Funding for this research came, in part, from the Crohn’s and Colitis Foundation of America, National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant K99-DK088589; UCSD DDRDC Pilot Grant DK080506; the Croucher Foundation and China Postdoctoral Science Foundation; the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation; SPAR Austria; National Institutes of Health grants R01CA082223, A1043477 and DK035108 and the American Association for Cancer Research.

Co-authors include Kepeng Wang, UCSD Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology and the Biomedical Research Institute, Shenzhen-PKU-HKUST Medical Center, China; Daniel Mucida, La Jolla Institute for Allergy and Immunology and the Laboratory of Mucosal Immunology, The Rockefeller University, New York; C. Andrew Stewart, Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health; Bernd Schnabl, UCSD Department of Medicine, School of Medicine; Dominik Jauch and Guann-Yi Yu, UCSD Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Pathology; Koji Taniguchi, UCSD Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and
Pathology and Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo; Christoph H. Österreicher, UCSD Department of Medicine, School of Medicine and Institute of Pharmacology, Center for Physiology and Pharmacology Medical University of Vienna, Austria; Kenneth E. Hung, Department of Medicine, Tufts Medical Center, Boston; Christian Datz, Department of Internal Medicine, Oberndorf Hospital, Paracelsus Medical University Salzburg, Austria; Ying Feng and Eric R. Fearon, Departments of Internal Medicine, Human Genetics and Pathology, University of Michigan Medical School; Mohamed Oukka, Seattle Children’s Research Institute, Washington; Lino Tessarollo, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health; Vincenzo Coppola, Department of MVIMG, Ohio State University-CCC, Wexner Medical Center; Felix Yarovinsky, Department of Immunology, University of Texas Southwestern Medical Center; Hilde Cheroutre, La Jolla Institute for Allergy and Immunology;  Lars Eckmann, UCSD Department of Medicine, School of Medicine; and Giorgio Trinchieri, Cancer and Inflammation Program, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Two proteins previously found to contribute to ALS, also known as Lou Gehrig’s disease, have divergent roles.  But a new study, led by researchers at the Department of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine, shows that a common pathway links them.

Gene Yeo, PhD

The discovery reveals a small set of target genes that could be used to measure the health of motor neurons, and provides a useful tool for development of new pharmaceuticals to treat the devastating disorder, which currently has no treatment or cure.

Funded in part by the National Institutes of Health and the California Institute for Regenerative Medicine (CIRM), the study will be published in the advance online edition of Nature Neuroscience on September 30.

ALS is an adult-onset neurodegenerative disorder characterized by premature degeneration of motor neurons, resulting in a progressive, fatal paralysis in patients.

The two proteins that contribute to the disease – FUS/TLS and TDP-43 – bind to ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins. In normal cells, both TDP-43 and FUS/TLS are found in the nucleus where they help maintain proper levels of RNA. In the majority of ALS patients, however, these proteins instead accumulate in the cell’s cytoplasm – the liquid that separates the nucleus from the outer membrane, and thus are excluded from the nucleus, which prevents them from performing their normal duties.

Since the proteins are in the wrong location in the cell, they are unable to perform their normal function, according to the study’s lead authors, Kasey R. Hutt, Clotilde Lagier-Tourenne and Magdalini Polymenidou. “In diseased motor neurons where TDP-43 is cleared from the nucleus and forms cytoplasmic aggregates,” the authors wrote, “we saw lower protein levels of three genes regulated by TDP-43 and FUS/TLS.   We predicted that this, based on our mouse studies, and found the same results in neurons derived from human embryonic stem cells.”

In 2011, this team of UC San Diego scientists discovered that more than one-third of the genes in the brains of mice are direct targets of TDP-43, affecting the functions of these genes.  In the new study, they compared the impact of the FUS/TLS protein to that of TDP-43, hoping to find a large target overlap.

“Surprisingly, instead we saw a relatively small overlap, and the common RNA targets genes contained exceptionally long introns, or non-coding segments.  The set is comprised of genes that are important for synapse function,” said principal investigator Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine at UC San Diego and a visiting professor at the Molecular Engineering Laboratory in Singapore. “Loss of this common overlapping set of genes is evidence of a common pathway that appears to contribute to motor neuron degeneration.”

In an effort to understand the normal function of these two RNA binding proteins, the scientists knocked down the proteins in brains of mice to mimic nuclear clearance, using antisense oligonucleotide technology developed in collaboration with ISIS Pharmaceuticals.  The study resulted in a list of genes that are up or down regulated, and the researchers duplicated the findings in human cells. 

“If we can somehow rescue the genes from down regulation, or being decreased by these proteins, it could point to a drug target for ALS to slow or halt degeneration of the motor neurons,” said Yeo.

These proteins also look to be a central component in other neurodegenerative conditions. For example, accumulating abnormal TDP-43 and FUS/TLS in neuronal cytoplasm has been documented in frontotemporal lobar dementia, a neurological disorder that has been shown to be genetically and clinically linked to ALS, and which is the second most frequent cause of dementia after Alzheimer’s disease. 

The team was led by Gene Yeo, PhD and Don W. Cleveland, PhD, professor and chair of the UCSD Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research. Additional contributors include Anthony Q. Vu, Michael Baughn, Stephanie C. Huelga, Kevin M. Clutario, Shuo-Chien Ling, Tiffany Y. Liang and John Ravits, UC San Diego; Curt Mazur, Edward Wancewicz, Aneeza S. Kim, Andy Watt, Sue Freier and Frank Bennett, Isis Pharmaceuticals, Carlsbad, CA; Geoffrey G. Hicks, University of Manitoba, Winnipeg, Canada; and John Paul Donohue and Lily Shiue, UC Santa Cruz.

This work was supported by grants from the US National Institutes of Health (R37NS27036 to Cleveland and K99NS075216 to Polymenidou).  Polymenidou is the recipient of a long-term fellowship from the international Human Frontier Science Program Organization. Lagier-Tourenne is the recipient of a Career Development Award from the Muscular Dystrophy Association and the Milton-Safenowitz post-doctoral fellowship from the Amyotrophic Lateral Sclerosis Association. D.W.C. receives salary support from the Ludwig Institute for Cancer Research.  Huelga is funded by a US National Science Foundation Graduate Research Fellowship. This work was also supported by grant number R01NS075449 from the US National Institute of Neurological Disorders and Stroke, and was partially supported by grants from the US National Institutes of Health (HG004659 and GM084317) and the California Institute for Regenerative Medicine (RB1-01413 and RB3-05009) to Yeo. Yeo is a recipient of the Alfred P. Sloan Research Fellowship.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

NCI funding continues work focused on chronic lymphocytic leukemia  

An international consortium of scientists studying chronic lymphocytic leukemia (CLL), based at the University of California, San Diego School of Medicine, has been awarded a 5-year, $20 million grant by the National Cancer Institute, part of the National Institutes of Health. The grant is the second renewal of funding for a broad-based effort designed to better understand the pathology of CLL – the most common form of leukemia in the Western world – and develop new drugs and treatments.

Magnified blood smear showing darker CLL cells.

“This funding allows us to continue critical research that has already produced substantial, new insights into how and why CLL develops and progresses differently in patients,” said Thomas J. Kipps, MD, PhD, professor of medicine in the UCSD School of Medicine, deputy director of research at UC San Diego Moores Cancer Center and director of the Chronic Lymphocytic Leukemia Research Consortium (CRC). “Our work has revealed new targets and approaches for both mitigating the disease and perhaps eventually preventing it.”

The CRC consists of eight diverse institutions: UC San Diego, The Sanford-Burnham Medical Research Institute, the Mayo Clinic, Ohio State University, the Dana-Farber Cancer Institute at Harvard Medical School, the University of Texas M.D. Anderson Cancer Center, the North Shore-Long Island Jewish Health System and the BARTS and London Cancer Centre in England. Under the auspices of veteran CLL scientists, researchers and doctors in the CRC have created distinct projects addressing different aspects of the disease. Among them:

• The genetic basis for CLL and how genes change as the disease progresses
• The resistance of CLL cells to apoptosis or programmed cell death, a trait that makes them less susceptible to chemotherapy
• The potential of immunotherapy – using the body’s natural immune system to reject cancer – to halt and reverse CLL
• Repairing defective immune cells to maximize immunological response to mutations
• Development of new anticancer agents that either inhibit development of CLL or render the surrounding microenvironment inhospitable to cancer cells

CLL is a particularly confounding challenge. It is a blood cancer characterized by the accumulation of abnormal, dysfunctional lymphocytes (a type of white blood cell) in the blood and bone marrow. As these lymphocytes swell in number, they interfere with normal body functions, including disabling of the immune system.

Prevalence of CLL in the United States is high: 1 in 20 people over the age of 40 may have apparently pre-cancerous CLL-like cells in their blood. These people may develop actual CLL at a rate of about 1 percent per year. More than 15,000 new cases of CLL are diagnosed each year in the United States. Roughly 4,400 patients with CLL die annually.

The condition is most often diagnosed in elderly patients, usually from a standard blood test. The course of the disease can vary dramatically with each individual. In some patients, CLL develops very slowly with no obvious symptoms for many years. In others, it is much more rapid, requiring quicker medical intervention.

Currently, there is no cure and existing treatments frequently involve adverse, even life-threatening, side effects, prompting doctors to often delay aggressive treatment until absolutely necessary.

Though a blood cancer, Kipps said CLL research may have implications for understanding and treating of solid tumor cancers, such as breast and ovary. For example, researchers have found that tumor suppressor genes in CLL appear to play a similar role in solid tumor cancers. Also, CLL does not require access to often hard-to-reach tumors. It can be studied with a simple blood draw, over time in the same patient. The lessons learned may have broader application.

“For more than a decade, the CRC has brought together scientists and institutions to focus completely on CLL, people and places that might otherwise not be able to collaborate,” Kipps said. “In that time, we’ve made real advances, both at the bench and at the bedside. We’ve got a long way to go. CLL is a tough disease. But this grant means we’ll be able to continue pushing forward.”

The NCI grant runs through August 2017, and totals $19,527,174.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Atherosclerosis – the hardening of arteries that is a primary cause of cardiovascular disease and death – has long been presumed to be the fateful consequence of complicated interactions between overabundant cholesterol and resulting inflammation in the heart and blood vessels.

However, researchers at the University of California, San Diego School of Medicine, with colleagues at institutions across the country, say the relationship is not exactly what it appears, and that a precursor to cholesterol actually suppresses inflammatory response genes. This precursor molecule could provide a new target for drugs designed to treat atherosclerosis, which kills tens of thousands of Americans annually.

The findings are published in the September 28, 2012 issue of Cell.

When macrophages take up massive amounts of cholesterol they form “foam cells,” characterized by multiple lipid droplets (stained red). Image courtesy of Marten Hoeksema, University of Amsterdam.

Lurking within our arterial walls are immune system cells called macrophages (Greek for “big eater”) whose essential function is to consume other cells or matter identified as foreign or dangerous. “When they do that, it means they consume the other cell’s store of cholesterol,” said Christopher Glass, MD, PhD, a professor in the Departments of Medicine and Cellular and Molecular Medicine and senior author of the Cell study.  “As a result, they’ve developed very effective ways to metabolize the excess cholesterol and get rid of it.”

But some macrophages fail to properly dispose of the excess cholesterol, allowing it to instead accumulate inside them as foamy lipid (fat) droplets, which gives the cells their particular name: macrophage foam cells.  

These foam macrophages produce molecules that summon other immune cells and release molecules, signaling certain genes to launch an inflammatory response. Glass said conventional wisdom has long assumed atherosclerotic lesions – clumps of fat-laden foam cells massed within arterial walls – were the unhealthy consequence of an escalating association between unregulated cholesterol accumulation and inflammation.

Glass and colleagues wanted to know exactly how cholesterol accumulation led to inflammation, and why the macrophages failed to do their job. Using specialized mouse models that produced abundant macrophage foam cells, they made two unexpected discoveries that upend previous assumptions about how lesions form and how atherosclerosis might be more effectively treated.

“The first is that foam cell formation suppressed activation of genes that promote inflammation. That’s exactly the opposite of what we thought happened,” said Glass. “Second, we identified a molecule that helps normal macrophages manage cholesterol balance. When it’s in abundance, it turns on cellular pathways to get rid of cholesterol and turns off pathways for producing more cholesterol.”

That molecule is desmosterol – the final precursor in the production of cholesterol, which cells make and use as a structural component of their membranes. In atherosclerotic lesions, Glass said the normal function of desmosterol appears to be “crippled.”

“That’s the next thing to study; why that happens,” Glass said, hypothesizing that the cause may be linked to overwhelming, pro-inflammatory signals coming from proteins called Toll-like receptors on macrophages and other cells that, like macrophages, are critical elements of the immune system.

The identification of desmosterol’s ability to reduce macrophage cholesterol presents researchers and drug developers with a potential new target for reducing the risk of atherosclerosis.

Glass noted that a synthetic molecule similar to desmosterol already exists, offering an immediate test-case for new studies. In addition, scientists in the 1950s developed a drug called triparanol that inhibited cholesterol production, effectively boosting desmosterol levels. The drug was sold as a heart disease medication, but later discovered to cause severe side effects, including blindness from an unusual form of cataracts. It was pulled from the market and abandoned.

“We’ve learned a lot in 50 years,” said Glass. “Maybe there’s a way now to create a new drug that mimics the cholesterol inhibition without the side effects.” 

Co-authors are first author Nathanael J. Spann, Norihito Shibata, Donna Reichart, Jesse N. Fox and Daniel Heudobler, UCSD Department of Cellular and Molecular Medicine; Lana X. Garmire, UCSD Department of Bioengineering; Jeffrey G. McDonald and David W. Russell, Department of Molecular Genetics, UT Southwestern Medical Center; David S. Myers, Stephen B. Milne and Alex Brown, Department of Pharmacology, Vanderbilt Institute of Chemical Biology; Iftach Shaked and Klaus Ley, La Jolla Institute of Allergy and Immunology; Christian R.H. Raetz, Department of Biochemistry, Duke University School of Medicine; Elaine W. Wang, Samuel L. Kelly, M. Cameron Sullards and  Alfred H. Merrill, Jr., Schools of Biology, Chemistry and Biochemistry and the Parker H. Petit Institute of Bioengineering and Bioscience, George Institute of Technology; Edward A. Dennis, UCSD Department of Chemistry and Biochemistry; Andrew C. Li, Sotirios Tsimikas and Oswald Quehenberger, UCSD Department of Medicine; Eoin Fahy, UCSD Department of Bioengineering; and Shankar Subramaniam, UCSD Departments of Cellular and Molecular Medicine, Bioengineering and Chemistry and Biochemistry.

Funding for this research came, in part, from National Institutes of Health grants GM U54069338 (to the LIPID MAPS Consortium), P01 HC088093 and P01 DK074868.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Researchers at the University of California, San Diego School of Medicine have found that recovery from an emerging, minimally invasive surgical technique called Laparo-Endoscopic Single-Site Surgery (LESS) was less painful for kidney cancer patients than traditional laparoscopic surgery. Study results were published in the September online edition of Urology.

Ithaar Derweesh, MD, is an expert in minimally invasive surgery.

“In the largest prospective study of kidney cancer patients to date, the UC San Diego study showed less use of narcotic pain medication and lower pain scores upon hospital discharge,” said Ithaar Derweesh, MD, senior author and urologic oncologist at UC San Diego Moores Cancer Center. “For patients and surgeons, this research shows that reducing the number of incisions to one confers benefits beyond fewer scars.”

Led by Derweesh, the study compared single-site laparoscopy, also known as LESS, and traditional multiport laparoscopy in a total of 74 patients needing either complete or partial removal of the kidney for malignancy. LESS was performed with one small incision in the umbilicus through which all tools were inserted to reach the tumor. The patients undergoing traditional laparoscopy underwent four to six incisions.

After surgery, surgeons used the visual analog pain (VAP) test to establish a patient’s comfort level. The test is composed of simple line drawings of the human face. One end of the scale shows a smile and “no hurt,” the opposite end expresses tears and “hurts worst.”

“We found that patients rated the LESS surgery as 40 percent less painful than traditional laparoscopic surgery, while requiring approximately 50 percent less narcotic pain medication,” said Derweesh. “This is an excellent sign that the LESS technique may further improve the quality of life of appropriate patients undergoing major cancer surgery.”

The incidence of renal cell carcinoma is increasing worldwide. In the United States, kidney cancer is the most lethal of the commonly diagnosed urologic malignancies, diagnosed in more than 64,000 Americans every year.  According to the American Cancer Society, kidney cancer is increasing at a rate of two to three percent each year in the U.S.

Additional contributors to this paper include Wassim M. Bazzi, Sean P. Stroup, Ryan P. Kopp, Seth A. Cohen, and Kyoko Sakamoto from the UC San Diego School of Medicine.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Researchers at University of California, San Diego Moores Cancer Center are evaluating the safety and tolerability of a synthetic cannabinoid called dexanabinol (ETS2101). Delivered as a weekly intravenous infusion, the drug is being tested in patients with all forms of brain cancer, both primary and metastatic.

Santosh Kesari, MD, PhD, neuro-oncologist, UC San Diego Moores Cancer Center.

“In this Phase I study, we are examining the safety of multiple doses of dexanabinol, extent of penetration into the brain, and suitability for future trials,” said Santosh Kesari, MD, PhD, principal investigator, and director of neuro-oncology, UC San Diego Moores Cancer Center. “What we hope to determine is the safe and optimal dose of drug in the brain.”

Dexanabinol is a cannabinoid derivative that causes no psychotropic effects. It was tested previously as a neuroprotective in patients with traumatic brain injury. During these trials the drug was found to cross the blood-brain barrier.  More recently, researchers at e-Therapeutics plc, who are supporting the current trial, showed that dexanabinol kills cultured cancer cells derived from many tumor types. Additional research in Kesari’s lab demonstrated the drug’s anti-cancer effects in patient-derived brain cancer cell lines.

Dexanabinol’s potential in fighting cancer was identified through a new approach to drug discovery called network pharmacology, a way to analyze the network of proteins underlying a disease process. Network pharmacology enables scientists to seek drugs from among existing compounds, or design new molecules, that act simultaneously on a number of individual proteins to disrupt the cancer-related networks.

Kesari added that this trial fits well with a broader national effort to re-purpose existing drugs for the treatment of cancer. He asked, “Why not use drugs that are currently available and learn how they can be applied in new effective ways for different indications?”

Dexanabinol is thought to act on proteins including NFĸB, TNFα, COX-2 HAT, FAT and cyclin-dependent kinases. The trial at UCSD Moores Cancer Center is one of two ongoing Phase I studies with dexanabinol, and the first to evaluate the drug in cancer patients.

“In time, we will explore the association between the molecular phenotype of the tumor and the patient’s response, which may allow us to personalize future therapies,” said Kesari, associate professor, Department of Neurosciences at UC San Diego School of Medicine.

Patients who are eligible for this trial must have failed prior therapy including surgical resection, radiation therapy and systemic therapy.

Questions about this clinical trial may be directed to 858-822-6346.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

The region’s only comprehensive cardiovascular facility receives 2012 Modern Healthcare Award

UC San Diego Sulpizio Family Cardiovascular Center has received Modern Healthcare’s highest design honor, the 2012 Modern Healthcare Design Award.  Out of more than one hundred entries, only one other project received this honor in 2012. 

UC San Diego Sulpizio Cardiovascular Center awarded for design by Modern Healthcare.

“We are honored to receive this prestigious recognition,” said Lisa Murphy, Associate Administrator for UC San Diego Health System, who shepherded the project from design to completion.  “UC San Diego Sulpizio Cardiovascular Center was a project built by an exceptional team of physicians, architects and construction workers with a shared vision for world class heart care.  It’s exhilarating to know that the physical manifestation of that vision resonated with leading national designers.”

These prestigious awards known to the world-wide architecture community recognize excellence in the design and planning of new and remodeled healthcare facilities by registered architects.  "Effective healthcare design serves the needs of patients, caregivers, communities and the environment," said David Burda, editor of Modern Healthcare. "How well the designs serve those four stakeholders is central to our annual Design Awards competition."

The 128,000-square-foot facility is the first dedicated cardiovascular center in the San Diego region. It is situated to maximize views of the La Jolla surroundings and to capture natural light into each department.  The state-of-the-art facility provides an integrated platform for research, teaching, and care-giving, all under one roof. 

“UC San Diego Sulpizio Cardiovascular Center is a unique project that truly captures the spirit of collaboration,” said Jacky Yung, AIA, LEED AP, principal at RTKL Associates, Inc.  “The success of delivering a world class facility that provides a new standard of healthcare, a sustainable building design leading to the LEED Gold certification, and now being awarded for design excellence are all due to the sophisticated planning and execution by the High Performance Team (HPT).  RTKL is so fortunate to be part of this journey, delivering the first cardiovascular center in the region serving this special community.”

“Building UC San Diego Sulpizio Cardiovascular Center represents an ongoing transformation of our La Jolla campus,” said David Brenner, MD, vice chancellor for UC San Diego Health Sciences and dean of UC San Diego School of Medicine.  “Along with Shiley Eye Center, Moores Cancer Center and Thornton Hospital, Sulpizio Cardiovascular Center sets the standard for care locally and globally.”

The LEED Gold-certified facility takes full advantage of the movement of the sun with shading devices and massing elements to minimize heat gain and reduce energy consumption.  The design also embraces the idea of blurring the lines between interior and exterior regions, to provide the facility with a “natural” feel that picks up on the stunning geography of the nearby coastal canyons.  The end product is a state-of-the-art facility with the latest technology promoting a collaborative approach to care in a high-tech, high-touch building design with a strong, independent identity that closely relates back to the existing hospital.

In February 2005, UC San Diego received a $10 million gift from Richard and Maria (Gaby) Sulpizio to help construct this state-of-the-art cardiovascular patient care and clinical research facility.  The $138 million project came in on budget and ahead of time.

For more information about the awards: www.modernhealthcare.com/designawards; For more information about UC San Diego Sulpizio Cardiovascular Center: www.health.ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Recognized by Medicare as Heart-Lung Transplant “Center of Excellence”

UC San Diego’s Center for Transplantation has met or exceeded all of its necessary requirements for approval as a center of excellence under the Federal Medicare program.  This approval – from the Center for Medicare and Medicaid Services (CMS) – allows UC San Diego Health System to accept into its program potential cardiac transplant patients covered by Medicare. 

“This will open our doors even wider to qualifying patients who deserve a second chance at life” said Jack Copeland, MD, surgical director, Heart Transplantation and Mechanical Assist Devices UC San Diego Health System.

Eric Adler, MD, medical director, Heart Transplantation and Mechanical Assist Devices, added that the health system now offers comprehensive Medicare-approved organ transplant and mechanical heart assist services including kidney, pancreas, liver, heart, lung transplant, Heartmate II and Total Artificial Heart mechanical assist devices.

“Heart and heart-lung transplantation is a vital part of our continuing commitment to providing comprehensive cardiothoracic care – all under one roof in San Diego’s only dedicated cardiovascular center,” said Stuart Jamieson, MB, chief of cardiothoracic surgery and director of cardiothoracic transplantation.  “The team of thought leaders we have assembled in this area is second-to-none and brings California the level of expertise and care it deserves.”

The UC San Diego Health System heart transplant program began in 1989 under the direction of Jamieson, Distinguished Professor of Surgery at UC San Diego School of Medicine, who performed the hospital’s first heart transplant in 1990.  The comprehensive program also offers one of the most sought after lung transplant programs on the West Coast.  Both programs are based at UC San Diego Sulpizio Cardiovascular Center, the region’s first and only award-winning facility dedicated strictly to heart and lung care.

“This recent certification is not limited to the cardiothoracic transplant program,” explained Alexander Aussi, transplant services administrator, UC San Diego Health System.  “Our mechanical heart assist device program will benefit significantly since Medicare patients will now qualify from mechanical heart assist device support as a bridge to transplantation.”

The facility’s mechanical heart assist device program was independently certified by The Joint Commission (TJC), an independent accreditation body which certifies health care organizations, in November 2011. 

An updated list of CMS approved heart and heart/lung transplant programs is available at:
http://www.cms.gov/Medicare/Provider-Enrollment-and-Certification/CertificationandComplianc/downloads/ApprovedTransplantPrograms.pdf

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Inflammation is the hallmark of many human diseases, from infection to neurodegeneration.  The chemical balance within a tissue is disturbed, resulting in the accumulation of reactive oxygen species (ROS) such as hydrogen peroxide, which can cause oxidative stress and associated toxic effects.  

Adah Almutairi, PhD

Although some ROS are important in cell signaling and the body’s defense mechanisms, these chemicals also contribute to and are indicators of many diseases, including cardiovascular dysfunction.  A non-invasive way of detecting measurable, low levels of hydrogen peroxide and other ROS would provide a viable way to detect inflammation. Such a method would also provide a way to selectively deliver drugs to their targets. 

Adah Almutairi, PhD, associate professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences, the Department of NanoEngineering, and the Materials Science and Engineering Program at the University of California, San Diego, and colleagues have developed the first degradable polymer that is extremely sensitive to low but biologically relevant concentrations of hydrogen peroxide.  

Their work is currently published in the online issue of the Journal of the American Chemical Society.

These polymeric capsules, or nanoparticles, are taken up by macrophages and neutrophils – immune system cells that rush to the site of inflammation.  The nanoparticles then release their contents when they degrade in the presence of hydrogen peroxide produced by these cells.

“This is the first example of a biocompatible way to respond to oxidative stress and inflammation,” said Almutairi, director of the UC San Diego Laboratory of Bioresponsive Materials. “Because the capsules are tailored to biodegrade and release their cargo when encountering hydrogen peroxide, they may allow for targeted drug delivery to diseased tissue.”

Almutairi is looking to test this method in a model of atherosclerosis. “Cardiologists have long needed a non-invasive method to determine which patients are vulnerable to a heart attack caused by ruptured plaque in the arteries before the attack,” she said.  “Since the most dangerous of plaques is inflamed, our system could provide a safe way to detect and treat this disease.”

Additional contributors to the study include Caroline de Gracia Lux, Shivanjali Joshi-Barr, Trung Nguyen, Enas Mahmoud, Eric Schopf and Nadezda Fomina.

This research was supported by the NIH Director’s New Innovator Award (1DP2OD006499-0) and a King Abdulaziz City for Science and Technology center grant to the Center of Excellence in Nanomedicine at UC San Diego.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

“My Answer to Cancer” will analyze patient tumor DNA to individualize cancer care

UC San Diego Moores Cancer Center launched a bold plan today aimed at personalizing cancer treatment.  The “My Answer to Cancer” team of oncologists, bioinformaticians, pathologists and geneticists pledges to “sequence” or analyze the DNA of large numbers of patients with cancer in order to match each patient to the best available drug for his or her particular tumor. There will be two parallel approaches: a research approach to discover new mutations that cause cancer and a patient-care approach that will use confirmed mutations and other DNA abnormalities to direct patients to clinical studies of agents targeting these abnormalities.

“No two cancers are alike, just as no two people are exactly alike,” said Barbara Parker, MD, medical director of oncology services at UC San Diego Moores Cancer Center. “Recent advances have made it possible to generate a profile of the DNA abnormalities in a tumor.  With this information, we can identify profiles that will allow us to tailor cancer treatments to individual patients. This approach will open a new world of cancer treatment with  ‘targeted agents’ and could lead to significantly better therapies. Additionally, this research approach will identify new tumor DNA profile abnormalities that could lead to the development of new drugs and new combinations of drugs.”

A project of this scope depends on strong community support. UC San Diego Moores Cancer Center is calling on people living in San Diego County and beyond to help raise an initial $5 million for this effort.  Donors will receive regular updates on medical breakthroughs, the number of patients treated, the number of community members joining in the project, and the amount of money raised, in addition to expert interviews. 

“A hundred experts, thousands of patients, a million hopes – that’s our goal,” explained Scott Lippman, MD, director of UC San Diego Moores Cancer Center.  “We are taking this very personally and inviting everyone to get involved, from our staff and experts, to our patients and donors.”

How It Works:
UC San Diego Moores Cancer Center will use state-of-the-art technology to analyze the tumor DNA of large numbers of cancer patients.  Based on these analyses, Moores experts will construct a comprehensive data analysis model of clinical and biological data, which will be used to predict the effects of treatment on tumors with each particular DNA profile. Based on this model’s predictions, patients will be offered available clinical trials that match their individual tumors to the best targeted agents for them. These clinical studies offer hope for improved treatments with fewer side effects. For more information, visit the My Answer to Cancer website at http://myanswertocancer.ucsd.edu

UC San Diego Moores Cancer Center
UC San Diego Moores Cancer Center is home to nearly 350 medical and radiation oncologists, cancer surgeons, and researchers. It is one of only 41 National Cancer Institute‒designated comprehensive cancer centers in the country, a rare honor distinguishing exceptionally high achievement in research, clinical care, education and community outreach and partnerships. For more information, visit www.cancer.ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

122 UCSD Physicians Named Best Doctors in San Diego Region

More than one hundred physicians from University of California, San Diego Health System were named “Top Docs” in the 2012 San Diego Magazine “Physicians of Exceptional Excellence” annual survey. These physicians represent 35 specialties from internal medicine to oncology, obstetrics, cardiovascular and surgical care.

“As the region’s only academic health system, we offer a wide array of complex specialties to treat the diverse needs of our patients,” said Paul Viviano, CEO, UC San Diego Health System. “The majority of our doctors are national experts who strive to develop compassionate, lifesaving treatments, even cures, based on their unique roles as both clinicians and scientists.”

The “Top Docs” are named each year by physician peers who are members of the San Diego County Medical Society. Members are asked to vote for board-certified physicians practicing in San Diego County to whom they would refer their own patients and family members. This year, 122 physicians were ranked “tops” in 35 specialties. Four physicians within this group rank in more than one area.

“UC San Diego Health System physicians are not only taking care of today’s patients, but also educating tomorrow’s doctors and health care experts,” explained David Brenner, MD, vice chancellor of UC San Diego Health Sciences and dean of UC San Diego School of Medicine.  “To be recognized by our colleagues demonstrates to our patients, and the greater health care community, that our physicians truly deserve to be recommended as the best.” 

To learn more about our “Top Docs,” please visit: http://doctors.ucsd.edu/?groups=17 or www.health.ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Roger Tsien, PhD, professor of pharmacology, chemistry and biochemistry at the University of California, San Diego School of Medicine who shared the 2008 Nobel Prize in chemistry for his role in helping develop and expand the use of green fluorescent proteins (GFP) was honored today with one of the first-ever  “Golden Goose Awards.”

Roger Tsien, PhD

Eight inaugural Golden Goose recipients were honored today at a Capitol Hill ceremony in Washington, D.C. The award was conceived by U.S. Representative Jim Cooper (D-Tenn) to celebrate scientists “whose research was funded by the federal government and benefited society in some important way, such as a new technology or an advance in health, but which seemed odd or obscure at the time it was conducted, or led to that benefit unexpectedly or serendipitously.” It is supported by several notable scientific and educational organizations, among them the American Association for the Advancement of Science, the Association of American Universities and the Progressive Policy Institute.

Tsien was joined by Martin Chalfie and Osamu Shimomura, who shared the 2008 chemistry Prize; Charles Townes, who received the 1964 Nobel Prize in physics for his research leading to the invention of laser technology; and Eugene White, Rodney White and Della Roy, whose study of tropical coral led to the development of new bone grafting materials.

Tsien, a Howard Hughes Medical Institute investigator, Chalfie, a molecular biologist at Columbia University and Shimomura, a professor emeritus at the Marine Biological Laboratory in Woods Hole, Mass, gained international acclaim in 2008 for their studies explaining and expanding the use of GFPs – glowing proteins that researchers now broadly use to peer inside living cells or whole animals, watch molecules interact in real-time and ask questions once thought impossible.

“Our work is often described as building and training molecular spies,” Tsien explained in 2008. “Molecules enter a cell or organism and report back to us what the conditions are, what’s going on with the biochemistry, while the cell is still alive.”

Tsien continues to develop and deepen the beneficial uses of GFPs. Last year, for example, he and colleague Quyen T. Nguyen, MD, assistant professor of head and neck surgery at the UC San Diego School of Medicine, showed in animal models how injectable fluorescent peptides could be used to highlight hard-to-see peripheral nerves, allowing surgeons to avoid them when removing or repairing other tissues.

About the Golden Goose Award
The purpose of the award is to highlight the human and economic benefits of federally funded but perhaps obscure or seemingly odd research that has resulted in major scientific advances and social benefit. Nominees must have received a federally funded research grant within the past 60 years from agencies such as the National Institutes of Health, the National Science Foundation or the Departments of Defense, Agriculture or Energy. Recipients are chosen by a partnership of the award’s founding universities, think tanks, and businesses. Awards will be announced three to four times a year, with an annual ceremony in Washington, D.C. For more information, see www.goldengooseaward.org.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

New relay circuits, formed across sites of complete spinal transaction, result in functional recovery in rats

In a study at the University of California, San Diego and VA San Diego Healthcare, researchers were able to regenerate “an astonishing degree” of axonal growth at the site of severe spinal cord injury in rats.  Their research revealed that early stage neurons have the ability to survive and extend axons to form new, functional neuronal relays across an injury site in the adult central nervous system (CNS). 

The study also proved that at least some types of adult CNS axons can overcome a normally inhibitory growth environment to grow over long distances.  Importantly, stem cells across species exhibit these properties. The work will be published in the journal Cell on September 14.

The scientists embedded neural stem cells in a matrix of fibrin (a protein key to blood clotting that is already used in human neuron procedures), mixed with growth factors to form a gel.  The gel was then applied to the injury site in rats with completely severed spinal cords.

“Using this method, after six weeks, the number of axons emerging from the injury site exceeded by 200-fold what had ever been seen before,” said Mark Tuszynski, MD, PhD, professor in the UC San Diego Department of Neurosciences and director of the UCSD Center for Neural Repair, who headed the study. “The axons also grew 10 times the length of axons in any previous study and, importantly, the regeneration of these axons resulted in significant functional improvement.”

In addition, adult cells above the injury site regenerated into the neural stem cells, establishing a new relay circuit that could be measured electrically. “By stimulating the spinal cord four segments above the injury and recording this electrical stimulation three segments below, we detected new relays across the transaction site,” said Tuszynski.

To confirm that the mechanism underlying recovery was due to formation of new relays, when rats recovered, their spinal cords were re-transected above the implant.  The rats lost motor function – confirming formation of new relays across the injury. 

The grafting procedure resulted in significant functional improvement: On a 21-point walking scale, without treatment, the rats score was only 1.5; following the stem cell therapy, it rose to 7 – a score reflecting the animals’ ability to move all joints of affected legs.

Results were then replicated using two human stem cell lines, one already in human trials for ALS.  “We obtained the exact results using human cells as we had in the rat cells,” said Tuszynski.

The study made use of green fluorescent proteins (GFP), a technique that had never before been used to track neural stem cell growth. “By tagging the cells with GFP, we were able to observe the stem cells grow, become neurons and grow axons, showing us the full ability of these cells to grow and make connections with the host neurons,” said first author Paul Lu, PhD, assistant research scientist at UCSD’s Center for Neural Repair. “This is very exciting, because the technology didn’t exist before.”

According to the researchers, the study makes clear that early-stage neurons can overcome inhibitors present in the adult nervous system that normally work to maintain the elaborate central nervous system and to keep cells in the adult CNS from growing aberrantly.

Additional contributors to the study include Yaozhi Wang, Lori Graham, Karla McHale, Mingyong Gao, Di Wu, John Brock, Armin Blesch, Ephron S. Rosenzweig, Binhai Zheng and James M. Conner, UCSD Department of Neurosciences; Leif A. Havton, UCLA Department of Neurology; and Martin Marsala, UCSD Department of Anesthesiology.

The work was supported by the Veterans Administration, National Institutes of Health (NS09881), Canadian Spinal Research Organization, The Craig H. Neilsen Foundation, and the Bernard and Anne Spitzer Charitable Trust.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

The governing board of the California Institute for Regenerative Medicine (CIRM) has announced that six investigators from the University of California, San Diego Stem Cell Research program have received a total of more than $7 million in the latest round of CIRM funding. This brings UC San Diego’s total to more than $128 million in CIRM funding since the first awards in 2006.

Human stem cells, false color.

UC San Diego scientists funded by the newly announced CIRM Basic Biology Awards IV include Maike Sander, MD, professor of Pediatrics and Cellular and Molecular Medicine; Miles Wilkinson, PhD, professor, Division of Reproductive Endocrinology; Gene Yeo, PhD, MBA, assistant professor with the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine; George L. Sen, PhD, assistant professor of cellular and molecular medicine; David Traver, PhD, associate professor with the Department of Cellular and Molecular Medicine and Ananda Goldrath, PhD, associate professor in the Division of Biological Sciences.

Sander was awarded nearly $1.4 million for her proposal to define and characterize the key transcription factors necessary to promote maturation of human embryonic stem cell (hESC)-derived pancreatic progenitors into mature insulin-secreting beta cells. The loss of pancreatic beta cells in type 1 diabetes results in the absence of insulin secreted by the pancreas. The goal of this work is to enable scientists to one day produce an unlimited source of transplantable beta-cells for patients with diabetes.

Wilkinson’s grant of $1.36 million will allow his lab to develop and test induced pluripotent stem cells (iPS cells) from patients with genetic mutations in a component of the pathway that results in intellectual disabilities. Many of these patients also have autism, attention-deficit disorders or schizophrenia. Directed towards understanding fundamental mechanisms by which all stem cells are maintained, his research has the potential to impact non-psychiatric disorders as well.

A grant of almost $1.4 million will fund Yeo’s research to help decode the mechanisms that underlie the single most frequent genetic mutation found to contribute to neurodegenerative diseases amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and frontotemporal dementia (FTD). Yeo will generate iPSCs and differentiated motor neurons derived from patients with these mutations, then use genome-wide technologies to analyze these and normal cells and test strategies to rescue mutation-induced defects in iPSC-derived motor neurons.

Sen received a grant of just over $1 million to investigate how tissue specific stem and progenitor cells exist to replenish both healthy, normal tissue and for regeneration from a wound. Disease and aging deplete stem and progenitor cells, impeding the body’s ability to regenerate itself. Sen’s work aims to better understand the mechanisms of self-renewal and differentiation in epidermal (skin) stem cells. Imbalanced growth and differentiation of epidermal cells can lead to a variety of human skin disorders, including psoriasis and cancer.

Traver, who was awarded a CIRM grant of more than $1.3 million in collaboration with Thierry Jaffredo of the Université Pierre et Marie Curie in Paris, studies hematopoietic stem cells. HSCs are rare, multipotent stem cells that give rise to all blood cell types, including red blood and immune cells. Traver’s lab investigates the genes and signaling pathways used by vertebrate embryos to create the first HSCs. An understanding of this developmental process has implications for producing restorative stem cell-based therapies for diseases like leukemia and congenital blood disorders. Currently, medical treatments using HSCs are hampered by cell shortages and finding compatible matches between donors and recipients.

Goldrath’s $1.16 million grant will help develop strategies to induce immunological tolerance to hESC-derived tissues and cells.  Immune-mediated rejection of hESC-derived tissues remains a significant barrier to the promise of regenerative therapies. She proposes a novel approach to promote long-term acceptance of hESC-derived tissues by exploring the molecular pathways and immune cell types that mediate the induction of immune tolerance and pursuing additional targets that halt rejection of tissue grafts derived from these stem cells. If successful, this would increase the potential reach of cellular therapies by decreasing the undesirable side effects of generalized immune suppression. 

The CIRM Basic Biology Awards are designed to fund investigations into the basic mechanisms underlying stem cell biology, cellular plasticity, and cellular differentiation. These awards will also fund the development and use human stem cell based models for exploring disease. According to CIRM, “studies supported by these awards will form the foundation for future translational and clinical advances, enabling the realization of the full potential of human stem cells and reprogrammed cells for therapies and as tools for biomedical innovation.”

CIRM was established in November 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The statewide ballot measure provided $3 billion in funding for stem cell research at California universities and research institutions and called for the establishment of an entity to make grants and provide loans for stem cell research, research facilities, and other vital research opportunities.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

In mice, added amino acid reduced associated epilepsy, eased neurobehavioral symptom

An international team of researchers, led by scientists at the University of California, San Diego and Yale University schools of medicine, have identified a form of autism with epilepsy that may potentially be treatable with a common nutritional supplement.

The findings are published in the September 6, 2012 online issue of Science. 

Roughly one-quarter of patients with autism also suffer from epilepsy, a brain disorder characterized by repeated seizures or convulsions over time. The causes of the epilepsy are multiple and largely unknown. Using a technique called exome sequencing, the UC San Diego and Yale scientists found that a gene mutation present in some patients with autism speeds up metabolism of certain amino acids. These patients also suffer from epileptic seizures. The discovery may help physicians diagnose this particular form of autism earlier and treat sooner.  

The researchers focused on a specific type of amino acid known as branched chain amino acids or BCAAs.  BCAAs are not produced naturally in the human body and must be acquired through diet.  During periods of starvation, humans have evolved a means to turn off the metabolism of these amino acids. It is this ability to shut down that metabolic activity that researchers have found to be defective in some autism patients.

“It was very surprising to find mutations in a potentially treatable metabolic pathway specific for autism,” said senior author Joseph G. Gleeson, MD, professor in the UCSD Department of Neurosciences and Howard Hughes Medical Institute investigator. “What was most exciting was that the potential treatment is obvious and simple: Just give affected patients the naturally occurring amino acids their bodies lack.”

Gleeson and colleagues used the emerging technology of exome sequencing to study two closely related families that have children with autism spectrum disorder.  These children also had a history of seizures or abnormal electrical brain wave activity, as well as a mutation in the gene that regulates BCAAs. In exome sequencing, researchers analyze all of the elements in the genome involved in making proteins.

In addition, the scientists examined cultured neural stem cells from these patients and found they behaved normally in the presence of BCAAs, suggesting the condition might be treatable with nutritional supplementation. They also studied a line of mice engineered with a mutation in the same gene, which showed the condition was both inducible by lowering the dietary intake of the BCAAs and reversible by raising the dietary intake. Mice treated with BCAA supplementation displayed improved neurobehavioral symptoms, reinforcing the idea that the approach could work in humans as well.

“Studying the animals was key to our discovery,” said first author Gaia Novarino, PhD, a staff scientist in Gleeson’s lab. “We found that the mice displayed a condition very similar to our patients, and also had spontaneous epileptic seizures, just like our patients.  Once we found that we could treat the condition in mice, the pressing question was whether we could effectively treat our patients.”

Using a nutritional supplement purchased at a health food store at a specific dose, the scientists reported that they could correct BCAA levels in the study patients with no ill effect. The next step, said Gleeson, is to determine if the supplement helps reduce the symptoms of epilepsy and/or autism in humans.

“We think this work will establish a basis for future screening of all patients with autism and/or epilepsy for this or related genetic mutations, which could be an early predictor of the disease,” he said.  “What we don’t know is how many patients with autism and/or epilepsy have mutations in this gene and could benefit from treatment, but we think it is an extremely rare condition.”

Co-authors are Paul El-Fishawy, Child Study Center, Yale University School of Medicine; Hulya Kayserili, Medical Genetics Department, Istanbul University, Turkey; Nagwa A. Meguid, Rehab O. Khalil, Adel F. Hashish and Hebatalla S. Hashem, Department of Research on Children with Special Needs, National Research Centre, Cairo, Egypt; Eric M. Scott, Jana Schroth, Jennifer L. Silhavy, Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, UC San Diego; Majdi Kara, Pediatric Department, Tripoli Children’s Hospital, Libya; Tawfeq Ben-Omran, Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar; A. Gulhan Ercan-Sencicek, Stephan J. Sanders and Matthew W. State, Program on Neurogenetics, Child Study Center, Department of Psychiatry and Department of Genetics, Yale University School of Medicine; Abha R. Gupta, Child Study Center, Department of Pediatrics, Yale University School of Medicine; Dietrich Matern, Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic; Stacy Gabriel, Broad Institute of Harvard and Massachusetts Institute of Technology; Larry Sweetman, Institute of Metabolic Disease, Baylor Research Institute; Yasmeen Rahimi and Robert A. Harris, Roudebush VA Medical Center and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine.

Funding for this research came, in part, from the National Institutes of Health (grants P1HD070494, R01NS048453, P30NS047101, RC2MH089956, K08MH087639, T32MH018268, U54HG003067), the Center for Inherited Disease Research, the Simons Foundation Research Initiative, Veterans Administration Merit Award, the German Research Foundation, the American Academy of Child and Adolescent Psychiatry Pilot Research Award/Elaine Schlosser Lewis Fund and the American Psychiatric Association/Lilly Research Fellowship.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Protein expression also causes changes in gene splicing

A study led by researchers at the UC San Diego Stem Cell Research program and funded by the California Institute for Regenerative Medicine (CIRM) looks at an important RNA binding protein called LIN28, which is implicated in pluripotency and reprogramming as well as in cancer and other diseases.  According to the researchers, their study – published in the September 6 online issue of Molecular Cell – will change how scientists view this protein and its impact on human disease.

Gene Yeo, PhD

Studying embryonic stem cells and somatic cells stably expressing LIN28, the researchers defined discrete binding sites of LIN28 in 25 percent of human transcripts.  In addition, splicing-sensitive microarrays demonstrated that LIN28 expression causes widespread downstream alternative splicing changes –variations in gene products that can result in cancer or other diseases.

“Surprisingly, we discovered that LIN28 not only binds to the non-coding microRNAs, but can also bind directly to thousands of messenger RNAs,” said first author Melissa Wilbert, a doctoral student in the UC San Diego Biomedical Sciences graduate program. 

Messenger RNA or mRNA, are RNA molecules that encode a chemical "blueprint" for the synthesis of a protein.  MicroRNAs (miRNAs) are short snippets of RNA that are crucial regulators of cell growth, differentiation, and death.  While they don’t encode for proteins, miRNAs are important for regulating protein production in the cell by repressing or “turning off” genes.

“The LIN28 protein is linked to growth and development and is important very early in human development,” said principal investigator Gene Yeo, PhD, MBA, of the Department of Cellular and Molecular Medicine, the Stem Cell Research Program and the Institute for Genomic Medicine at UC San Diego. “It is usually turned off in adult tissue, but can be reactivated, for instance, in certain cancers or metabolic disorders, such as obesity.”

Using genome-wide biochemical methods to look at the set of all RNA molecules across the transcriptome, the researchers found that LIN28 recognizes and binds to a known hairpin-like structure found on the let-7 family of miRNA, but surprisingly, this same structure is also found on mRNAs, allowing LIN28 to directly regulate thousands of targets.

“One of these targets actually encodes for the LIN28 protein itself. In other words, LIN28 helps to make more of itself,” said Yeo.  This process, known as autoregulation, helps to maintain a so-called “steady-state” system in which a protein positively regulates its own production by binding to a regulatory element of the mRNA for the gene coding it. 

“Since these mRNA targets include those known to be involved in gene splicing, we also implicate LIN28 in the regulation of alternative splicing,” said Wilbert, adding that abnormal variations in splicing are often implicated in cancer and other disorders.   

In the splicing process, fragments that do not typically code for protein, called introns, are removed from gene transcripts, and the remaining sequences, called exons, are reconnected.  The splicing factor proteins themselves, as well as the location where these proteins bind, dictate which pieces of the RNA are included or excluded in the final gene transcript – in much the same way that removing and inserting scenes, or splicing, can alter the plot of a movie.

The discovery of thousands of precise binding sites for LIN28 within human genes offers a novel look at the role this protein plays in development and disease processes.  For example, scientists had looked at targeting a particular miRNA called let-7 to halt cancer growth.  “But we now see that LIN28 can, in essence, bypass let-7 and find many, many other binding sites – perhaps with the same adverse effect of uncontrolled cell overgrowth,” said Yeo.  “This suggests that LIN28 itself should be the therapeutic target for diseases, rather than let-7 or other miRNAs.”

Additional contributors to the study include, Stephanie C. Huelga, Katannya Kapeli, Thomas J. Stark, Tiffany Y. Liang, Stella X. Chen, Bernice Y. Yan, Jason L. Nathanson, Kasey R. Hutt, Michael T. Lovci, and Anthony Q. Vu, UC San Diego; Hilal Kazan and Quaid Morris, University of Toronto; Katlin B. Massirer, UC San Diego and State University of Campinas, Brazil; and Shawn Hoon, A*Star and National University of Singapore. 

This study was supported in part by the National Institutes of Health (HG004659, GM084317 and NS075449), the National Institute of General Medical Sciences (T32 GM008666), and the California Institute for Regenerative Medicine (RB1-01413).

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

A study from the University of California, San Diego School of Medicine, published August 22 online by PLoS ONE, reports that muscle problems reported by patients taking statins were related to the strength or potency of the given cholesterol-lowering drugs.

Adverse effects such as muscle pain and weakness, reported to the U.S. Food and Drug Administration (FDA) were related to a statin’s potency, or the degree by which it typically lowers cholesterol at commonly prescribed doses.

“These findings underscore that stronger statins bear higher risk – and should be used with greater caution and circumspection,” said investigator Beatrice Golomb, MD, PhD, professor in the Departments of Medicine and Family and Preventive Medicine at the University of California, San Diego.

Golomb teamed up with researchers from California-based AdverseEvents, Inc., using the company’s software platform to conduct a detailed examination of statin side-effect data from the FDA’s Adverse Event Reporting System (AERS).  The study analyzed muscle-related adverse events linked to each of the major statin drugs in total of 147,789 AERS reports, gathered between July 2005 and March 2011.

Looking at the most commonly used statins – both brand names and, when available, generic forms of the drugs – rosuvastatin, the strongest statin, had the highest rates of reported problems.  This was followed by atorvastatin, simvastatin, pravastatin, and lovastatin. 

“These rankings closely match the individual potencies of each statin. Thus, the strength of the statin drug appears to be a dominant factor in determining how likely muscle problems are to occur,” said Golomb, who directs the Statin Adverse Effects Study at UC San Diego.

Rates were determined for each statin by tallying reports of muscle side effects, standardized to the number of prescriptions filled for that drug. This was done for individual muscle side effects, as well as for side effects overall.

Some experts have maintained that rosuvastatin, the strongest statin, should have superior safety, because it is less fat soluble, and was thereby assumed not to penetrate into muscle cells as much as other statins.  In addition, rosuvastatin is not cleared by common drug-clearance pathways that are sometimes involved in adverse drug interactions.

“The FDA AERS data analyzed in this study, however, suggests that the higher potency of rosuvastatin may more than offset any safety advantages due to such factors,” Golomb said.  She added that pooled analysis of statin studies in patients with stable heart disease do not indicate that higher strength statins result in a lower death rate.  Therefore, “evidence showing that stronger statins may pose a greater risk of side effects is particularly important.”

“Post-marketed studies utilizing AERS data are becoming increasingly important to understand the lasting side effect risks of widely used medications in disparate populations. Until recently, conducting such studies has been difficult due to the fractured and inaccessible nature of the FDA’s raw data,” said Brian Overstreet, CEO of AdverseEvents. The study utilized the company’s unique data sourcing method called RxFilter™, which analyzed more than 140,000 AERS case reports filed with FDA over a six-year time period.

Statins are among the most widely taken prescription medications in the world, with over 30 million users in the United States alone and $19 billion in domestic sales. They are prescribed to lower cholesterol, and reduce the risk of cardiovascular disease.  Their use has been linked to a variety of muscle-related side effects (together termed “statin myopathy”) that occur in as many as 10 to 15 percent of all statin users.  These include commonly reported problems such as pain and weakness, as well as life-threatening muscle breakdown, known as rhabdomyolysis. Statin myopathies can significantly increase pain and injury risk and affect mobility, especially in older individuals.

“Only a fraction of adverse effects are reported to the FDA, and a range of factors can influence reporting rates and accuracy of this information,” Golomb said. “However, findings from this study align with – and extend— other forms of evidence.”

For instance, an earlier study from Golomb’s group at UC San Diego showed that patients with muscle problems related to statins often found relief from symptoms after stopping one statin.  However, muscle pain or weakness consistently redeveloped if the patient was then placed on a higher potency statin, while patients placed on a lower potency statin had significantly lower risk of recurrence.

“Our findings suggest that individual statin potency is a critical determinant of how likely a statin is to cause problems,” Golomb concluded.  “This information should help guide prescribing decisions for statins by offering more information on the risk-benefit profile of the class. It should also be important for guiding decisions about statin selection and use after a patient has experienced a muscle-related adverse event.”

Additional contributors to the study include Keith B. Hoffman, Christina Kraus and Mo Dimbil of AdverseEvents, Inc.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Timing of brain maturation is more tightly controlled than previously known

A national team of researchers led by investigators at the University of California, San Diego School of Medicine have developed a multidimensional set of brain measurements that, when taken together, can accurately assess a child’s age with 92 percent accuracy.

"Developmental clock" shows increases and decreases in brain’s cortical surface, as well as the dynamic cascade of many other brain measures, all changing with increasing age (from age 3-20).Click on the photo for video.

“We have uncovered a ‘developmental clock’ within the brain—a biological signature of maturation that captures age differences quite well regardless of other kinds of differences that exist across individuals,” said first author Timothy T. Brown, PhD, a developmental cognitive neuroscientist in the Department of Neurosciences at UC San Diego School of Medicine.

This study of the anatomy of the developing human brain, to be published in the September 25 print edition of Current Biology, addresses a long-standing scientific question about individual biological variability in children.  It shows that, for certain structural measures, maturational differences in the developing human brain are much smaller than was previously thought – offering the first composite profile of different phases of brain development from ages 3 to 20 years.

Brown and principal investigators Terry Jernigan, PhD, professor of cognitive science at UC San Diego and Anders Dale, PhD, UC San Diego professor of neurosciences, collaborated with colleagues from Yale, Johns Hopkins and Cornell Universities, UCLA, USC, UC Irvine, UC Davis, the University of Massachusetts and the University of Hawaii.  The study, the first published research from the group’s Pediatric Imaging, Neurocognition, and Genetics Study (PING), was supported by a two-year stimulus grant from the National Institutes of Health.

The researchers developed a structural set of brain measurements including features of neuro-anatomical development such as the shape, size and tissue properties of various parts of the brain, resulting in what the researchers call a multi-dimensional phase metric.

The team capitalized on key advances in structural magnetic resonance imaging, or MRI, using a standardized MRI protocol implemented at nine different institutions, using 12 different MRI scanners.  Data was collected in a diverse sample of 885 typically developing children and teens, including information on anatomical brain features known to change over age; for example, measurements of cortical thickness and area, the volume of deep structures, tissue properties and signal intensities.

“No individual measurement closely reflects a child’s age across the childhood years, because changes of different kinds cascade dynamically as development progresses.  But taken together, the measurements reveal a phenotype that is tightly linked to the child’s chronological age,” said Jernigan.  She added that this collection of multimodal, multisite imaging advances now makes it possible for researchers across institutions to establish large-scale, shared databases.

“Since this multi-dimensional MRI method is entirely objective, quantitative, and noninvasive, and can powerfully distinguish among different phases of maturity, we hope it might also be useful for the early detection of developmental brain disorders,” said Brown.

Additional contributors to the study include Joshua M. Kuperman, Natacha Akshoomoff, Yoonho Chung, Matthew Erhart, Donald J. Hagler, Jr., Connor McCabe and Vijay K. Venkatraman, UC San Diego; David G. Amaral, UC Davis; Cinnamon S. Bloss and Sarah S. Murray, Scripps Translational Sciences Institute; B. J. Casey, Weill Cornell Medical College; Linda Chang and Thomas M. Ernst, University of Hawaii; Jean A. Frazier and David N. Kennedy, University of Massachusetts; Tal Kenet, Massachusetts General Hospital; Jeffrey R. Gruen, Yale University; Walter E. Kaufmann, Johns Hopkins University and Harvard Medical School; and Elizabeth R. Sowell, University of Southern California and Children’s Hospital, Los Angeles.

The study was funded by the Pediatric Imaging, Neurocognition, and Genetics Study (PING; National Institutes of Health grant RC2DA029475). PING is funded by the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health & Human Development. PING data are disseminated by the PING Coordinating Center at the Center for Human Development, UC San Diego. Anders Dale is a founder of and holds equity interest in CorTechs Labs, La Jolla, CA and serves on its scientific advisory board.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Oral Drug Shows Clinical Response and Remission in Some Patients 

An investigational drug currently under FDA review for the treatment of rheumatoid arthritis has now shown positive results in patients with moderate-to-severe ulcerative colitis, according to researchers at the University of California San Diego, School of Medicine. The study will appear in the August 16, 2012 issue of the New England Journal of Medicine (NEJM).

Click on the image above for video of Sandborn discussing ulcerative colitis.

Results from the phase 2 clinical trial showed the drug Tofacitinib achieved clinical response and remission in certain patients suffering from ulcerative colitis – a chronic inflammatory disease of the colon where patients experience painful episodes of rectal bleeding and diarrhea combined with the urgent need to use the restroom.

“Ulcerative colitis causes severe bouts of illness that adversely affect a patient’s quality of life at home and work.” said William Sandborn, MD, chief of the Division of Gastroenterology at the UC San Diego School of Medicine and director of the Inflammatory Bowel Disease Center at UC San Diego Health System.  “Oral treatment with Tofacitinib resulted in improvement and remission in some patients.”

Currently, there are limited types of drugs to treat ulcerative colitis.  Drugs available are not universally effective and some require intravenous administration.

“This is a whole new class of drug that affects the number of proteins in the immune system that cause this type of inflammatory bowel disease (IBD),” said Sandborn.

There are about 600,000 to 700,000 patients suffering from ulcerative colitis in the United States.  Half of these patients experience severe flare ups that in some cases could progress to surgery where the colon is completely removed.

“Patients with a more advanced case of ulcerative colitis need a  potent and highly effective therapy,” said Sandborn.  “The results of our study show Tofacitinib may  provide a new approach to attacking this disease.”

One hundred and ninety four patients were part of the randomized trial, which was conducted at 51 centers in 17 countries.  Eligible patients were at least 18 years of age, had a confirmed diagnosis of ulcerative colitis and had previously been treated with conventional therapy for the disease. 

The patients were treated for eight weeks.  They were given a dose of Tofacitinib twice daily, and benefits could be seen as early as two weeks.  A flexile sigmoidoscopy was performed at the beginning and end of the trial, along with blood work and stool samples as a measurement of intestinal inflammation.  

Among patients treated, the most commonly reported infections were influenza and nasopharyngitis - a respiratory infection with common-cold symptoms.  Two patients developed an abscess, and in some cases, headaches were reported and the ulcerative colitis worsened.

“The goal of this study was to show that the oral inhibitor is effective in treating ulcerative colitis.  The next phase of studies aim to confirm the efficacy and safety profile of the drug, will examine the long term or maintenance effect of Tofacitinib and confirm the results of this study,” said Sandborn. 

Researchers who also participated in this study include Subrata Ghosh, MD, University of Calgary; Julian Panes, MD, Hospital Clinic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain; Ivana Vranic, PhD, Chinyu Su, MD, Samantha Rousell, MSc, and Wojciech Niezychowski, MD, all at Pfizer Inc.

The study was funded by Pfizer Inc.

The Division of Gastroenterology at UC San Diego Health System is nationally recognized for its innovative and comprehensive care of patients by a multidisciplinary team of specialists in gastroenterology, endoscopy, oncology, surgery, transplantation and radiology.

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

Compound in human milk associated with reduced transmission from HIV-infected mother to breastfed infant

An international team of researchers has found that certain bioactive components found in human milk are associated with a reduced risk of HIV transmission from an HIV infected mother to her breast-fed infant.  Their study will be published in the August 15 online edition of American Journal of Clinical Nutrition.

“In developing countries, HIV-infected mothers are faced with the decision of whether or not to breastfeed their babies,” said Lars Bode, PhD, assistant professor in the Department of Pediatrics at the University of California, San Diego School of Medicine.  “Breastfeeding exposes the baby to the virus and increases the risk of the baby dying from HIV infection; but not breastfeeding increases the risk for the baby to die from other intestinal or respiratory infections.”

Bode and colleagues set out to find why the vast majority of breast-fed infants do not acquire HIV-1, despite continuous exposure to the virus in their mother’s milk over many months. Even in the absences of antiretroviral drugs, only 10 to15 percent of infants will acquire HIV infection from their HIV-infected mothers.

They discovered that immunologically active components called human milk oligosaccharides (HMO) – a type of carbohydrate made up of several simple sugars linked together – may protect from HIV transmission.  These complex oligosaccharides are the third-most abundant component of breast milk, yet are not digestible and therefore become highly concentrated in the mucosal surfaces of the infant’s gastrointestinal tract.

“HMO act as prebiotics that promote the growth of desirable bacterial communities in the infant’s intestine,” said Bode.  Additionally, HMO structurally resembles sugar chains called glycans that are normally found on epithelial cell surfaces, and can serve as “decoy” receptors to inhibit pathogens from binding. Last, HMO exhibit anti-inflammatory activity and have been shown to modulate immune cell responses in cell and animal models.

The researchers analyzed HMO amount and composition in breast milk samples collected from more than 200 women as part of a larger study of HIV-infected women and their infants in Lusaka, Zambia, following them from birth to 24 months.  (Most were recruited to the study and followed before antiretroviral therapy became available to them, thus offering a unique look at associations between HMO and HIV transmission.)

Higher concentrations of HMO in milk were associated with protection against postnatal HIV transmission, independent of other known risk factors. In the future, a better understanding of how individual HMO facilitate or obstruct HIV transmission may guide the development of interventions to complement antiretroviral strategies and more effectively prevent transmission, according to the researchers.

Additional contributors to the study included Lauren Hsiao and Caroline Nissan, UC San Diego; Louise Kuhn and Hae-Young Kim, Columbia University; Moses Sinkala, Lusaka District Health Management Team, Zambia; Chipepo Kankasa and Mwiya Mwiya, University Teaching Hospital, University of Zambia; Donald M. Thea, Boston University; and Grace M. Aldrovandi, Children’s Hospital Los Angeles, USC.

Funding was provided by the National Institute of Dental and Craniofacial Research (NIDCR) (DE021238) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH) (HD39611, HD40777, HD57617) and a University of California, San Diego, Center for AIDS Research Pilot Development Grant.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Heavy drinking is known to affect an adolescents’ developing brain, but certain patterns of brain activity may also help predict which teens are at risk of becoming problem drinkers, according to a study by researchers in the University of California, San Diego School of Medicine and VA San Diego Healthcare System.   Their results will be published in the September issue of the Journal of Studies on Alcohol and Drugs, online August 8.

Color indicates area of increasing brain activity in frontal lobe of adolescents who initiated heavy drinking, when compared to controls.

This study focused on 12 to 16-year-olds whose brains were scanned using special functional magnetic resonance imaging (fMRI) prior to the onset of drinking, and then again three years later.  About half of this group transitioned into heavy drinking over the 3-year period.  However, when imaged before they began drinking, this cohort already showed less fMRI response in regions of the brain previously linked to heavy drinking.

“Interestingly, this study showed that teens who initially showed less activation in certain brain areas were at greater risk for becoming heavy drinkers over the next three years,” said principal investigator Susan Tapert, PhD, professor of psychiatry at UC San Diego School of Medicine and VA San Diego Healthcare System.

Over time, adolescents who initiated heavy drinking exhibited less efficient processing of information.

“That’s the opposite of what you’d expect, because their brains should be getting more efficient as they get older,” said lead researcher Lindsay M. Squeglia, PhD of UC San Diego Department of Psychiatry. 

Once this group began drinking heavily – defined by episodes of consuming four or more drinks on an occasion for females, and five or more drinks for males – their brains already started showing the patterns previously seen in heavy drinkers: more activity in certain areas of the brain as they tried to perform a memory test. These brain areas included the parietal lobe (which helps process spatial information), and frontal lobe (the portion of the brain involved in, among other things, short-term memory tasks, planning, and organization). 

“At the point these teens began drinking heavily, the fMRI data revealed greater parietal and frontal activity during a spatial working memory task in heavy drinkers versus light drinkers, despite equivalent performance on the tasks and after considering their brain activation patterns before drinking started,” said Squeglia.

The study’s findings add to evidence that heavy episodic drinking during adolescence may be followed by subtle alterations in brain functioning. But the research also points to neural response patterns that could indicate a risk factor for future substance use.

“Our results suggest there could be a pre-existing vulnerability, and could provide clues to the biological origins of problem drinking,” said Squeglia.
 
Additional contributors to the study include Reagan R. Wetherill, PhD, UC San Diego; and Carmen Pulido, PhD, Joanna Jacobus, PhD, and Gregory G. Brown, PhD, UC San Diego and VA San Diego Healthcare.

The study was funded by grants from the National Institute of Alcohol Abuse and Alcoholism, part of the National Institutes of Health (#F31 AA18940, R21 AA019748 and R01 AA13419).

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

A study published in the online journal Hepatology reports a potential new NADPH oxidase (NOX) inhibitor therapy for liver fibrosis, a scarring process associated with chronic liver disease that can lead to loss of liver function.

“While numerous studies have now demonstrated that advanced liver fibrosis in patients and in experimental rodent models is reversible, there is currently no effective therapy for patients,” said principal investigator David A. Brenner, MD, vice chancellor for Health Sciences and dean of the School of Medicine at the University of California, San Diego. “This new study provides important validation of the role of NOX in liver fibrosis, and suggests that a NOX inhibitor could provide an effective treatment for this devastating disease.”

Most chronic liver diseases are associated with progressive fibrosis, which is triggered by the loss of liver cells and the activation of inadequate wound healing pathways.  In addition, oxidative stress – which results from an inappropriate balance between the production and clearance of highly reactive molecules involved in cell signaling called reactive oxidative species (ROS) – leads to aberrant tissue repair in the liver.

When the liver is injured – for example, through hepatitis or alcohol abuse –HSCs are activated to become myofibroblasts, cells which play a crucial role in wound healing and the body’s response to inflammation by recruiting immune cells called macrophages to the injury site.  This process, triggered by intracellular signalling pathways involving NOX, can result in an abundance of scarring and eventually result in the loss of organ function. 

By inhibiting NOX, the researchers theorized that myofibroblast activation and macrophage recruitment could be interrupted, preventing further fibrosis and potentially allowing regression of established fibrosis.

They assessed the effectiveness of treatment with GKT137831 – a NOX1/4 inhibitor developed by Genkyotex SA of Geneva, Switzerland – in mouse models, and found that treatment with this NOX inhibitor suppressed ROS production, as well as NOX and fibrotic gene expression. 

“These data highlight the excellent pharmacological properties of GKT137831 and the broad potential for its use in fibrotic diseases,’’ said Patrick Page, chief development officer at Genkyotex and contributor to the study. 

According to Brenner, the next steps include a clinical trial with this drug in patients with liver fibrosis.

Additional contributors include Tomonori Aoyama, UC San Diego and Juntendo University School of Medicine, Tokyo; Yong-Han Paik, Yonsei University College of Medicine, Seoul, Korea; Sumio Watanabe,  Juntendo University; Benoît Laleu, Francesca Gaggini, Laetitia Fioraso-Cartier, Sophie Molangpo, Freddy Heitz, Cédric Merlot and Cédric Szyndralewiez, GenKyoTex SA, Geneva. 

The study was funded in part by grants 1 R24 DK090962, 5 P50 AA011999 and 5 R01 GM041804 from the National Institutes of Health and by the American Liver Foundation.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Neutrophils’ role is a surprise – and a potential new target for treating diabetes

Researchers at the University of California, San Diego School of Medicine say neutrophils, an abundant type of white blood cell typically tasked with attacking bacteria and other foreign invaders, also plays an unexpected role in mediating insulin resistance – the central characteristic of type 2 diabetes, which afflicts an estimated 26 million Americans.

The findings are published in the August 5, 2012 Advance Online Publication of Nature Medicine.

A false-colored, scanning electron micrograph of a neutrophil.

Neutrophils are the first immune cells to respond to tissue inflammation, and can promote chronic inflammation by summoning other white blood cells called macrophages. Chronic low-grade inflammation – common in adipose or fat tissue – is an important cause of systemic insulin resistance.

Using liver and fat cells from mice and humans and live mouse models, a team led by Jerrold M. Olefsky, MD, associate dean for scientific affairs at UC San Diego Health Sciences and professor of medicine, discovered that an enzyme secreted by neutrophils called neutrophil elastase (NE) impairs insulin signaling and boosts resistance. Conversely, deletion of NE in obese mice fed a high-fat diet improved insulin sensitivity.

“These results are largely unexpected,” said Da Young Oh, an assistant project scientist in Olefsky’s lab and study co-author. “Although several immune cells have been established in the etiology of insulin resistance, the role of neutrophils in this process has remained unclear until now.”

Oh said neutrophils were considered to be “transient infiltrates,” temporary cells (average lifespan: 5 days) that were incapable of sustaining chronic, low-grade inflammation. “Our studies now suggest neutrophils possess powerful immune modulatory effects,” Oh said. 

Specifically, neutrophils use NE to activate a signaling pathway which triggers pathogen-eating macrophages to secrete proinflammatory molecules called cytokines. NE degrades IRS1, a key protein in the insulin signaling pathway in both liver and fat cells. Although NE has been shown to degrade this protein in lung cancer cells, the scientists said, the effect on insulin target tissues such as liver and adipose is striking.

The insulin-mediating role of neutrophils makes them a new target for developing treatments of insulin resistance in particular and diabetes in general. “Given that NE mediates insulin resistance, one could, in theory, take an NE activity inhibitory approach to reverse or improve insulin resistance,” Oh said, noting that NE inhibitors are already used for treatment of emphysema in Japan and are being tested in the United States, both for emphysema and type 1 diabetes.

Co-authors are Saswata Talukdar, Gautan Bandyopadhyay, Jianfeng Xu, Joanne McNelis, Min Lu, Pingping Li, Jachelle Ofrecio and Michael Lin, Department of Medicine, UCSD; Dongmei Li, Qingyun Yan, Yimin Zhu and Martin B. Brenner, Pfizer.

Funding for this research came, in part, from the National Institutes of Health (grants DK033651, DK074868, T32 DK007494, DK090962, and DK063491) and the Eunice Kennedy Shriver NICHD/NIH agreement (U54 HD 012303-25), part of the specialized Cooperative Centers Program in Reproduction and Infertility Research.

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Media Contact: Scott LaFee, 6190543-6163, slafee@ucsd.edu

The greatest risk factor for Alzheimer’s disease (AD) is advancing age. By age 85, the likelihood of developing the dreaded neurological disorder is roughly 50 percent. But researchers at the University of California, San Diego School of Medicine say AD hits hardest among the “younger elderly” – people in their 60s and 70s – who show faster rates of brain tissue loss and cognitive decline than AD patients 80 years and older. 

The findings, reported online in the August 2, 2012 issue of the journal PLOS One, have profound implications for both diagnosing AD – which currently afflicts an estimated 5.6 million Americans, a number projected to triple by 2050 – and efforts to find new treatments. There is no cure for AD and existing therapies do not slow or stop disease progression.

“One of the key features for the clinical determination of AD is its relentless progressive course,” said Dominic Holland, PhD, a researcher at the Department of Neurosciences at UC San Diego who led the study and the is the paper's first author. “Patients typically show marked deterioration year after year. If older patients are not showing the same deterioration from one year to the next, doctors may be hesitant to diagnose AD, and thus these patients may not receive appropriate care, which can be very important for their quality of life.”

Holland and colleagues used imaging and biomarker data from participants in the Alzheimer’s Disease Neuroimaging Initiative, a multi-institution effort coordinated at UC San Diego. They examined 723 people, ages 65 to 90 years, who were categorized as either cognitively normal, with mild cognitive impairment (an intermediate stage between normal, age-related cognitive decline and dementia) or suffering from full-blown AD.

“We found that younger elderly show higher rates of cognitive decline and faster rates of tissue loss in brain regions that are vulnerable during the early stages of AD,” said Holland. “Additionally cerebrospinal fluid biomarker levels indicate a greater disease burden in younger than in older individuals.”

Holland said it’s not clear why AD is more aggressive among younger elderly.

“It may be that patients who show onset of dementia at an older age, and are declining slowly, have been declining at that rate for a long time,” said senior author Linda McEvoy, PhD, associate professor of radiology. “But because of cognitive reserve or other still-unknown factors that provide ‘resistance’ against brain damage, clinical symptoms do not manifest till later age.”

Another possibility, according to Holland, is that older patients may be suffering from mixed dementia – a combination of AD pathology and other neurological conditions. These patients might withstand the effects of AD until other adverse factors, such as brain lesions caused by cerebrovascular disease, take hold. At the moment, AD can only be diagnosed definitively by an autopsy. “So we do not yet know the underlying neuropathology of participants in this study,” Holland said.

Clinical trials to find new treatments for AD may be impacted by the differing rates, researchers said. “Our results show that if clinical trials of candidate therapies predominately enroll older elderly, who show slower rates of change over time, the ability of a therapy to successfully slow disease progression may not be recognized, leading to failure of the clinical trial,” said Holland. “Thus, it’s critical to take into account age as a factor when enrolling subjects for AD clinical trials.”

The obvious downside of the findings is that younger patients with AD lose more of their productive years to the disease, Holland noted. “The good news in all of this is that our results indicate those who survive into the later years before showing symptoms of AD will experience a less aggressive form of the disease.”

Co-authors are Rahul S. Desikan, Department of Radiology, UCSD and Anders M. Dale, Departments of Neurosciences and Radiology, UCSD.

Funding for this research came, in part, from the National Institutes of Health (grants R01AG031224, R01AG22381, U54NS056883, P50NS22343 and P50MH08755); the National Institute on Aging (grant K01AG029218) and the National Institute of Biomedical Imaging and Bioengineering (grant T32EB005970).

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Researchers at the University of California, San Diego School of Medicine have identified a link between patients who undergo total nephrectomy - complete kidney removal - and erectile dysfunction. Results from the multi-center study were recently published online in the British Journal of Urology International.

Ithaar Derweesh, MD, urologic surgeon, UC San Diego Health System

“This is the first study in medical literature to suggest that surgery for kidney removal can negatively impact erectile function while partial kidney removal can protect sexual function,” said Ithaar Derweesh, MD, senior author, associate professor of surgery, UC San Diego School of Medicine and urologic surgeon at UC San Diego Health System.

The retrospective study evaluated two cohorts of men, totaling 432 patients, who underwent surgery for renal cell carcinoma. One group underwent complete removal of the kidney while the other had kidney-sparing surgery. Sexual function was accessed pre- and post-operatively with a sexual health questionnaire known as the International Index of Erectile Function.

“What we are seeing is a dramatic yet delayed effect. Approximately six years after surgery, patients who had a total nephrectomy were 3.5 times more likely to develop erectile dysfunction compared to those who had kidney reconstruction,” said Derweesh.

“The primary argument for kidney-sparing surgery over total kidney removal has been to preserve the kidney filtration function. However, we are also beginning to understand that total kidney removal may also increase the risk of metabolic diseases and significantly decrease quality of life,” said lead author Ryan Kopp, MD, chief resident, Division of Urology, UC San Diego School of Medicine.

Derweesh added that this is the latest in a series of studies that point to the wisdom of saving the kidney in appropriate patients. Prior research led by Derweesh also shows that partial nephrectomy can reduce the risk of osteoporosis and chronic kidney insufficiency, which can lead to cardiac events and metabolic disturbances. Further investigation is needed to prevent erectile dysfunction in patients and to predict its potential occurrence.

Funding for this study was provided by the Sexual Medicine Society of North America Scholars in Sexuality Research Grant.

Contributors to this paper included Ryan P. Kopp, Jonathan L. Silberstein, Caroline J. Colangelo, Wassim M. Bazzi and Christopher J. Kane of UCSD; Brian M. Dicks and Irwin Goldstein of UCSD and Alvarado Hospital; Reza Mehrazin, Aditya Bagrodia, Robert W. Wake, Anthony L. Patterson, and Jim Y. Wan of University of Tennessee.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Molecular markers help reveal nature of chronic lymphocytic leukemia – slow or fast
 
Using a new assay method to study tumor cells, researchers at the University of California, San Diego School of Medicine and UC San Diego Moores Cancer Center have found evidence of clonal evolution in chronic lymphocytic leukemia (CLL). The assay method distinguishes features of leukemia cells that indicate whether the disease will be aggressive or slow-moving, a key factor in when and how patients are treated.
 
The findings are published in the July 26, 2012 First Edition online issue of Blood.

The schematic above depicts some of the subnetworks of interacting proteins that either promote or slow the progression of CLL.

The progression of CLL is highly variable, dependent upon the rate and effects of accumulating monoclonal B cells in the blood, marrow, and lymphoid tissues. Some patients are symptom-free for years and do not require treatment, which involves the use of drugs that can cause significant side effects and are not curative. In other patients, however, CLL is relatively aggressive and demands therapeutic intervention soon after diagnosis.

“Our study shows that there may not be a sharp dividing line between the more aggressive and less aggressive forms of CLL,” said Thomas J. Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research and senior author of the study. “Instead, it seems that over time the leukemia cells of patients with indolent disease begin to use genes similar to those that are generally used by CLL cells of patients with aggressive disease.  In other words, prior to requiring therapy, the patterns of genes expressed by CLL cells appear to converge, regardless of whether or not the patient had aggressive versus indolent disease at diagnosis.”

Existing markers for aggressive or indolent disease are mostly fixed and have declining predictive value the longer the patient is from his or her initial diagnosis. When the blood sample is collected, these markers cannot reliably predict whether a CLL patient will need therapy soon, particularly when the patient has had the diagnosis of CLL for many years.

Kipps and colleagues studied thousands of genes, particularly those that code for proteins, in a group of 130 CLL patients with varying risks of disease progression. They identified 38 prognostic subnetworks of interacting genes and proteins that, at the time of sample collection, indicate the relative the aggressiveness of the disease and predict when the patient will require therapy. They confirmed their work using the method on two other, smaller CLL patient cohorts in Germany and Italy.

The subnetworks offer greater predictive value because they are based not on expression levels of individual genes or proteins, but on how they dynamically interact and change over time, influencing the course of the CLL and patient symptoms.  

“In a sense, we looked at families rather than individuals,” said Kipps. “If you find in an interconnected family where most genes or proteins are expressed at higher levels, it becomes more likely that these genes and proteins have functional significance.”

He added that while the subnetworks abound in data, their complexity actually makes them easy to interpret and understand. “It’s like when you look out of a window and see the sky, clouds, trees, people, cars. You’re getting tremendous amounts of information that individually doesn’t tell you much. But when you look at the scene as a whole, you see patterns and networks. This work is similar. We’re taking all of the individual gene expression patterns and making sense of them as a whole. We’re more able to more clearly see how they control and regulate function.”

The findings help define how CLL – and perhaps other cancers – evolve over time, becoming more aggressive and deadly. “It’s as if each tumor has a clock which determines how frequently it may acquire the chance changes that make it behave more aggressively. Although the rates can vary, it appears that tumors march down similar pathways, which converge over time to a point where they become aggressive enough to require therapy.” 

The study may alter how scientists think about CLL and how clinicians treat the disease: whether it is better to wait for later stages of the disease when tumor cells are more fragile and easier to kill, or treat early-stage indolent tumor cells aggressively, when they are fewer in number but harder to find and more resistant to therapy.

Co-authors are Han-Yu Chuang and Trey Ideker, Bioinformatics and Systems Biology Program, Department of Bioengineering, Department of Medicine, Moores Cancer Center, all at UCSD; Laura Rassenti, Department of Medicine and Moores Cancer Center, UCSD; Michelle Salcedo, Division of Biological Science, UCSD; Kate Licon, Department of Bioengineering and Department of Medicine, UCSD; Alexander Kohlmann, Roche Molecular Systems, Inc.; Torsten Haferlach, MLL Munchner Leukamielabor GmbH, Germany; and Robin Foa, Division of Hematology, University “La Sapienza,” Italy.

Funding for this research came, in part, from National Science Foundation grant NSF425926, National Institutes of Health grant ES14811, Pfizer and Agilent laboratories. Additional support came from NIH grants for the CLL Research Consortium (P01-CA081534), a Merit Award to Kipps and trainee research award to Chuang from the American Society of Hematology.

About Chronic Lymphocytic Leukemia
CLL is the most common form of leukemia, and most commonly diagnosed in adults after the age of 50. Incidence rates increase with age. The majority of CLL patients are men. Roughly 16,000 Americans are diagnosed with the disease each year; 4,400 die from the disease annually. CLL is currently considered incurable, but typically progresses slowly with no ill effect. Treatment is often postponed until serious symptoms appear that affect quality of life. 

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

A study conducted by researchers from the University of California, San Diego School of Medicine along with colleagues from Rural/Metro Ambulance San Diego and the San Diego Fire-Rescue Department, shows that emergency medical personnel can obtain an electrocardiogram (ECG) in the field for chest pain patients without an increase in scene time or transport time to the hospital. Furthermore, in patients with an ST-elevation myocardial infarction (STEMI) diagnosed on the electrocardiogram– in the field prior to transporting to the hospital – care is actually expedited and the patients are more rapidly transported to the hospital. The study appears in the July 25 online version of the Journal of American College of Cardiology.

“Prior to this study, questions remained as to whether the time required in the field to perform an ECG would lead to a delay in transporting patients to the hospital. For patients suffering from the most severe form of heart attack (STEMI), where a significant amount of heart muscle is being damaged by the minute, time in the field and transport times were actually lowered,” said senior author, Ehtisham Mahmud, MD, professor of medicine, UC San Diego School of Medicine, chief of cardiovascular medicine and co-director, UC San Diego Sulpizio Cardiovascular Center. “This indicates that pre-hospital electrocardiography offers a more timely diagnosis and has the potential to reduce ischemic time and limit heart muscle damage.”

Coronary heart disease remains the leading cause of death in the United States. A number of pharmacologic therapies and advancements in interventional techniques and improved systems of care have led to significantly improved outcomes for heart attack patients.  Pre-hospital ECG helps quickly make the diagnosis of a heart attack even prior to arrival at the hospital and enables faster delivery of optimal medical therapy and preferential transport of patients to hospitals with the ability to provide an angioplasty (balloon catheter used to open blocked artery with stent placement to improve blood flow to the heart).

“The combination of the pre-hospital ECG and our EMS system design helps get patients to the cath lab more quickly to open up the blocked artery,” explained co-author and City Medical Director, James Dunford, MD, professor emeritus of clinical medicine, Department of Emergency Medicine, UCSD School of Medicine.  “We deploy paramedics on both fire first-responders and on ambulances.  This increases the efficiency of rapid patient assessment, diagnosis and as demonstrated in this study, clear benefit for heart attack patients.”

This study analyzed the data on nearly 22,000 patients complaining of chest pain of suspected cardiac origin encountered over a five-year period by San Diego City paramedics.

Other contributors to this study include: Mitul Patel, MD, Division of Cardiovascular Medicine, UCSD; Steve Aguilar, MD, and Edward Castillo, PhD, MPH, Department of Emergency Medicine, UCSD; Ekta Patel, BE, Rural/Metro Ambulance, San Diego; and Roger Fisher, BS, and Ginger Ochs, RN, San Diego Fire-Rescue Department.

About UC San Diego Sulpizio Cardiovascular Center
UC San Diego Sulpizio Cardiovascular Center is dedicated to innovative care and the prevention, diagnosis and treatment of cardiovascular disease. The state-of-the-art facility, which opened in La Jolla in 2011, is the region’s first academic-based facility to combine all heart and vascular-related services, programs and technology under one roof. For more information, visit www.heartcenter.ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Davey Smith, MD, associate professor of medicine in the Division of Infectious Diseases at the University of California, San Diego School of Medicine and the VA San Diego Health System is one of three recipients of the 2012 Avant-Garde Award for HIV/AIDS research.  This prestigious award, announced today by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health, is intended to stimulate high-impact research that may lead to groundbreaking opportunities for the prevention and treatment of HIV/AIDS in drug abusers.

Davey Smith, MD

Smith will receive $500,000 per year for the next five years to support a project for HIV prevention for drug users and other high-risk groups. His research group will work to develop a system that integrates patient demographics, geographic location, drug use and HIV strain in order to map patterns of new HIV infections as they occur.  Such a system is designed to ensure quick delivery of prevention resources that are tailored to specific groups at risk for HIV, with the goal of stopping transmission of the disease, particularly among illicit substance users.

“We believe this could be the key to ending HIV transmission in some of the most at-risk populations in San Diego and, in turn, other communities,” said Smith.

Smith is a translational research virologist who works both at the UC San Diego Antiviral Research Center, where he is medical director of the Early Intervention Program, and as director of the Center for AIDS Research (CFAR) Translational Virology Core. His primary research focus is on the transmission of HIV and finding new ways to interrupt the spread of the disease.

In 2010, Smith was one of two recipients of the HIV Medicine Association’s 2010 HIV Research Award, recognizing up-and-coming HIVMA members who have made outstanding contributions to HIV medicine early in their careers.  He is also a member of the San Diego County HIV Planning Council, where he chairs the standards of care committee.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

One of only 10 California hospital systems to make Hospitals & Health Networks’ annual list

University of California, San Diego Health System’s hospitals and facilities are among "Health Care’s Most Wired," according to the 14th annual survey conducted by Hospitals & Health Networks magazine.

Hospitals and Health Networks highlights top-ranking hospitals that are evaluated by how they use information technology in five areas: business processes, customer service, safety and quality, workforce, and public health and safety.

Ed Babakanian, CIO, UC San Diego Health Sciences, leads a multidisciplinary team dedicated to advancing health care technology.

“This is our seventh year in a row on this list, which demonstrates UC San Diego Health System’s dedication to information technology expansion,” said Ed Babakanian, chief information officer, UC San Diego Health Sciences. “Our primary goal is always to provide excellent patient care – from access to online medical information to improved patient outcomes – and UC San Diego Health System fully supports our efforts to provide that by staying ahead of the IT curve.”

Almost half of the Most Wired hospitals, including UC San Diego Health System, reported using social media for community outreach and crisis communication.  More than 25 percent of the Most Wired hospitals offer care management messages and chats with physicians, such as UC San Diego’s “MyChart” online messaging program.

Additionally, last year, UC San Diego Health System achieved HIMSS Stage 7 status, which represents the pinnacle of an environment where paper charts are no longer used to deliver patient care.  UC San Diego Health System is one of only 58 hospitals – 1.1 percent, of the more than 5,000 hospitals in the database – to be recognized by HIMSS Analytics with its Stage 7 Award.

Additional key findings show that:

• 100 percent of Most Wired hospitals check drug interactions and drug allergies when medications are ordered as a major step in reducing medication errors
• 93 percent of Most Wired hospitals employ intrusion detection systems to protect patient privacy and security of patient data, in comparison to 77 percent of the total respondents
• 74 percent of Most Wired hospitals use automated patient flow systems
• 90 percent of Most Wired hospitals use performance improvement scorecards to help reduce inefficiencies

Hospitals & Health Networks polled 1,570 hospitals for the survey, conducted in partnership with McKesson, the College of Healthcare Information Management Executives (CHIME) and the American Hospital Association.

For more information on the Most Wired hospitals issue, click here.

To view the list of Most Wired hospitals, click here.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Newly opened Sulpizio Cardiovascular Center makes Soliant Health’s top ten list

University of California, San Diego’s LEED-Gold certified Sulpizio Cardiovascular Center is ranked #10 on Soliant Health Care’s annual list of top 20 most beautiful hospitals in the United States.  According to Soliant leaders, participants cast nearly 170,000 votes this year. 

UC San Diego Sulpizion Cardiovascular Center

UC San Diego Sulpizio Cardiovascular Center is the only San Diego hospital on the list and is one of only two facilities in California to make the list. 

“We are so very proud of our facility, the physicians and staff who work here, and the excellent patient care that is provided,” said Ehtisham Mahmud, MD, co-director, UC San Diego Sulpizio Cardiovascular Center. 

“What makes this recognition even more notable is that we are the only center on the list specifically dedicated to cardiovascular treatment, and the only academic medical center,” added Michael Madani, MD, co-director UC San Diego Sulpizio Cardiovascular Center.
After receiving more than 300 nominations, Soliant assembled a panel of experts that reviewed each hospital and picked the top 51 entries, based on measures such as architectural style, photogenic properties, landscaping and distinctiveness.

Regarding Sulpizio Cardiovascular Center, Soliant officials commented that, “This world-class cardiovascular center was strikingly-lit in red at night throughout February 2012 to commemorate the American Heart Association’s ‘Go Red for Women’ campaign. A fine gesture for a hospital that looks good in any light.”

“We knew this building was going to be special and stand out from the moment we started visualizing it,” said Lisa Murphy, associate administrator for Cardiovascular and Medicine Service Lines, who shepherded the project from inception to completion.  “From design, to construction, to the art work inside and the people delivering care, we have always put the patient’s comfort first.”

The Sulpizio Cardiovascular Center is the culmination of a 40-year dream to have a facility in which all disciplines providing cardiac care are housed under one roof, with practitioners of various disciplines working in close proximity.  The four-story, 128,000 square foot building has four operating rooms, six catherization labs, 22 day beds, 54 acute care beds and an expanded emergency department, shared with Thornton Hospital. 

The beauty of the natural San Diego environment played an important role in the design of the building, from the locally selected rocks for the front-entrance fountain to the floors color-coded with art-glass, to the use of natural light in each room.

Click here to read the list of the “20 Most Beautiful Hospitals in the United States."

About Soliant Health
Soliant Health, an Adecco Group company, is a leading provider of specialized healthcare staffing services to hospitals and healthcare providers. By supplying traveling healthcare professionals on both temporary and direct hire assignments, Soliant Health delivers comprehensive healthcare staffing services to leading facilities across the United States. Soliant's teams of professionals are qualified to fill physician, nursing, therapy, pharmacy, clinical research, imaging, and other healthcare positions.

UC San Diego Sulpizio Cardiovascular Center
UC San Diego Sulpizio Cardiovascular Center is dedicated to innovative care and the prevention, diagnosis and treatment of cardiovascular disease. The state-of-the-art facility, which opened in La Jolla in 2011, is the region’s first academic-based facility to combine all heart and vascular-related services, programs and technology under one roof. For more information, visit http://heartcenter.ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

An international team of scientists, led by researchers from the Department of Pediatrics at the University of California, San Diego School of Medicine, have identified the first reported inhibitors of a key enzyme involved in survival of the parasite responsible for malaria.  Their findings, which may provide the basis for anti-malarial drug development, are currently published in the online version of the Journal of Medicinal Chemistry.

Tropical malaria is responsible for more than 1.2 million deaths annually.  Severe forms of the disease are mainly caused by the parasite Plasmodium falciparum, transmitted to humans by female Anopheles mosquitoes.  Malaria eradication has not been possible due to the lack of vaccines and the parasite’s ability to develop resistance to most drugs. 

The researchers conducted high-throughput screening of nearly 350,000 compounds in the National Institutes of Health’s Molecular Libraries Small Molecule Repository (MLSMR) to identify compounds that inhibit an enzyme which plays an important role in parasite development: Plasmodium falciparum glucose-6-phosphate dehydrogenase (PfG6PD) is essential for proliferating and propagating P. falciparum.

“The enzyme G6PD catalyzes an initial step in a process that protects the malaria parasite from oxidative stress in red blood cells, creating an environment in which the parasite survives,” said senior author Lars Bode, PhD, assistant professor in the UCSD Department of Pediatrics, Division of Neonatology and the Division of Gastroenterology, Hepatology and Nutrition.  People with a natural deficiency in this enzyme are protected from malaria and its deadly symptoms, an observation that triggered the reported research.

The parasitic form of the enzyme (PfG6PD) is what contributes the majority of G6PD activity in infected red blood cells.  Because the parasite lives in the blood of a malaria-infected person, the scientists aimed at identifying compounds that inhibit the parasitic form but not the human form of the enzyme.  “We didn't want to interfere with the human form of the enzyme and risk potential side effects,” Bode explained.

Scientific testing had previously been limited by a lack of recombinant PfG6PD.  Team members in the lab of Katja Becker, PhD, at the Interdisciplinary Research Center at Justus-Liebig-University in Giessen, Germany produced the first complete and functional recombinant PfG6PD, and researchers led by Anthony Pinkerton, PhD, at Sanford-Burnham Medical Research Institute used it to identify the lead compound resulting from their efforts, ML276.

ML276 represents the first reported selective PfG6PD inhibitor, which stops the growth of malaria parasites in cultured red blood cells – even those parasites that developed resistance to currently available drugs.  “ML276 is a very promising basis for future drug design of new anti-malarial therapeutics,” said Bode.

Contributors to the study include Janina Preuss, UC San Diego, Justus-Liebig-University and Sanford-Burnham Medical Research Institute; Esther Jortzik, Stefan Rahlfs and Katja Becker, Justus-Liebig-University; Patrick Maloney, Satyamaheshwar Peddibhotla, Paul Hershberger, Eliot Sugarman, Becky Hood, Eigo Suyama, Kevin Nguyen, Stefan Vasile, Arianna Mangravita-Novo, Michael Vicchiarelli, Danielle McAnally, Layton H. Smith. Gregory P. Roth, Michael P. Hedrick, Palak Gosalia, Monika Milewski, Yujie Linda Li, Eduard Sergienko, Jena Diwan, Thomas D.Y. Chung, and Anthony B. Pinkerton, Sanford-Burnham.

The study was supported by the National Institutes of Health (1R21AI082434), the Deutsche Forschungsgemeinschaft, and an NIH Molecular Libraries grant (U54 HG005033) to the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Medical Research Institute, one of the comprehensive centers of the NIH Molecular Libraries Probe Production Centers Network (MLPCN).

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

CONFIRM study results point to a doubling of success in treating heart rhythm disorder

Researchers  from UC San Diego, the University of California Los Angeles and Indiana University report having found, for the first time, that atrial fibrillation  or irregular heart rhythms is caused by small electrical sources within the heart, in the form of electrical spinning tops (“rotors”) or focal beats.  Importantly, they found a way of detecting these key sources, then precisely targeting them for therapy that can shut them down in minutes with long lasting results.
 
The team, which included cardiologists, physicists and bioengineers, report the findings in the July issue of the Journal of the American College of Cardiology as the CONFIRM trial (Conventional Ablation for Atrial Fibrillation
With or Without Focal Impulse and Rotor Modulation). 

Left panel shows the eye of a hurricane. Right panel   shows the striking similarity of the rotor or localized source of an arrhythmia in a patient with atrial fibrillation. Ablation targeted at these rotors or "eyes of the storm" successfully terminated and eliminated atrial fibrillation in the   CONFRIM trial. Photo credit: UCSD/UCLA.

Currently, many patients treated for atrial fibrillation with standard therapies will experience a recurrence due to the difficulty of finding the source of the arrhythmia.  The new findings will help cardiologists better target and treat arrhythmias.

The CONFIRM study examined 107 patients with atrial fibrillation referred for a non-surgical catheter ablation procedure.  During this procedure, doctors thread a wire with a metal-tipped catheter inside the body, from a vein in the groin, to apply heat to the area of the heart that is producing the arrhythmia to stop it. 

In one group of patients, the team used the new technique to help perform precise burns, called Focal Impulse and Rotor Modulation (FIRM) that were aimed directly at the fundamental source of the arrhythmia – tiny electrical disturbances in the heart called rotors or focal sources that look like mini tornadoes or spinning tops. 

Remarkably, this new procedure shut down atrial fibrillation or very significantly slowed it in 86 percent of patients in an average of only 2.5 minutes. 

In comparison, conventional catheter procedures were performed in a second group of patients.  Since this approach is less targeted, it involved hours of treatment over larger regions in the heart and often did not shut down the atrial fibrillation.

To track outcomes, patients received an implanted ECG monitor that very accurately assessed their heart rhythms over time. Researchers found that after two years, the FIRM-guided group had an 82.4 percent freedom from atrial fibrillation episodes, compared to only 44.9 percent freedom in the group that received standard therapy. 

The new targeted method demonstrated an 86 percent improvement over the conventional method in the study.

"We are very excited by this trial, which for the first time shows that atrial fibrillation is maintained by small electrical hotspots, where brief FIRM guided ablation can shut down the arrhythmia and bring the heart back to a normal rhythm after only minutes of ablation," said lead author Sanjiv Narayan, MD, PhD, professor of medicine at UC San Diego Sulpizio Cardiovascular Center, director of Electrophysiology at the San Diego Veterans Affairs Medical Center and visiting professor at the UCLA Cardiac Arrhythmia Center. 

"The results of this trial, with an 80 percent ablation success rate after a single procedure, are very gratifying. This is the dawn of a new phase of managing this common arrhythmia that is mechanism-based,” said Kalyanam Shivkumar, MD, PhD, director of the UCLA Cardiac Arrhythmia Center, and professor of medicine and radiological sciences at UCLA.

This study also represents a successful example of technology transfer from U.S. researchers supported by U.S. research funding to a small U.S. enterprise.  The science behind this work was funded by grants to Narayan from the National Institutes of Health, including a grant awarded as part of the American Recovery and Reinvestment Act, and by the Doris Duke Charitable Foundation.

These discoveries, owned by the Regents of the University of California, were then licensed to a local startup company, Topera Medical, which has recently obtained FDA clearance for the mapping system it developed (RhythmView^TM) from this early science.  Narayan is a co-founder with equity interest in Topera. Wouter-Jan Rappel, PhD, holds equity interest in Topera. John Miller, MD, has received modest honoraria from Topera. Shivkumar is an unpaid advisor to Topera, and the other authors report no relationship with Topera.
 
Other authors included John Miller, MD, chief of electrophysiology at Indiana University; David Krummen, MD, associate professor of medicine with UC San Diego Sulpizio Cardiovascular Center and associate director of electrophysiology at the San Diego Veterans Affairs Medical Center; Wouter-Jan Rappel, PhD, University of California San Diego Department of Theoretical Biological Physics; and Paul Clopton from the San Diego Veterans Affairs Medical Center Department of Statistics.

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Media Contacts: Kim Edwards, UC San Diego, 619-543-6163, kedwards@ucsd.edu; Rachel Champeau, UCLA, 310-794-2270, rchampeau@mednet.ucla.edu

Imaging technique offers novel way to monitor neurodegenerative disorders in live animal models of Parkinson’s disease

Using a two-photon microscope capable of peering deep within living tissue, researchers at the University of California, San Diego School of Medicine have found new evidence that alpha-synuclein protein build-up inside neurons causes them to not only become “leaky,” but also to misfire due to calcium fluxes.

The findings – the first recorded in vivo using a transgenic mouse model of Parkinson’s disease – are published in the July 18 issue of The Journal of Neuroscience and provide new insights into how Parkinson’s disease and other neurodegenerative disorders known as synucleinopathies work and progress at the cellular level.

Previous in vitro studies using cell cultures had suggested abnormal accumulation of alpha-synuclein dysregulated intracellular handling and movement of calcium, which is used as a signaling molecule and neurotransmitter. It was unclear, however, whether calcium alterations occurred in more complex, living animals.

“This is the first time we’ve been able to verify the role of alpha-synuclein aggregates in vivo,” said senior author Eliezer Masliah, MD, professor of neurosciences and pathology.

“The aggregates affect the cell membrane of neurons, making them more porous. They also affect the membranes of organelles inside neurons, such as the mitochondria that are part of the cell’s machinery for generating energy. Energy is necessary to pump calcium in and out of the cell. If mitochondria membranes are compromised, calcium accumulates, further damaging the neuron and causing it to misfire.”

Masliah said the new revelations, made using imaging technologies developed by first author Anna Devor, PhD, associate adjunct professor of neuroscience, may help scientists and doctors quantify and repair neuronal damage caused by alpha-synuclein accumulation.

“We have already started to utilize this discovery as a bio-marker and reporter of neuronal damage,” said Masliah. “We have compounds developed in collaboration with others to ‘plug’ the holes in the neurons and mitochondria and prevent the abnormal calcium currents. We can monitor in real-time in live animals how our drugs revert the toxic effects of alpha-synuclein. This represents a unique and fast strategy to evaluate novel compounds.”

Co-authors are Lidia Reznichenko, Qun Cheng, Krystal Nizar, Payam A. Saisan, Edward M. Rockenstein, Tanya Gonzalez, Christina Patrick, Brian Spencer and Paula Desplats, Department of Neurosciences, UCSD; Sergey L. Gratiy, Department of Radiology, UCSD; Anders M. Dale, departments of Neurosciences and Radiology, UCSD; Anna Devor, departments of Neurosciences and Radiology, UCSD; and Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School.

Funding for this research came, in part, from the National Institute on Aging (grant AG-02270), The National Institute of Neurological Disorders and Stroke (grants NS-051188, NS-057198 and NS-0507096), the National Institute of Biomedical Imaging and Bioengineering (grants EB-009118 and EB-000790) and the Short Family Fund.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Karim Kader, MD, PhD, associate clinical professor at the UC San Diego School of Medicine, together with a team of researchers from Wake Forest University School of Medicine, have developed a genetic test to predict a man’s risk for prostate cancer. Use of the test could reduce the need for repeat biopsies in men who have had a negative biopsy. Results of the multicenter study were recently published online in the journal of European Urology.

Karim Kader, MD, PhD, urologic surgeon at UC San Diego Health System.

“The genetic test outperformed the PSA test in assessing cancer risk,” said Kader, co-investigator and urologic surgeon at UC San Diego Health System. “If results of this blood test were factored into prostate cancer predictors such as total free PSA, free PSA, number of core samples taken at biopsy, and family history, we would have a more accurate picture of a whether or not a man is likely to develop the sometimes fatal disease.”

Kader and researchers evaluated 1,654 men in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) clinical trial. All the men had biopsies and consented to genetic studies that looked for the presence of germline single nucleotide polymorphisms (SNPs). SNPs are genetic variations within an individual’s DNA sequence which may have a positive association with prostate cancer risk as well as other chronic diseases.

“Avoiding repeat procedures, particularly in older men, can help reduce the risk of infection and potential hospitalizations,” said Kader. “The genetic score is available at any time in a man’s lifetime and could be used as a pre-screening test thus leaving aggressive PSA screening to men at a higher genetic risk.”

About 1 man in 6 will be diagnosed with prostate cancer during his lifetime. In 2012, more than 241,700 new cases of prostate cancer will be diagnosed. During the course of diagnosing patients, more than one million men are biopsied each year in the U.S. Approximately 30 percent go on to have repeat biopsies.

Funding for this study was partially supported by a National Cancer Institute RC2 grant (CA148463) and a research contract by GlaxoSmithKline.

Researchers included Kader and Jianfeng Xu who led the team from Wake Forest University School of Medicine, including Jielin Sun, Seong-Tae Kim, Fang-Chi Hsu, Ralph B. D’Agostino Jr.,  Sha Tao, Zheng Zhang, Aubrey R. Turner, Deborah A. Meyers, Eugene R. Bleecker, Frank M. Torti, John D. McConnell and S. Lilly Zheng; Brian H. Reck and Paul J. Newcombe, Greg T. Platek,  Colin F. Spraggs, John C. Whittaker, Lynn D. Condreay, and Roger S. Rittmaster of GlaxoSmithKline; Brian R. Lane of Spectrum Health; William B. Isaacs of Johns Hopkins Medical Institutions; and Jeffery M. Trent of Van Andel Research Center.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

2012 US News & World Report ranks health system among the nation’s best

UC San Diego Health System is ranked among the nation’s best in U.S. News & World Report’s 23rd annual “America’s Best Hospitals” issue.  The magazine ranked UC San Diego Health System #1 in the San Diego metropolitan area.

UC San Diego Health System is ranked #1 in the region by U.S. News & World Report.

“As the region’s only academic health system, we are proud to be recognized as San Diego’s top hospital,” said Paul Viviano, CEO, UC San Diego Health System.  “Patients seek out UC San Diego Health System for our ability to provide superior care for the full spectrum of medical needs including the most serious and rare conditions. To be recognized for this dedication, at a national level, is a credit to our physicians, nurses and staff.”   

UC San Diego Medical Center was ranked in four categories including geriatrics (#37), nephrology (#32), pulmonology (#22) and urology (#37).  Additionally, it ranked “high-performing” in cancer; cardiology & heart surgery; diabetes & endocrinology; ear, nose & throat; gastroenterology, gynecology, neurology & neurosurgery; orthopedics; psychiatry; and rheumatology.
 
“By translating our research findings into lifesaving medical and surgical care, we have a profound impact on health care locally and nationally,” said David Brenner, MD, vice chancellor for Health Sciences and dean of UC San Diego School of Medicine. “This top ranking also reflects our expertise in training physicians who deliver compassionate, leading-edge care while pushing the boundaries of medical practice.”

This year’s Best Hospitals edition showcases more than 720 of the nation’s roughly 5,000 hospitals. Whereas UC San Diego is ranked in four of 16 medical specialties, nationally, fewer than 150 are ranked nationally in at least one of 16 medical specialties.

“The hospital rankings are like a GPS-type aid to help steer patients to hospitals with strong skills in the procedures and medical conditions that present the biggest challenges,” said U.S. News Health Rankings Editor Avery Comarow.  “They are where other hospitals send the toughest cases.”

The rankings were published by U.S. News in collaboration with RTI International, a research organization based in Research Triangle Park, N.C. Highlights of the 2012-13 rankings will appear in the U.S. News Best Hospitals 2013 guidebook, to go on sale in August.

The complete rankings and methodology are available at http://health.usnews.com/best-hospitals.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Researchers at the UC San Diego School of Medicine are evaluating a new social media tool called Wellaho to treat patients with type I and II diabetes. The clinical trial will study whether the use of social networking can improve patient-physician interactions and the patient’s overall health and wellbeing.

Jason Bronner, MD, UC San Diego Health System

“This trial will study how an online social network may better enable patient care,” said Jason Bronner, MD, associate clinical professor, UC San Diego School of Medicine and internist at UC San Diego Health System. “With a controlled group of the patient’s clinicians, friends, family and fellow patients, we will measure any changes in knowledge, attitudes and self care towards diabetes.”

Wellaho, developed by Sanitas Inc. in La Jolla, is an interactive online system designed to help patients manage their care outside the hospital. The system is HIPAA compliant, compatible with provider networks, and includes telemedicine capabilities.

“Social networking provides a common way for patients with chronic disease to learn about their condition while interacting with others in similar situations,” said Bronner. “As opposed to open networks, the use of this tool allows us to ensure that the medical information they receive and share is accurate, safe and absent of advertising.”

The online site provides self-monitoring tools as well as evidenced-based education customized for the patient’s specific condition. Subjects will be monitored for the number of times they access the site, length of use, and number of invited participants. The site will also track measures of weight, blood pressure, and glycostated hemoglobin.

“Long-term, we hope that patients will learn behaviors that impact blood sugar, control blood pressure, improve satisfaction and potentially decrease cost of care,” said Bronner.

According to the American Diabetes Association, diabetes now affects 25.8 million children and adults in the United States. An additional 79 million Americans are considered pre-diabetic.

To learn more about this clinical trial, please call 858-657-8000.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Pair helps remove and prevent misfolding of proteins that cause neurodegeneration

In a paper published in the July 11 online issue of Science Translational Medicine, researchers at the University of California, San Diego School of Medicine have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington’s disease (HD).
 

A human neuron. UC San Diego scientists have identified a pair of proteins that help clear away other misfolded proteins responsible for the progressive degeneration of brain cells in Huntington’s disease.

The findings explain a fundamental aspect of how HD wreaks havoc within cells and provides “clear, therapeutic opportunities,” said principal investigator Albert R. La Spada, MD, PhD, professor of cellular and molecular medicine, chief of the Division of Genetics in the Department of Pediatrics and associate director of the Institute for Genomic Medicine at UC San Diego.

“We think the implications are significant,” said La Spada. “It’s a lead we can vigorously pursue, not just for Huntington’s disease, but also for similar neurodegenerative conditions like Parkinson’s disease and maybe even Alzheimer’s disease.”

In HD, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells, leading to progressive deterioration of involuntary movement control, cognitive decline and psychological problems. More than 30,000 Americans have HD. There are no effective treatments currently to either cure the disease or slow its progression.

La Spada and colleagues focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function.

“It’s all about energy,” La Spada said. “Neurons have a constant, high demand for it. They’re always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity.”

Previous studies by La Spada and others discovered that the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha. “This study confirms that,” La Spada said. More surprising was the discovery that elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins.

Specifically, PGC-1alpha influenced expression of another protein vital to autophagy – the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival.

“Mitochondria get beat up and need to be recycled,” La Spada said. “PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. We were unaware of this connection before, because TFEB is a relatively new player, though clearly emerging as a leading actor.  We discovered that even without PGC-1alpha induction, TFEB can prevent htt aggregation and neurotoxicity.”

In their experiments, HD mice crossbred with mice that produced greater levels of PGC-1alpha showed dramatic improvement. Production of misfolded proteins was essentially eliminated and the mice behaved normally. “Degeneration of brain cells is prevented. Neurons don’t die,” said La Spada.

PGC-1alpha and TFEB provide two new therapeutic targets for Huntington’s disease, according to La Spada. “If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time. If we could achieve the level of increased function necessary to eliminate misfolded proteins, we might nip the disease process in the bud. That would go a long way toward treating this devastating condition.”

Co-authors are Taiji Tsunemi, Travis D. Ashe and Bradley E. Morrison, Department of Pediatrics, UCSD; Kathryn R. Soriano, Jonathan Au and Vincent A. Damian, Department of Laboratory Medicine, University of Washington; Ruben A. Vazquez Roque, Department of Pathology, UCSD; Eduardo R. Lazarowski, Department of Medicine, University of North Carolina; and Eliezer Masliah, Departments of Pathology and Neurosciences, UCSD.  
 
Funding for this research came, in part, from the Hereditary Disease Foundation, the CHDI and the National Institutes of Health (grant numbers R01 AG033083, R01 NS065874, P01 HL034322, R01 AG018440, R01 NS057096 and R01 AG022074).

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Researchers say lab-based tests may be boon to both clinicians and researchers

In the current online issue of PLoS ONE, researchers at the University of California, San Diego School of Medicine say they have identified a set of laboratory-based biomarkers that can be useful for understanding brain-based abnormalities in schizophrenia. The measurements, known as endophenotypes, could ultimately be a boon to clinicians who sometimes struggle to recognize and treat the complex and confounding mental disorder.

“A major problem in psychiatry is that there are currently no laboratory tests that aid in diagnosis, guide treatment decisions or help predict treatment response or outcomes,” said Gregory A. Light, PhD, associate professor of psychiatry and the study’s first author. “Diagnoses are currently based on a clinician's ability to make inferences about patients' inner experiences.”

Diagnosing and treating schizophrenia is a particularly troubling challenge. The disorder, which affects about 1 percent of the U.S. population or roughly 3 million people, is characterized by a breakdown of normal thought processes and erratic, sometimes dangerous or harmful, behaviors.

“Schizophrenia is among the most severe and disabling conditions across all categories of medicine,” said Light, who also directs the Mental Illness, Research, Education and Clinical Center at the San Diego VA Healthcare System.

The precise cause or causes of schizophrenia are not known, though there is a clear genetic component, with the disorder more common in some families.

Clinicians typically diagnose schizophrenia based upon inferences drawn from the patient’s inner experiences. That is, their ability to describe what’s happening inside their minds.

“But even the best clinicians struggle with diagnostic complexities based on sometimes fuzzy clinical phenomenology,” said Light. The clinical challenge is compounded by the fact that “many schizophrenia patients have cognitive and functional impairments,” said Light. They may not be able to reasonably explain how or what they think.

Light and colleagues investigated whether a select battery of neurophysiological and neurocognitive biomarkers could provide clinicians with reliable, accurate, long-term indicators of brain dysfunction, even when overt symptoms of the disorder were not apparent. These markers ranged from tests of attention and memory to physiological assessments of basic perceptual processes using scalp sensors to measure brain responses to simple sounds.

The researchers measured the biomarkers in 550 schizophrenia patients, and then re-tested 200 of the patients one year later. They found that most of the markers were significantly abnormal in schizophrenia patients, were relatively stable between the assessments and were not affected by modest fluctuations in clinical status of the patient.

Light said further research is required, including whether the endophenotypes can differentiate other psychiatric disorders, be used to anticipate patient response to different kinds of drugs or non-pharmacological interventions or even be used to predict which subjects are at high risk of developing a psychotic illness.

“We believe this paper is an important step towards validating laboratory-based biomarkers for use in future genomic and clinical treatment studies of schizophrenia,” Light said.

Co-authors are Neal R. Swerdlow, Anthony J. Rissling and Marlena Pela, Department of Psychiatry, UCSD; Allen Radant, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle; Catherine A. Sugar, Departments of Psychiatry and Biostatistics, UCLA; Joyce Sprock, Mark A. Geyer and David L. Braff, Mental Illness, Research, Education and Clinical Center, San Diego VA Healthcare System and Department of Psychiatry, UCSD.

Funding for this research came, in part, from National Institute of Mental Health grants MH042228, MH079777 and MH065571 and the Department of Veterans Affairs.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Researchers describe inflammatory mechanism for first time

The biological mechanism of sunburn – the reddish, painful, protective immune response from ultraviolet (UV) radiation – is a consequence of RNA damage to skin cells, report researchers at the University of California, San Diego School of Medicine and elsewhere in the July 8, 2012 Advance Online Publication of Nature Medicine.

The findings open the way to perhaps eventually blocking the inflammatory process, the scientists said, and have implications for a range of medical conditions and treatments.

A photomicrograph of superficial keratinocytes or skin cells. Image courtesy of Thomas Deerinck, National Center for Microscopy and Imaging Research, UC San Diego.

“For example, diseases like psoriasis are treated by UV light, but a big side effect is that this treatment increases the risk of skin cancer,” said principal investigator Richard L. Gallo, MD, PhD, professor of medicine at UC San Diego School of Medicine and Veterans Affairs San Diego Healthcare System. “Our discovery suggests a way to get the beneficial effects of UV therapy without actually exposing our patients to the harmful UV light. Also, some people have excess sensitivity to UV light, patients with lupus, for example. We are exploring if we can help them by blocking the pathway we discovered.”

Using both human skin cells and a mouse model, Gallo, first author Jamie J. Bernard, a post-doctoral researcher, and colleagues found that UVB radiation fractures and tangles elements of non-coding micro-RNA – a special type of RNA inside the cell that does not directly make proteins. Irradiated cells release this altered RNA, provoking healthy, neighboring cells to start a process that results in an inflammatory response intended to remove sun-damaged cells.

We see and feel the process as sunburn.

“The inflammatory response is important to start the process of healing after cell death,” said Gallo. “We also believe the inflammatory process may clean up cells with genetic damage before they can become cancer. Of course, this process is imperfect and with more UV exposure, there is more chance of cells becoming cancerous.”

Gallo said it’s still not known how gender, skin pigmentation and individual genetics may affect the mechanism of sunburn. “Genetics is closely linked to the ability to defend against UV damage and develop skin cancers,” he said. “We know in our mouse genetic models that specific genes will change how the mice get sunburn. Humans have similar genes, but it is not known if people have mutations in these genes that affect their sun response.”

Jamie J. Bernard is currently at the Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University. Other co-authors are Christopher Cowing-Zitron, Teruakai Nakatsuji, Beda Muehleisen, Jun Muto, Andrew W. Borkowski and Benjamin D. Yu, Division of Dermatology, UC San Diego; Laisel Martinez, Miami Veterans Affairs Medical Center; and Eric L. Greidinger, Miami Veterans Affairs Medical Center and Division of Rheumatology, University of Miami Miller School of Medicine.

Funding for this research came, in part, from National Institutes of Health grants R01-AR052728, R01-A1052453 and R01-A10833358, a Veteran Affairs Merit Award, National Institute of Environmental Health Sciences Training Grant ES007148 and NIEHS Center Grant ES005022, Department of Veterans Affairs, NIH AR48805 and the Lupus Research Institute.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

In the July 6 issue of Cell Stem Cell, researchers at the University of California, San Diego School of Medicine describe how human epidermal progenitor cells and stem cells control transcription factors to avoid premature differentiation, preserving their ability to produce new skin cells throughout life.

The findings provide new insights into the role and importance of exosomes and their targeted gene transcripts, and may help point the way to new drugs or therapies for not just skin diseases, but other disorders in which stem and progenitor cell populations are affected.

A magnification of the four distinct strata of human skin. At the top is the stratum corneum consisting of several layers of flat, dead, waterproof keratinocytes – the outer layer of skin cells. Beneath the stratum corneum are the strata granulosum, spinosum and basale. It is in the stratum basale that resident stem cells differentiate to provide new cells and renew the skin. Below the stratum basale is the dermis, a collagen rich tissue that cushions the body.

Stem cells, of course, are specialized cells capable of endlessly replicating to become any type of cell needed, a process known as differentiation. Progenitor cells are more limited, typically differentiating into a specific type of cell and able to divide only a fixed number of times.

Throughout life, human skin self-renews. Progenitor and stem cells deep in the epidermis constantly produce new skin cells called keratinocytes that gradually rise to the surface where they will be sloughed off. One of the ways that stem and progenitor cells maintain internal health during their lives is through the exosome – a collection of approximately 11 proteins responsible for degrading and recycling different RNA elements, such as messenger RNA that wear out or that contain errors resulting in the translation of dysfunctional proteins which could potentially be deleterious to the cell.

“In short,” said George L. Sen, PhD, assistant professor of medicine and cellular and molecular medicine, “the exosome functions as a surveillance system in cells to regulate the normal turnover of RNAs as well as to destroy RNAs with errors in them.”

Sen and colleagues Devendra S. Mistry, PhD, a postdoctoral research fellow, and staff scientist Yifang Chen, MD, PhD, discovered that in the epidermis the exosome functions to target and destroy mRNAs that encode for transcription factors that induce differentiation. Specifically, they found that the exosome degrades a transcription factor called GRHL3 in epidermal progenitor cells, keeping the latter undifferentiated. Upon receiving differentiation inducing signals, the progenitor cells lose expression of certain subunits of the exosome which leads to higher levels of GRHL3 protein. This increase in GRHL3 levels promotes the differentiation of the progenitor cells.

“Without a functioning exosome in progenitor cells,” said Sen, “the progenitor cells prematurely differentiate due to increased levels of GRHL3 resulting in loss of epidermal tissue over time.”

Sen said the findings could have particular relevance if future research determines that mutations in exosome genes are linked to skin disorders or other diseases. “Recently there was a study showing that recessive mutations in a subunit of the exosome complex can lead to pontocerebellar hypoplasia, a rare neurological disorder characterized by impaired development or atrophy of parts of the brain,” said Sen. “This may potentially be due to loss of progenitor cells. Once mutations in exosome complex genes are identified in either skin diseases or other diseases like pontocerebellar hypoplasia, it may be possible to design drugs targeting these defects.”

Funding for this research came, in part, from the National Institutes of Health grant K01AR057828-04 and a Ray Thomas Edwards Award.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

It’s not just our DNA that makes us susceptible to disease and influences its impact and outcome. Scientists are beginning to realize more and more that important changes in genes that are unrelated to changes in the DNA sequence itself – a field of study known as epigenetics – are equally influential.

A research team at the University of California, San Diego – led by Gary S. Firestein, MD, professor in the Division of Rheumatology, Allergy and Immunology at UC San Diego School of Medicine – investigated a mechanism usually implicated in cancer and in fetal development, called DNA methylation, in the progression of rheumatoid arthritis (RA). They found that epigenetic changes due to methylation play a key role in altering genes that could potentially contribute to inflammation and joint damage.  Their study is currently published in the online edition of the Annals of the Rheumatic Diseases.

In this artist’s rendering, a DNA molecule is methylated on both strands at the center cytosine. DNA methylation plays an important role in epigenetic gene regulation, and is involved in both normal development and in cancer.

“Genomics has rapidly advanced our understanding of susceptibility and severity of rheumatoid arthritis,” said Firestein.  “While many genetic associations have been described in this disease, we also know that if one identical twin develops RA that the other twin only has a 12 to 15 percent chance of also getting the disease.  This suggests that other factors are at play – epigenetic influences.”

DNA methylation is one example of epigenetic change, in which a strand of DNA is modified after it is duplicated by adding a methyl to any cytosine molecule (C) – one of the 4 main bases of DNA.  This is one of the methods used to regulate gene expression, and is often abnormal in cancers and plays a role in organ development.

While DNA methylation of individual genes has been explored in autoimmune diseases, this study represents a genome-wide evaluation of the process in fibroblast-like synoviocytes (FLS), isolated from the site of the disease in RA. FLS are cells that interact with the immune cells in RA, an inflammatory disease in the joints that damages cartilage, bone and soft tissues of the joint.

In this study, scientists isolated and evaluated genomic DNA from 28 cell lines.  They looked at DNA methylation patterns in RA FLS and compared them with FLS derived from normal individuals or patients with non-inflammatory joint disease. The data showed that the FLS in RA display a DNA methylome signature that distinguishes them from osteoarthritis and normal FLS.  These FLS possess differentially methylated (DM) genes that are critical to cell trafficking, inflammation and cell–extracellular matrix interactions.

“We found that hypomethylation of individual genes was associated with increased gene expression and occurred in multiple pathways critical to inflammatory responses,” said Firestein, adding that this led to their conclusion: Differentially methylated genes can alter FLS gene expression and contribute to the pathogenesis of RA.

Additional contributors include Kazuhisa Nakano and David L. Boyle, UCSD Department of Medicine; and John W. Whitaker and Wei Wang, UCSD Department of Chemistry and Biochemistry.

This project was supported by grant number UL1RR031980 from the National Institutes of Health’s National Center for Advancing Translational Science.

NexDx, Inc. licensed the technology from UC San Diego and provided informatics support for this study. Gary S. Firestein and Wei Wang are on the Scientific Advisory Board of NexDx, Inc.

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Media Contacts: Debra Kain, 619-543-6163, ddkain@ucsd.edu
Scott LaFee, 619-543-6163, slafee@ucsd.edu  

Regulatory sequences of mouse genome sequenced for first time

Popularly dubbed “the book of life,” the human genome is extraordinarily difficult to read. But without full knowledge of its grammar and syntax, the genome’s 2.9 billion base-pairs of adenine and thymine, cytosine and guanine provide limited insights into humanity’s underlying genetics.

In a paper published in the July 1, 2012 issue of the journal Nature, researchers at the Ludwig Institute for Cancer Research and the University of California, San Diego School of Medicine open the book further, mapping for the first time a significant portion of the functional sequences of the mouse genome, the most widely used mammalian model organism in biomedical research.

“We’ve known the precise alphabet of the human genome for more than a decade, but not necessarily how those letters make meaningful words, paragraphs or life,” said Bing Ren, PhD, head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research at UC San Diego. “We know, for example, that only one to two percent of the functional genome codes for proteins, but that there are highly conserved regions in the genome outside of protein-coding that affect genes and disease development. It’s clear these regions do something or they would have changed or disappeared.”

Chief among those regions are cis-regulatory elements, key stretches of DNA that appear to regulate the transcription of genes. Misregulation of genes can result in diseases like cancer. Using high-throughput sequencing technologies, Ren and colleagues mapped nearly 300,000 mouse cis-regulatory elements in 19 different types of tissue and cell. The unprecedented work provided a functional annotation of nearly 11 percent of the mouse genome, and more than 70 percent of the conserved, non-coding sequences shared with other mammalian species, including humans.

As expected, the researchers identified different sequences that promote or start gene activity, enhance its activity and define where it occurs in the body during development. More surprising, said Ren, was that the structural organization of the cis-regulatory elements are grouped into discrete clusters corresponding to spatial domains. “It’s a case of form following function,” he said. “It makes sense.”

While the research is fundamentally revealing, Ren noted it is also just a beginning, a partial picture of the functional genome. Additional studies will be needed in other types of cells and at different stages of development.

“We’ve mapped and understand 11 percent of the genome,” said Ren. “There’s still a long way to march.”

Co-authors are Yin Shen, Feng Yue, David F. McCleary, Zhen Ye, Lee Edsall, Samantha Kuan, Ulrich Wagner and Leonard Lee, all at the Ludwig Institute for Cancer Research; Jesse Dixon, Ludwig Institute for Cancer Research, Medical Scientist Training Program and Biomedical Sciences Graduate Program, UC San Diego; and Victor Lobanenkov, National Institute of Allergy and Infectious Diseases.

Funding for this research came, in part, from the National Human Genome Research Institute (grant R01HG003991), the Ludwig Institute for Cancer Research, the International Rett Syndrome Foundation and the California Institute for Regenerative Medicine.

About the Ludwig Institute for Cancer Research (LICR)
LICR is an international non-profit organization committed to improving the understanding and control of cancer through integrated laboratory and clinical discovery. Leveraging its worldwide network of investigators and the ability to sponsor and conduct its own clinical trials, the Institute is actively engaged in translating its discoveries into applications for patient benefit. Since its establishment in 1971, the Institute has expended more than $1.5 billion on cancer research.

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Media Contacts: Scott LaFee, UC San Diego Health Sciences, 619-543-6163, slafee@ucsd.edu
Rachel Steinhardt, Ludwig Institute for Cancer Research, 212-450-1582, rsteinhardt@licr.org  

NOTCH1 Signaling Promotes T-Cell Acute Lymphoblastic Leukemia-Initiating Cell Regeneration

Research suggests that patients with leukemia sometimes relapse because standard chemotherapy fails to kill the self-renewing leukemia initiating cells, often referred to as cancer stem cells.  In such cancers, the cells lie dormant for a time, only to later begin cloning, resulting in a return and metastasis of the disease.

One such type of cancer is called pediatric T cell acute lymphoblastic leukemia, or T-ALL, often found in children, who have few treatment options beyond chemotherapy.

A team of researchers – led by Catriona H. M. Jamieson, MD, PhD, associate professor of medicine at the University of California, San Diego School of Medicine and director of Stem Cell Research at UC San Diego Moores Cancer Center – studied these cells in mouse models that had been transplanted with human leukemia cells. They discovered that the leukemia initiating cells which clone, or replicate, themselves most robustly activate the NOTCH1 pathway, usually in the context of a mutation. The results appear online in the journal PLoS ONE.

Earlier studies showed that as many as half of patients with T-ALL have mutations in the NOTCH1 pathway – an evolutionarily conserved developmental pathway used during differentiation of many cell and tissue types.  The new study shows that when NOTCH1 activation was inhibited in animal models using a monoclonal antibody, the leukemia initiating cells did not survive.  In addition, the antibody treatment significantly reduced a subset of these cancer stem cells (identified by the presence of specific markers, CD2 and CD7, on the cell surface).

“We were able to substantially reduce the potential of these cancer stem cells to self-renew,” said Jamieson.  “So we’re not just getting rid of cancerous cells: we’re getting to the root of their resistance to treatment – leukemic stem cells that lie dormant.”

The study results suggest that such therapy would also be effective in other types of cancer stem cells, such as those that cause breast cancer, that also rely on NOTCH1 for self-renewal. 

“Therapies based on monoclonal antibodies that inhibit NOTCH 1 are much more selective than using gamma-secretase inhibitors, which also block other essential cellular functions in addition to the NOTCH1 signaling pathway,” said contributor A. Thomas Look, MD of Dana-Farber/Children Hospital Cancer Center in Boston. “We are excited about the promise of  NOTCH1-specific antibodies to counter resistance to therapy in T-ALL and possibly additional types of cancer.”

In investigating the role of NOTCH1 activation in cancer cell cloning, the researchers showed that leukemia initiating cells possess enhanced survival and self-renewal potential in specific blood-cell, or hematopoietic, niches: the microenvironment of the body in which the cells live and self-renew.

The scientists studied the molecular characterization of CD34+ cells – a protein that shows expression in early hematopoietic cells and that facilitates cell migration – from a dozen T-ALL patient samples.

They found that mutations in NOTCH1 and other genes capable of promoting the survival of cancer stem cells co-existed in the CD34+ niche.  Mice transplanted with CD34-enriched NOTCH1 mutated T-ALL cells demonstrated significantly greater leukemic cloning potential than did mice without the NOTCH1 mutation.  The mutated cells were uniquely susceptible to targeted inhibition with a human monoclonal antibody, according to the scientists.

Additional contributors to the study include Wenxue Ma, Daniel J. Goff, Ifat Geron, Anil Sadarangani, Christina A. M. Jamieson, Angela C. Court, Alice Y. Shih, Qingfei Jiang, Christina C. Wu, Kristen M. Smith, Leslie A. Crews, Ida Deichaite, Sheldon R. Morris and Dennis A. Carson, UC San Diego Department of Medicine and Stem Cell Program, UC San Diego Moores Cancer Center; Alejandro Gutierrez, Dana-Farber/Children Hospital Cancer Center in Boston; and Kang Li, Ping Wei and Neil W. Gibson, Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories, San Diego.

This work was supported by the Ratner Family Foundation, the Leichtag Family Foundation, and Moores Cancer Center Donor Funds; grants from the National Institute of Health (1K08CA133103 and 5P01CA68484); the William Lawrence Foundation, and the American Society of Hematology-Amos Medical Faculty Development program. Dr. Jamieson’s work was supported by the California Institute for Regenerative Medicine (CIRM).

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Discovery could help lead to prevention of radical surgery in rare childhood disease

Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.

Hemimegalencephaly

In a paper published in the June 24, 2012 online issue of Nature Genetics, a team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.

De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings – a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues – suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.

Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analyzing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva.

“Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition,” said Gleeson. Realizing they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.

The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.

“We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly,” said Gleeson. “These same mutations have been found in various solid malignancies, including breast and pancreatic cancer.  For reasons we do not yet understand, our patients do not develop cancer, but rather this unusual brain condition.  Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers.”

The mutations were found in 30 percent of the patients studied, indicating other factors are involved. Nonetheless, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.

“Although counterintuitive, hemimegalencephaly patients are far better off following the functional removal or disconnection of the enlarged hemisphere,” said Mathern. “Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, causing the seizures to stop. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay due to neural plasticity of the remaining hemisphere.”

But a less-invasive drug therapy would still be more appealing.

“We know that certain already-approved medications can turn down the signaling pathway used by the mutated genes in hemimegalencephaly,” said lead author and former UC San Diego post-doctoral researcher Jeong Ho Lee, now at the Korea Advanced Institute of Science and Technology. “We would like to know if future patients might benefit from such a treatment. Wouldn’t it be wonderful if our results could prevent the need for such radical procedures in these children?”

Co-authors are My Huynh, department of Neurosurgery and Psychiatry and Biobehavioral Sciences, Mattel Children’s Hospital, Geffen School of Medicine, UCLA;  Jennifer L. Silhavy, Tracy Dixon-Salazar, Andrew Heiberg, Eric Scott, Kiley J. Hill and Adrienne Collazo, Institute for Genomic Medicine, Rady Children’s Hospital, UC San Diego and Howard Hughes Medical Institute; Sangwoo Kim and Vineet Bafna, Department of Computer Sciences, Jacobs School of Engineering, UC San Diego; Vincent Furnari and Carsten Russ, Institute for Medical Genetics, Cedars-Sinai Medical Center, Los Angeles and Department of Pediatrics, Geffen School of Medicine, UCLA; and Stacey B. Gabriel, The Broad Institute of MIT and Harvard, Cambridge.

Funding for this research came, in part, from the Daland Fellowship from the American Philosophical Society, the National Institutes of Health (grants R01 NS038992, R01 NS048453, R01 NS052455, R01 NS41537 and P01 HD070494), the Simons Foundation Autism Research Initiative and the Howard Hughes Medical Institute.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Psoriasis is an autoimmune disorder in which skin cells proliferate out of control. For some hard-to-heal wounds, the problem is just the opposite: Restorative skin cells don’t grow well or fast enough. In a paper published in the June 21, 2012 issue of Immunity, researchers at the University of California, San Diego School of Medicine describe a molecule that may lead to new treatments for both problems.

A stained cross-sectional slide, magnified 10 times, of human epidermal and dermal skin layers, both normal.

An international team of scientists led by principal investigator Richard L. Gallo, MD, PhD, professor of medicine and chief of UC San Diego’s Division of Dermatology, and first author Yuping Lai, PhD, professor of microbiology and immunity at East China Normal University in Shanghai, analyzed skin biopsies of patients with and without psoriasis, as well as the skin of mice with psoriasis and with wounds on their backs. They discovered that a molecule called regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in skin cells during psoriasis and wound-healing, but not under normal skin conditions.

In tests on mice, researchers found that inhibiting REG3A slowed wound-healing but cleared up psoriasis, which is commonly characterized by patches of inflammation and white, scaly skin.

The scientists also noted that REG3A acts in concert with interleukin-17 (IL-17), an immune system protein involved in the signaling cascade which prompts skin cells to multiply in excess numbers. “IL-17 binds to receptors on skin cells and causes REG3A to be expressed, which then binds to another protein inside the cells that promotes cell growth,” said  Lai.

Gallo said the discovery of REG3A’s dual roles provides a new target for different therapies.

“A drug that inhibits the expression of REG3A could represent a more targeted way to treat psoriasis without the systemic immunosuppression problems of current treatments," added Lai. "Conversely, a drug that stimulates or mimics REG3A could boost cell growth and improve wound healing.”

Co-authors are Dongqing Li, Changwei Li, Ziwei Jiang, Zhiheng Li, Hu Lei, Yanchun Quan and Tian Zhang, all at the Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University; Beda Muhleisen, Paul Kotol and Tissa R. Hata, Division of Dermatology, Departments of Medicine and Pediatrics, UC San Diego; Katherine A. Radek, Department of Surgery, Burn and Shock Trauma Institute, Loyola University, Chicago; Hyun Jeong Park, Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul; Shin Morizane and Keiji Iwatsuki, Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan; Ge Tang, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo.

Funding for this research came, in part, from the National Institutes of Health (grants AR052728, AI052453, AI083358), the National Natural Science Foundation of China and the Science and Technology Commission of Shanghai Municipality.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Researchers at the University of California, San Diego School of Medicine have uncovered a new signal transduction pathway specifically devoted to the regulation of alternative RNA splicing, a process that allows a single gene to produce or code multiple types of protein variants. The discovery, published in the June 27, 2012 issue of Molecular Cell, suggests the new pathway might be a fruitful target for new cancer drugs.

Signal transduction in the cell involves kinases and phosphatases, enzymes that transfer or remove phosphates in protein molecules in a cascade or pathway. SRPK kinases, first described by Xiang-Dong Fu, PhD, professor of cellular and molecular medicine at UC San Diego in 1994, are involved in controlling the activities of splicing regulators in mammalian cells.

Prior studies have implicated SRPK1 in cancer and other human diseases.  For example, it has been shown that SRPK1 plays a critical role in regulating the function of Vascular Endothelial Growth Factor or VEGF, which stimulates blood vessel growth in cancer. SRPK1 has been found to be dysregulated in a number of cancers, from kidney and breast to lung and pancreatic.

Conversely, studies suggest the absence of SRPK1 may be problematic as well, at least in terms of controlling some specific cancer phenotypes. Reduced SRPK1, for example, has been linked to drug resistance, a major problem in chemotherapy of cancer.

In their new paper, Fu and colleagues place SRPK1 in a major signal transduction pathway in the cell. “The kinase sits right in the middle of the PI3K-Akt pathway to specifically relay the growth signal to regulate alternative splicing in the nucleus,” said Fu. “It’s a new signaling branch that has previously escaped detection.”

As such, the SRPK offers a new target for disease intervention and treatment, researchers say. “It’s a good target because of its central role and because it can be manipulated with compounds that suppress its activity, which appears quite effective in suppressing blood vessel formation in cancer,” Fu said.

Co-authors of the paper are Zhihong Zhou, Jinsong Qiu, Yu Zhou and Hairi Li, Department of Cellular and Molecular Medicine, UC San Diego; Liu Wen, Qidong Hu and Michael G. Rosenfeld, Howard Hughes Medical Institute, Department of Medicine; Ryan M. Plocinik and Joseph A. Adams, Department of Pharmacology, UC San Diego; and Gourisanker Ghosh, Department of Chemistry and Biochemistry, UC San Diego.

Funding came, in part, from National Institutes of Health grants GM52872, HG004659 and GM67969, the Ruth L. Kirchstein National Research Service Award (GM090484) and the Howard Hughes Medical Institute.

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Media contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Single treatment produces long-term improvement in animal models

With a single drug treatment, researchers at the Ludwig Institute for Cancer Research at the University of California, San Diego School of Medicine can silence the mutated gene responsible for Huntington’s disease, slowing and partially reversing progression of the fatal neurodegenerative disorder in animal models.

The findings are published in the June 21, 2012 print issue of the journal Neuron.

Stained mouse neurons. Image courtesy of Taylor Bayouth.

Researchers suggest the drug therapy, tested in mouse and non-human primate models, could produce sustained motor and neurological benefits in human adults with moderate and severe forms of the disorder. Currently, there is no effective treatment.

Huntington’s disease afflicts approximately 30,000 Americans, whose symptoms include uncontrolled movements and progressive cognitive and psychiatric problems. The disease is caused by the mutation of a single gene, which results in the production and accumulation of toxic proteins throughout the brain.

Don W. Cleveland, PhD, professor and chair of the UC San Diego Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research, and colleagues infused mouse and primate models of Huntington’s disease with one-time injections of an identified DNA drug based on antisense oligonucleotides (ASOs). These ASOs selectively bind to and destroy the mutant gene’s molecular instructions for making the toxic huntingtin protein.

The singular treatment produced rapid results. Treated animals began moving better within one month and achieved normal motor function within two. More remarkably, the benefits persisted, lasting nine months, well after the drug had disappeared and production of the toxic proteins had resumed.

“For diseases like Huntington's, where a mutant protein product is tolerated for decades prior to disease onset, these findings open up the provocative possibility that transient treatment can lead to a prolonged benefit to patients,” said Cleveland. “This finding raises the prospect of a ‘huntingtin holiday,’ which may allow for clearance of disease-causing species that might take weeks or months to re-form. If so, then a single application of a drug to reduce expression of a target gene could ‘reset the disease clock,’ providing a benefit long after huntingtin suppression has ended.”

 Beyond improving motor and cognitive function, researchers said the ASO treatment also blocked brain atrophy and increased lifespan in mouse models with a severe form of the disease. The therapy was equally effective whether one or both huntingtin genes were mutated, a positive indicator for human therapy.

Cleveland noted that the approach was particularly promising because antisense therapies have already been proven safe in clinical trials and are the focus of much drug development. Moreover, the findings may have broader implications, he said, for other “age-dependent neurodegenerative diseases that develop from exposure to a mutant protein product” and perhaps for nervous system cancers, such as glioblastomas.

Co-authors are first author Holly B. Kordasiewicz, Melissa M. McAlonis, Kimberly A. Pytel and Jonathan W. Artates, Ludwig Institute for Cancer Research and UC San Diego Department of Cellular and Molecular Medicine; Lisa M. Stanek, Seng H. Cheng and Lamya S. Shihabuddin, Genzyme Corporation; Edward V. Wancewicz, Curt Mazur, Gene Hung and C. Frank Bennett, Isis Pharmaceuticals; and Andreas Weiss, Novartis Institutes for BioMedical Research.

Funding for this research came, in part, from the CHDI Foundation.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Named as “Leader in LGBT Healthcare Equality” by National Survey

UC San Diego Health System has been recognized as a “Leader in LGBT Healthcare Equality” in the Healthcare Equality Index 2012 report, an annual survey conducted by the Human Rights Campaign (HRC) Foundation. The academic health system earned top marks for its commitment to equitable, inclusive care for lesbian, gay, bisexual and transgender (LGBT) patients and their families, who can face challenges in accessing adequate health care.

UC San Diego Health System has hospitals in La Jolla and Hillcrest and specialty clinics throughout the region.

“On behalf of UC San Diego Health System, I would like to express our pride in receiving this national recognition,” said Margarita Baggett, MSN, RN, chief nursing officer and interim chief operating officer at UC San Diego Health System. “We are committed to the equitable and inclusive care of all patients and families who visit our medical centers. Compassion is at the heart of what we do.”

Facilities awarded this title meet several key indicators for equitable care, including nondiscrimination policies for LGBT patients and employees, a guarantee of equal visitation for same-sex partners and parents, and LGBT health education for key staff. 

UC San Diego Health System was congratulated by HRC Family Project Director Ellen Kahn. “LGBT patients deeply appreciate the welcoming environment provided by a Leader in LGBT Healthcare Equality. It makes a big difference to know that your local health care facility is fully committed to giving you the same care it gives your neighbors and co-workers.”

UC San Diego Health System was one of a select group of 234 health care facilities nationwide to be named Leaders in Healthcare Equality.

The HRC Foundation is the educational arm of the country’s largest LGBT organization. For more information about the Healthcare Equality Index 2012, or to download a free copy of the report, visit www.hrc.org/hei.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Justin M. Brown, MD, reconstructive neurosurgeon at UC San Diego Health System, is one of only a few specialists in the world who have pioneered a novel technique to restore hand function in patients with spinal cord injury. In a delicate four-hour procedure, Brown splices together tiny nerve endings, only one millimeter in width, to help restore hand mobility. Most patients return home 24 hours after surgery.

Justin Brown, MD, neurosurgeon, UC San Diego Health System

“Even if a patient appears to have lost total hand function, as long as there is some nerve in the arm or shoulder under the patient’s control, some mobility may be regained,” said Brown, director of the Neurosurgery Peripheral Nerve Program and co-director of the Center for Neurophysiology and Restorative Neurology at UC San Diego Health System. “With a nerve transfer, the goal is to reverse paralysis. This means achieving functional grasp and release so that patients can eat independently, operate a computer or hold a loved one’s hand.”

Brown and his team treat hand impairments at cervical level 5 and below. Operating under a microscope, Brown disconnects the damaged nerve and reconnects it to a healthy one. The healthy nerve is taken from underneath the muscles of the upper arm and then connected to a nerve branch that provides finger function.  In contrast to muscle transfers, nerve transfers allow whole muscle groups to be restored in the arm without visibly changing the body’s anatomy.

“The nerves grow at a rate of 1 millimeter per day,” said Brown, who is also founding member and first president of the International Society for Restorative Neurology. “Over a period of six to 12 months, patients can essentially wake up their arms and hands and return to a satisfying level of functionality and improved quality of life.”

Brown said that patients occasionally experience temporary weakness where the original healthy nerve is taken. These muscles, however, can recover their original strength. Casting and immobilization is seldom needed after the surgery. He added that the overall result is that multiple hand functions can be restored with a single transplant.

“The recovery of hand function is consistently rated as the highest priority for persons with quadriplegia,” said Brown. “While nerve transfers take longer to heal so that axons can regenerate, patients often experience better long-term biomechanical outcomes.”

In the United States there are approximately 300,000 people living with spinal cord injuries with 12,000 new injuries occurring each year. More than half of these injuries result in neck-level injures that lead to loss of hand and arm function. Brown said this technique may also be offered in select cases to patients with paralysis as a result of trauma, stroke, or brain injury.

Brown earned his medical degree from the Eastern Virginia Medical School in Norfolk. He completed a surgical internship and neurosurgical residency at Baylor College of Medicine in Houston and a peripheral nerve fellowship in the Division of Plastic and Reconstructive Surgery at Washington University School of Medicine.  He was formerly co-director of the Peripheral Nerve Center at Washington University in St. Louis.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Sequencing Protein-making Part of Genome Can Change Diagnosis and Patient Care

In the June 13 issue of Science Translational Medicine, an international team led by researchers from the University of California, San Diego School of Medicine reports that the new technology of exome sequencing is not only a promising method for identifying disease-causing genes, but may also improve diagnoses and guide individual patient care.

In exome sequencing, researchers selectively and simultaneously target and map all of the portions of the genome where exons reside. Exons are short, critical sequences of DNA in genes that are translated into proteins – the biological workhorses involved in virtually every cellular function, plus various structural or mechanical duties.

Joseph G. Gleeson, MD

The researchers, headed by principal investigator Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego and Rady Children’s Hospital-San Diego, sequenced the exomes of 118 patients who had been diagnosed with specific neurodevelopmental diseases. In each of the cases, all known genetic causes of their disease had been previously excluded.

Not surprisingly, the scientists found that exome sequencing newly identified numerous disease-causing genes, including the identification of the EXOC8 gene as a cause of Joubert syndrome, a condition affecting the developing cerebellum, and GFM2 as a cause for a condition that results in a small brain combined with pediatric diabetes.

More surprising, the researchers discovered that in approximately 10 percent of cases, exome sequencing led to the identification of a known disease-causing gene, prompting a change in diagnosis and care for some patients.  

“Initially, we were surprised to find mutations in genes already known to cause human disease, because we had previously excluded the known causes based upon the patient diagnosis,” said Gleeson.  “When we went back to the patients to figure out what had happened, we determined that, in each case, the original diagnosis did not agree with the genetic diagnosis. This happened in about 10 percent of the cases we studied, even though the patients had been diagnosed according to standard clinical practice.”

In each case, the researchers determined that the genetic diagnosis was fully correct, and by careful review of the patient record, determined that the original diagnosis was incorrect. “If we extrapolate these results to the general population seen in these clinics, we can infer that a large number of patients could possibly have their diagnosis and treatment modified by advanced genetic testing.”

Gleeson said the reason for these inconsistencies were manifold, but did not reflect errors in medical diagnosis – at least none that the research team could identify.  Instead, he said the differences highlight the inherent difficulty of achieving specific diagnoses, particularly given the complexities of brain development and function.

Tracy Dixon-Salazar, PhD, a member of Gleeson’s lab and first author of the study, said the findings provide proof that exome sequencing in the clinic can be a valuable tool for diagnosing disease, especially in patients like those with neurodevelopmental disorders where the prognosis is poor and treatments are limited.  

Co-authors are Jennifer L. Silhavy, Jana Schroth, Stephanie Bielas, Ashleigh E. Schaffer, Jesus Olvera, Kiley J. Hill, Adrienne Collazo, Ali G. Fenstermaker, Gaia Navarino and Naiara Akizu, Howard Hughes Medical Institute, UC San Diego Institute for Genomic Medicine, Rady Children’s Hospital; Nitin Udpa and Vineet Bafna, Department of Computer Sciences, School of Engineering, UC San Diego; Maha S. Zaki and Ghada H. Abdel-Salam, Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Center, Cairo, Egypt; Lobna A. Mansour, Laila Selim and Sawsan Abdel-Hadi, Cairo University Children’s Hospital; Naima Marzouki, Laboratoire Genetique Moleculaire, El Razi University Hospital, Marrakech, Morocco; Tawfeg Ben-Omran, Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar; Nouriya A. Al-Saana, Department of Pediatrics, Dhahran Health Center, Saudi Aramco Corporation, Dhahan, KSA; F. Mujgan Sonmez and Figen Celep, Child Neurology Department, Medical School of Karaderiz Technical University, Trabzon, Turkey; Matloob Azam, Department of Pediatrics and Child Neurology, Wah Medical College, Wah Cantt, Pakistan; Kiran V. Garimella, Carrie Sougnez, Carsten Russ and Stacey B. Gabriel, Broad Institute of Massachusetts Institute of Technology and Harvard.

Funding for this research came, in part, from the Howard Hughes Medical Institute; the National Institute of Neurological Disorders and Stroke grants R01N5041537, R01NS048453 and R01NS052455; National Human Genome Research Institute grants P01HD070494 and US4HG003067; National Institute on Alcohol Abuse and Alcoholism/Center for Inherited Disease Research grant N01-HG-65403; and National Science Foundation grants III-081905 and CCF-1115206.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

For many beach-goers summertime means shredding waves.  It is estimated that more than 17 million Americans are active surfers, including one million in California alone.  Even though the benefits for the body and mind are unquestionable, there are inherent health risks associated with the sport.

Kenneth Taylor, MD, practicing what he preaches.

“The most common acute injuries are sprains, strains, lacerations, dislocations and fractures, often caused by contact with the surfer’s own board,” said Kenneth Samuel Taylor, MD, professor of Family and Preventive Medicine at the UC San Diego School of Medicine. “However, this is not always the case.  In fact, some injuries are challenging for doctors to diagnose if they occurred by water because there are typically no external wounds.”

Taylor is an international expert in the field and serves as Medical Director for the International Surfing Association where he is responsible for developing medical protocols and providing medical coverage at the World Surfing Games – the world’s largest surfing tournament.

“Several safety devices, such as helmets, protective eye-wear and rubber guards for the board's fins are available, but none have proven to completely prevent injuries,” said Taylor.

The use of a surfboard leash for protection is recommended but can occasionally backfire.  Leashes keep the board near the surfer, providing a flotation device in case of an accident, as well as reducing the number of accidents caused by run-away boards hitting other surfers.  Leashes, however, can make it more likely for a loose board to recoil back at the surfer and cause serious complications, such as eye damage.

“That is why it is important to always stay focused and protect your head with your arms every time when surfacing from a wipe-out,” said Taylor.  “Of course surfers should also make sure that weather and water conditions are safe.”  Several studies have shown that advanced surfers are prone to more severe injuries than less experienced ones because they often risk surfing larger waves in more extreme conditions.

Additional surfing hazards may come from the marine environment.  “Although many people associate water sports with shark attacks, they are in fact, extremely rare,” said Taylor.  Stingray injuries are much more common, and in most cases, can initially be treated with hot water to inactivate the nerve toxin.  Taylor adds that shuffling your feet while walking through shallow water can prevent stings because bottom-dwelling fish scatter when they are alerted by human presence.

Surfers should also be aware of shallow corals reefs – another common danger.  “Wounds sustained in contact with coral reefs usually heal slowly due to various toxins and microbes originating from the reefs.  In many cases, thorough cleansing, antibiotics and tetanus immunization might be required,” said Taylor.

Furthermore, surfers are also at risk of chronic conditions resulting from long-term environmental exposure.  These include serious illnesses, such as skin cancer and ear problems.

“Subjecting the ear to cold water and wind for extended periods of time stimulates the abnormal bone growth that can eventually block the ear canal reducing sound transmission to the eardrum, as well as trapping water deep in the canal, predisposing surfers to otitis externa – a condition known as surfer's ear,” said Taylor.  “Drying ears out with a 50/50 white vinegar/rubbing alcohol solution aids in keeping ears healthy.” 

Taylor also emphasizes the importance of applying sunscreen with UVA and UVB protection, wearing protective clothing and limiting sun exposure between 10:00 a.m. and 4:00 p.m.

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Written by: Maja Gawronska
Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

In a study of more than 1,000 adults, researchers at the University of California, San Diego, found that individuals taking cholesterol-lowering statin drugs are more likely than non-users to experience decreased energy, fatigue upon exertion, or both. The researchers suggest that these findings should be taken into account by doctors when weighing risk versus benefit in prescribing statins. 

Beatrice Golomb, MD, PhD

Statin drugs are among the best selling and most widely used prescription drugs on the market. Recently, increasing attention has focused on statins’ side effects, particularly their effect on exercise. While some patients have reported fatigue or exercise intolerance when placed on statins, randomized trials had not previously addressed occurrence of fatigue-with-exertion or impaired energy in patients on statins relative to placebo.

In the June 11 issue of Archives of Internal Medicine, Beatrice Golomb, MD, PhD, associate professor of medicine at UC San Diego School of Medicine, and colleagues present randomized trial data which show that these side effects were significantly greater in persons placed on statins than those on a placebo.

More than 1,000 adults from San Diego were randomly allocated to identical capsules with placebo, or one of two statins at relatively low potencies: pravastatin (Pravachol) at 40mg, or simvastatin (Zocor) at 20mg – chosen as the most water-soluble and most fat-soluble of the statins, at doses expected to produce similar LDL (“bad cholesterol”) reduction. According to the researchers, the cholesterol reduction would be similar to that expected with atorvastatin (Lipitor) at 10mg, or rosuvastatin (Crestor) at 2.5-5mg.

Persons with heart disease and diabetes were excluded. Neither subjects nor investigators knew which agent the subject had received. Subjects rated their energy and fatigue with exertion relative to baseline, on a five-point scale, from “much worse” to “much better.”

Those placed on statins were significantly more likely than those on placebo to report worsening in energy, fatigue-with-exertion, or both. Both statins contributed to the finding, though the effect appeared to be stronger in those on simvastatin. (Simvastatin led to significantly greater cholesterol reduction.)

“Side effects of statins generally rise with increasing dose, and these doses were modest by current standards,” said Golomb. “Yet occurrence of this problem was not rare – even at these doses, and particularly in women.”

The magnitude of the effect observed can be seen in the research findings if, for example, 4 of 10 treated women on simvastatin cited worsened energy or exertional fatigue; 2 in 10 cited worsening in both, or rated either one as “much worse”; or if 1 in 10 study participants rated energy and exertional fatigue as “much worse.”

“Energy is central to quality of life. It also predicts interest in activity,” said Golomb. “Exertional fatigue not only predicts actual participation in exercise, but both lower energy and greater exertional fatigue may signal triggering of mechanisms by which statins may adversely affect cell health.”

For these reasons, the researchers state that decreases in energy, and increases in exertional fatigue on statins represent important findings which should be taken into account in risk-benefit determinations for statins.  According to Golomb, this is particularly true for groups for whom evidence does not support mortality benefit on statins – such as most patients without heart disease, and women and those over 70 or 75, even if heart disease is present.

Additional contributors to the paper include Marcella A. Evans, Department of Anatomy and Neurobiology, UC Irvine; Joel E. Dimsdale, MD, UC San Diego Department of Psychiatry; and Halbert L. White, UC San Diego Department of Economics. 

This study was funded by the National Heart, Lung and Blood Institute, part of the National Institutes of Health, # RO1 HL63055; and supported by the UCSD General Clinical Research Center, NIH # MO1 RR00827.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Studies suggest greater danger, but risk appears to vary by definition

Millions of pre-diabetic Americans may be at increased risk of future stroke, say researchers at the University of California, San Diego School of Medicine in a new meta-analysis of epidemiological studies, but the precise degree of that threat is confounded by differing medical definitions and factors that remain unknown or unmeasured.

“The immediate implication of our findings is that people with pre-diabetes should be aware they are at increased risk of stroke, and that this condition is frequently associated with one or more major risk factors for cardiovascular disease,” said Bruce Ovbiagele, MD, a professor of neurosciences at UC San Diego School of Medicine and the study’s senior author. “Beyond that, there’s a great need to further refine our understanding of that risk and how it’s measured.”

Writing in the June 8 online edition of the British Medical Journal, Ovbiagele and an international team of colleagues reviewed 15 qualifying prospective cohort studies that looked at the association between pre-diabetes and stroke risk. The studies, published between 2004 and 2011, involved 760,925 participants.

Pre-diabetes occurs when blood glucose levels are consistently higher than normal, but not yet high enough to be diagnosed as diabetes. The condition is widespread in the United States: An estimated 35 percent of American adults – approximately 79 million people – are believed to be pre-diabetic, and thus at greater risk of developing full-blown type-2 diabetes, which afflicts roughly 26 million Americans. Diabetes is the seventh leading cause of death in the U.S., and a major risk factor for heart disease and stroke, the first and fourth leading causes of death.

People with pre-diabetes typically have the same risk factors for cardiovascular disease as people with type 2 diabetes – specifically, high blood pressure, high cholesterol levels and obesity – but the condition’s effect on future stroke risk has not been established.

Ovbiagele and colleagues found that an association between future stroke risk and pre-diabetes depended upon the definition of the latter. To determine whether someone has pre-diabetes, blood glucose levels are typically measured after a 12-hour fast. According to the 1997 American Diabetes Association (ADA), a normal fasting glucose measurement ranges between 70.2 to 100 milligrams per deciliter (mg/dL). A level between 100 and 126 mg/dL is considered pre-diabetic. A level of 126 mg/dL or above is diabetic.

By the 1997 standard, the researchers found that pre-diabetics in the studies with a fasting glucose measurement of 110 to 125 mg/dL carried a 21 percent higher chance of suffering a future stroke. Heart disease and stroke account for roughly two-thirds of all deaths among people with diabetes.

In 2003, however, the ADA redefined the fasting glucose level for pre-diabetes to 100 to 125 mg/dL. Using this less stringent definition, the researchers found no increased stroke risk for pre-diabetics.  Indeed, when they analyzed three studies that provided information on participants with fasting glucose levels of 100 to 109 mg/dL they found no increased risk of stroke.

Ovbiagele said the difference in the findings suggests there may be a “threshold effect” in the relationship between fasting glucose levels and future stroke risk. “Elevated risk may only begin at or above a fasting glucose level of 110 mg/dL,” he said.

Additional research is needed to determine the best definition predicting stroke risk among diabetics, Ovbiagele noted. It should include an assessment of more recent glycemic biomarkers, such as glycosylated hemoglobin, and be followed by randomized, controlled trials involving drugs and/or lifestyle modification to evaluate the effect of treatments on reducing the risk of future strokes.

“In the meantime, to avoid progression to diabetes or occurrence of strokes, clinicians should strongly consider recommending therapeutic lifestyle changes and maximizing the control of established stroke risk factors in their patients with pre-diabetes,” Ovbiagele said.

Co-authors of the study are Meng Lee, Chang Gung University College of Medicine, Chiayi, Taiwan; Jeffrey L. Saver and Sarah Song, University of California, Los Angeles; Heun-Sik Hong, Inje University, South Korea and Kuo-Hsuan Chang, Chang Gung University College of Medicine, Linkuo, Taiwan.

Funding, in part, came from Chang Gung Memorial Hospital and the National Institutes of Health (grants P50 NS044378 and U01 NS079179).

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

On June 6, 2012, UC San Diego Health System was honored with an “A” Hospital Safety Score^SM by The Leapfrog Group, an independent national nonprofit run by employers and other large purchasers of health benefits. U.S. hospitals were assigned an A, B, C, D, or F based on safety performance.

UC San Diego Health System has locations throughout the San Diego region.

“The ‘A’ level award for UC San Diego Health System reflects of our commitment to patient safety, across all locations, from primary care offices to surgical suites,” said Paul Viviano, CEO of UC San Diego Health System. “Patients seek out UC San Diego Health System for our ability to provide superior care for the full spectrum of medical needs including the most serious and rare conditions. This grade demonstrates to patients that we can use the latest technology and research findings in a safe manner. Our patients are in the best possible clinical hands.”

The safety score was calculated under the guidance of The Leapfrog Group’s Blue Ribbon Expert Panel using publicly available data on patient injuries, medical and medication errors, and infections.

“UC San Diego Health System’s Quality Council has continuously pursued the goals of achieving outstanding clinical outcomes and preventing patient harm,” said Angela Scioscia, MD, CMO, UC San Diego Health System. “Through teamwork and a thoughtful, evidenced-based approach to care we have been able to expand resuscitation services, prevent health care associated infections, and improve medication safety.”

To see UC San Diego Health System scores as they compare nationally and locally, visit http://hospitalsafetyscore.org/, the Hospital Safety Score^SM website, which also provides information on how the public can protect themselves and loved ones during a hospital stay.

Calculated under the guidance of The Leapfrog Group’s nine-member Blue Ribbon Expert Panel, the Hospital Safety Score^SM uses 26 measures of publicly available hospital safety data to produce a single score representing a hospital’s overall capacity to keep patients safe from infections, injuries, and medical and medication errors.

The panel includes: John Birkmeyer (University of Michigan), Ashish Jha (Harvard University), Lucian Leape (Harvard University), Arnold Millstein (Stanford University), Peter Pronovost (Johns Hopkins University), Patrick Romano (University of California, Davis), Sara Singer (Harvard University), Tim Vogus (Vanderbilt University), and Robert Wachter (University of California, San Francisco). 

About The Leapfrog Group

The Leapfrog Group is a national organization using the collective leverage of large purchasers of health care to initiate breakthrough improvements in the safety, quality, and affordability of health care for Americans. The flagship Leapfrog Hospital Survey allows purchasers to structure their contracts and purchasing to reward the highest performing hospitals. The Leapfrog Group was founded in November 2000 with support from the Business Roundtable and national funders, and is now independently operated with support from its purchaser and other members.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Researchers at the Stein Institute for Research on Aging at the University of California, San Diego have received a $4 million grant from the National Institute of Mental Health (NIMH), part of the National Institutes of Health, to study accelerated biological aging in schizophrenia.

Dilip V. Jeste, MD

“Schizophrenia is one of the most serious, challenging, and disabling mental illnesses,” said principal investigator Dilip V. Jeste, MD, Estelle and Edgar Levi Chair in Aging, Distinguished Professor of Psychiatry and Neurosciences at UC San Diego School of Medicine, and director of the Stein Institute.

Characterized by symptoms such as delusions, loss of touch with reality and social withdrawal, this chronic condition has become one of the leading causes of disability and premature mortality in the world. In the United States alone, the overall annual cost of schizophrenia is estimated to be more than $60 billion.

Scientists have long observed that schizophrenia is more than a brain disease, as it also affects a wide range of physical functions and entails more rapid biological aging. A number of studies have suggested that physiological changes seen throughout the body occur at an earlier age in people with schizophrenia. For example, young adults suffering from this mental condition are prone to diseases associated with growing older, such as diabetes and cardiovascular problems.

“Even though schizophrenia has been associated with a higher risk for suicide, two-thirds of the excess deaths in patients suffering from this mental illness are from other causes,” said Jeste. “The lifespan of patients with schizophrenia is usually 20 to 25 years shorter than those of unaffected individuals.”

The new study will directly examine biological aging in schizophrenia by using a battery of psychiatric and medical interviews, as well as several state-of-the-art laboratory techniques. Over the course of five years, the team will annually follow more than 250 subjects, aged 26 to 65 years.

Root causes of a decrease in average lifespan in people with schizophrenia have long remained a mystery. Although some studies have suggested that it could be explained by poorer access to treatment, many scientists have suspected that there may be other, more fundamental factors involved.

However, previous attempts to decipher these factors failed to provide a conclusive answer. “Often studies lacked the longitudinal approach that involves repeated observations over long periods of time,” said Jeste. “In addition, there was an insufficient understanding of the biology and neuroscience underlying the condition at the time of these studies.”

To unravel biological mechanisms underlying faster aging, Jeste and colleagues will measure and analyze a panel of biomarkers associated with insulin dysregulation, inflammation, oxidative stress, and cell aging. The last study involves measuring the length of telomeres – regions of DNA that protect the ends of chromosomes from deterioration and have been linked to longevity. In addition, researchers will investigate the effects of factors related to chronicity of schizophrenia, such as cumulative effects of medication.

“Up to one percent of adults are affected by schizophrenia. By providing new insights into the mechanisms of the disease, our study might open pathways to novel therapies and interventions to improve the health and quality of life of schizophrenia patients,” said Jeste.

The investigative team includes Dilip V. Jeste, MD; Gregory Light, PhD, associate professor of psychiatry; Nicole Lanouette, MD, assistant clinical professor of psychiatry; Paul Mills, PhD, professor of psychiatry and Director of UC San Diego Clinical Translational Research Institute (CTRI) Research Tools Program; Wesley Thompson, PhD, assistant professor of psychiatry; all at UC San Diego School of Medicine; and Owen Walkowitz, MD, Professor-in-Residence, Department of Psychiatry, UC San Francisco.  

This study is funded by NIMH grant # R1 MH094151.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

UC San Diego Health System Toxicologist Offers Venomous Bite Advice

Each year, approximately 8,000 Americans are bitten by venomous snakes.  On average, 800 or so bites occur annually in California, home to an abundance of snake species, but only one family is native and venomous: rattlesnakes.

“This is the time of year when we see a rise in snake bites,” said Richard Clark, MD, director of the Division of Medical Toxicology at UC San Diego Health System.

Toxin levels in rattler venom vary from year to year and season to season, but typically venom is weaker in winter and stronger in summer because snakes are more active, fighting for food and territory. 

“We really don’t know why the venom is becoming increasingly potent.  Some speculate that with the modern world encroaching on nature it could be survival of the fittest.  Perhaps only the strongest, most venomous snakes survive,” said Clark.  “The anti-venom is costly at around $2,500 a vial.  Patients may need a series of anti-venom shots and insurance does not always cover the treatment.”

The majority of the injuries are on hands, fingers and feet, and the most typical result is swelling and tissue damage that looks like blisters or frost bite. 

Symptoms of severe bites can include: extreme pain at the location of the bite, nausea and sometimes diarrhea, followed by swelling in the mouth and throat, making it difficult to breathe.  Within minutes, victims can get lightheaded, collapse and go into shock. 

“Many of our snake bite victims show symptoms of severe weakness, trouble breathing and low blood pressure,” said Clark who is also medical director for the California Poison Control System (CPCS), San Diego Division.  “For anyone who suspects a bite, their next move should be to a hospital emergency department.”

With some rattlesnake bites, no venom is injected into the wound, but because it is impossible to know if venom has or has not been injected, getting medical treatment quickly is important.

What to Do?

• If bitten by a snake, go to the emergency department or a nearby health care facility immediately.
• There are potential risks to applying ice, using a tourniquet or suctioning the wound.   For the direct application of ice, the main concern is the risk of a frostbite-like injury.  If tourniquets are applied too tightly, they will decrease blood flow to the affected area and might also concentrate the venom, increasing local tissue damage.  Suctioning the wound is ineffective in removing venom because the venom is usually injected too deeply into tissue.  When people use their mouths to suck the bite site, they can actually make things worse by introducing harmful bacteria.
• If in a remote area when bitten by a rattler, first immobilize the wounded area, especially for a hand or arm bite, then proceed slowly to a vehicle.  Moving slowly will keep the heart rate low and help prevent the venom from spreading. 
• If bitten on the leg or foot, it might be necessary to use that limb to get to the vehicle, unless someone can carry the victim.  If walking is necessary, it is very important to move slowly.  Drive to the nearest phone, call 911 and wait for assistance.  If there is no phone nearby, proceed to the nearest hospital.

The California Poison Control System (CPCS) is available at 800-222-1222, 24 hours a day, seven days a week for immediate expert help and information in case of poison exposure, including snake bites.

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu  

Inactivation of two genes may have allowed escape from bacterial pathogens, researchers say

Roughly 100,000 years ago, human evolution reached a mysterious bottleneck: Our ancestors had been reduced to perhaps five to ten thousand individuals living in Africa. In time, “behaviorally modern” humans would emerge from this population, expanding dramatically in both number and range, and replacing all other co-existing evolutionary cousins, such as the Neanderthals.

The cause of the bottleneck remains unsolved, with proposed answers ranging from gene mutations to cultural developments like language to climate-altering events, among them a massive volcanic eruption.

Add another possible factor: infectious disease.

Escherichia coli bacteria, like these in a false-color scanning electron micrograph by Thomas Deerinck at UC San Diego’s National Center for Microscopy and Imaging Research, cause a variety of often life-threatening conditions, particularly among the young. Varki and colleagues suggest a genetic change 100,000 or so years ago conferred improved protection from these microbes, and likely altered human evolutionary development.

In a paper published in the June 4, 2012 online Early Edition of The Proceedings of the National Academy of Sciences, an international team of researchers, led by scientists at the University of California, San Diego School of Medicine, suggest that inactivation of two specific genes related to the immune system may have conferred selected ancestors of modern humans with improved protection from some pathogenic bacterial strains, such as Escherichia coli K1 and Group B Streptococci, the leading causes of sepsis and meningitis in human fetuses, newborns and infants.  

“In a small, restricted population, a single mutation can have a big effect, a rare allele can get to high frequency,” said senior author Ajit Varki, MD, professor of medicine and cellular and molecular medicine and co-director of the Center for Academic Research and Training in Anthropogeny at UC San Diego. “We’ve found two genes that are non-functional in humans, but not in related primates, which could have been targets for bacterial pathogens particularly lethal to newborns and infants. Killing the very young can have a major impact upon reproductive fitness. Species survival can then depend upon either resisting the pathogen or on eliminating the target proteins it uses to gain the upper hand.”

In this case, Varki, who is also director of the UC San Diego Glycobiology Research and Training Center, and colleagues in the United States, Japan and Italy, propose that the latter occurred. Specifically, they point to inactivation of two sialic acid-recognized signaling receptors (siglecs) that modulate immune responses and are part of a larger family of genes believed to have been very active in human evolution. 

Working with Victor Nizet, MD, professor of pediatrics and pharmacy, Varki’s group had previously shown that some pathogens can exploit siglecs to alter the host immune responses in favor of the microbe. In the latest study, the scientists found that the gene for Siglec-13 was no longer part of the modern human genome, though it remains intact and functional in chimpanzees, our closest evolutionary cousins. The other siglec gene – for Siglec-17 – was still expressed in humans, but it had been slightly tweaked to make a short, inactive protein of no use to invasive pathogens.

“Genome sequencing can provide powerful insights into how organisms evolve, including humans,” said co-author Eric D. Green, MD, PhD, director of the National Human Genome Research Institute at the National Institutes of Health.

In a novel experiment, the scientists “resurrected” these “molecular fossils” and found that the   proteins were recognized by current pathogenic strains of E. coli and Group B Streptococci. “The modern bugs can still bind and could potentially have altered immune reactions,” Varki said.

Though it is impossible to discern exactly what happened during evolution, the investigators studied molecular signatures surrounding these genes to hypothesize that predecessors of modern humans grappled with a massive pathogenic menace between 100,000 and 200,000 years ago. This presumed “selective sweep” would have devastated their numbers. Only individuals with certain gene mutations survived – the tiny, emergent population of anatomically modern humans that would result in everyone alive today possessing a non-functional Siglec-17 gene and a missing Siglec-13 gene.

Varki said it’s probable that humanity’s evolutionary bottleneck was the complex result of multiple, interacting factors. “Speciation (the process of evolving new species from existing ones) is driven by many things,” he said. “We think infectious agents are one of them.”

Co-authors of the paper include Xiaoxia Wang, Ismael Secundino, Nivedita Mitra, Kalyan Banda, Vered Padler-Karavani, Andrea Verhagen and Chris Reid, Victor Nizet and Jack D. Bui, Departments of Medicine, Cellular and Molecular Medicine, Pathology and Pediatrics, UC San Diego and the UC San Diego Glycobiology Research and Training Center; the Skaggs School of Pharmacy and Pharmaceutical Sciences and UC San Diego /Salk Center for Academic Research and Training in Anthropogeny; Martina Lari, Carlotta Balsamo and David Caramelli, Department of Evolutionary Biology, Laboratory of Anthropology, University of Florence; Ermanno Rizzi, Giorgio Corti, Gianluca De Bellis, Institute for Biomedical Technologies, National Research Council, Italy; Laura Longo, Department of Environmental Science, University of Siena, Italy; William Beggs and Sarah Tishkoff, Departments of Genetics and Biology, University of Pennsylvania; Toshiyuki Hayakawa, Primate Research Institute, Kyoto University; Pedro Cruz, Eric D. Green and James C. Mullikin, National Human Genome Research Institute, National Institutes of Health.

Funding for this research came, in part, from National Institutes of Health Grant 1P01HL107150 (NHLBI Program of Excellence in Glycosciences) and the Mathers Foundation of New York.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Stem cell grants covers heart failure, Alzheimer’s disease, ALS and spinal cord injuries

Five scientists from the University of California, San Diego and its School of Medicine have been awarded almost $12 million in new grants from the California Institute for Regenerative Medicine (CIRM) to conduct stem cell-based research into regenerating spinal cord injuries, repairing gene mutations that cause amyotrophic lateral sclerosis and finding new drugs to treat heart failure and Alzheimer’s disease.

The awards mark the third round of funding in CIRM’s Early Translational Awards program, which supports projects that are in the initial stages of identifying drugs or cell types that could become disease therapies. More than $69 million in awards were announced yesterday, including funding for first-ever collaboratively funded research projects with China and the federal government of Australia. 

“With these new awards, the agency now has 52 projects in 33 diseases at varying stages of working toward clinical trials,” said Jonathan Thomas, JD, PhD and CIRM governing board chair. “Californians should take pride in being at the center of this worldwide research leading toward new cures. These projects represent the best of California stem cell science and the best international experts who, together, will bring new therapies for patients.”

The five new UC San Diego awards are:

• With a $1.8 million award, Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program, and colleagues will continue their work developing new methods to find and test drug candidates for Alzheimer’s disease (AD). Currently, there is no effective treatment for AD. The researchers screen novel candidates using purified human brain cells made from human reprogrammed stem cells. Already, they have discovered that these human brain cells exhibit a unique biochemical behavior that indicates early development of AD in a dish.
• Mark H. Tuszynski, MD, PhD, professor of neurosciences and director of the Center for Neural Repair at UC San Diego, and colleagues seek to develop more potent stem cell-based treatments for spinal cord injuries. By combining grafts of neural stem cells with scaffolds placed at injury sites, the researchers have reported substantial progress in restoring functional improvement in impaired animal models. The new $4.6 million grant will fund work to identify the optimal human neural stem cells for preclinical development and, in an unprecedented step, test this treatment in appropriate preclinical models of spinal cord injury, providing the strongest validation for human translation.
• Amyotrophic lateral sclerosis or ALS (Lou Gehrig’s disease) is a progressive neurological condition that is currently incurable. Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine, and colleagues will use a $1.6 million grant to exploit recent discoveries that specific mutations in RNA-binding proteins cause neuronal dysfunction and death. They will use neurons generated from patient cells containing the mutations to identify the unique RNA “signature” of these doomed neurons and screen for drug-like compounds that bypass the mutations to correct the RNA signature to obtain healthy neurons.
• Eric David Adler, MD, an associate clinical professor of medicine and cardiologist, studies heart failure, including the use of stem cells to treat it. His $1.7 million award will fund research into Danon disease, a type of inherited heart failure that frequently kills patients by their 20s. Adler and colleagues will turn stem cells created from skin cells of patients with Danon disease into heart cells, then screen hundreds of thousands of drug candidates for beneficial effects. The most promising drugs will subsequently be tested on mice with a genetic defect similar to Danon disease, with the ultimate goal of identifying a suitable candidate for human clinical trials. The research may have broader applications for other conditions with similar pathogenesis, such as cancer and Parkinson’s disease.
• Yang Xu, PhD, a professor in the Division of Biological Sciences at UC San Diego, also investigates heart failure, which currently has limited, effective therapeutic options. His grant for $1.8 million will support research into using human embryonic stem cells to produce a renewable source of human cardiomyocytes (heart muscle cells) to replace cells damaged or destroyed by disease. Xu’s work will specifically focus upon overcoming immunological resistance to the new cells.

CIRM was established in November 2004 with the passage of Proposition 71, the California Stem Cell Research and Cures Act. The statewide ballot measure provided $3 billion in funding for stem cell research at California universities and research institutions and called for the establishment of an entity to make grants and provide loans for stem cell research, research facilities, and other vital research opportunities.

The May 24 grants bring UC San Diego’s total to more than $112 million in CIRM funding since the first awards in 2006.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Boosts immune response when vitamin D levels are low

Antimicrobial peptides (AMPs) are molecules produced in the skin to fend off infection-causing microbes. Vitamin D has been credited with a role in their production and in the body’s overall immune response, but scientists at the University of California, San Diego School of Medicine say a hormone previously associated only with maintaining calcium homeostasis and bone health is also critical, boosting AMP expression when dietary vitamin D levels are inadequate.

Staphylococcus aureus, magnified 50 thousand times.

The finding, published in the May 23, 2012 online issue of Science Translational Medicine, more fully explains how the immune system functions in different situations and presents a new avenue for treating infections, perhaps as an alternative to current antibiotic therapies.

The immunological benefits of vitamin D are controversial. In cultured cell studies, the fat-soluble vitamin provides strong immunological benefits, but in repeated studies with humans and animal models, results have been inconsistent: People with low levels of dietary vitamin D do not suffer more infections. For reasons unknown, their immune response generally remains strong, undermining the touted immunological strength of vitamin D.

Working with a mouse model and cultured human cells, Gallo and colleagues discovered why: When levels of dietary vitamin D are low (it’s naturally present in very few foods), production of parathyroid hormone (PTH), which normally helps modulate calcium levels in blood, is ramped up. More PTH or a related peptide called PHTrP spurs increased expression of AMPs, such as  cathelicidin, which kill a broad spectrum of harmful bacteria, fungi and viruses.

“No one suspected a role for PTH or the PTH-related peptide in immunity,” said Richard L. Gallo, MD, PhD, professor of medicine and chief of UCSD’s Division of Dermatology and the Dermatology section of the Veterans Affairs San Diego Healthcare System. “This may help resolve some of the controversy surrounding vitamin D. It fills in the blanks.”

For example, the findings relate to the on-going debate over sun exposure. Sunlight triggers the production of vitamin D. Low levels of vitamin D have been claimed in some studies to increase the risk of cardiovascular disease and cancer, but other studies have failed to confirm this. On the other hand, high levels of solar exposure that could increase vitamin D have been shown to increase the risk of skin cancer.

“Since sunlight is a carcinogen, it’s a bad idea to get too much of it,” said Gallo. “PTH goes up when levels of vitamin D from diet and sun exposure are low. PTH may be what permits us to have low D in the diet and not kill ourselves with too much UV radiation.” 

Gallo said PTH’s newly revealed immunological role provides a new connection between the body’s endocrine system (a system of glands secreting different regulatory hormones into the bloodstream) and its ability to fight invasive, health-harming pathogens.

While much more work remains to be done, including human studies, it’s possible that PTH or PTHrP might eventually become an effective antibiotic treatment without the risk of antibiotic resistance in targeted microbes. One challenge would be how to specifically limit treatment to the targeted infection. “Maybe that could be done by developing the therapy as a cream,” Gallo said. 

Co-authors of the study are Beda Muehleisen, Carolos Aguilera and George Sen, Division of Dermatology, UC San Diego; Daniel D. Bikle, Department of Medicine and Dermatology, UC San Francisco; Douglas W. Burton, Veterans Administration San Diego Healthcare System; Leonard J. Deftos, Veterans Administration San Diego Healthcare System and Department of Medicine, UC San Diego.

This research has been funded in whole or in part by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under contract number HHSN272201000020C to the Atopic Dermatitis Research Network and grant numbers R01 AI052453 and R01 AI0833358; the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, under grant numbers R01 AR052728;  and the Veterans Administration Merit Award (ID:1145995). Additional funding was received from the State of California Tobacco-Related Disease Research Program (#18XT-0182) and the Swiss National Science Foundation (PBZHP3-125571 and PASMP3_140073).

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

The National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health, has renewed funding for the Superfund Research Program (SRP) at the University of California, San Diego. Over the next five years, the $15 million grant will fund continued research on the molecular and genetic consequences of exposure to uncontrolled toxicants from Superfund and other hazardous waste sites.

It is the third funding cycle for UC San Diego’s SRP, which was originally funded by the NIEHS in 2000.

Among the research supported by UC San Diego’s Superfund Research Program is Michael Karin’s work identifying how hepatocytes (liver cells) become cancerous after exposure to chemical carcinogens.

“The overall goal of the Superfund Research Program is to understand why environmental toxicants cause disease,” said Robert H. Tukey, PhD, Professor of Pharmacology, Chemistry & Biochemistry at UC San Diego and Director of the UC San Diego SRP. “Our focus is on the development of novel biological models to define how toxicant exposure leads to illness and disease. We want to learn how to better detect toxicants and model the health effects of exposure, assess the risks, and find effective ways to remediate.”

Since 2000, the SRP at UC San Diego has chalked some notable achievements. Most recently:

• Michael Karin, PhD, Distinguished Professor of Pharmacology in UC San Diego’s   Laboratory of Gene Regulation and Signal Transduction, has identified initiating cells in the liver that progress into liver cancer following exposure to chemical carcinogens. The identity of these cells may lead to an understanding of the mechanisms that underlie the development of liver cancer.
• Robert Tukey, PhD has produced new mouse models expressing human genes that result in dramatically elevated levels of serum bilirubin, a potent and natural antioxidant that can be used to study the role of oxidative stress in toxicant-induced disease.
• Julian Schroeder, PhD, in the Biology Department at UC San Diego, has used the plant model Arabidopsis to create genetically engineered plants that may eventually prove useful to bioaccumulate heavy metals from contaminated soils on a commercially viable scale.
• David Brenner, MD, vice chancellor of UC San Diego Health Sciences, and dean, UCSD School of Medicine, and Ekihiro Seki, MD, from the Department of Medicine, have investigated the genetic mechanisms that lead to the development of toxicant induced liver fibrosis.
• Ronald Evans, PhD, at the Salk Institute, has identified key cellular receptors that serve to transport environmental toxicants to the nucleus, allowing for identification of the genes that may lead to disease.
• Paul Russell, PhD, at the Scripps Research Institute, has been successful in using yeast to characterize intracellular proteins important in arsenic induced toxicity. 
• William Trogler, PhD, Professor of Chemistry and Biochemistry, has developed novel chemical tools to detect toxicant exposure in the environment.

On-going and future projects, said Tukey, will use functional genomics and proteomics to investigate the cellular and molecular responses leading to toxicant -induced liver toxicity.

The SRP at UC San Diego is broad-based, with biomedical researchers, chemists, plant biologists, and public outreach experts. It includes research projects led by scientists from other institutions, including The Scripps Research Institute, the Salk Institute for Biological Studies and the Howard Hughes Medical Institute.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Research by a collaborative group of scientists from UC San Diego School of Medicine, UC San Francisco and Wake Forest School of Medicine has led to identification of an existing drug that is effective against Entamoeba histolytica. This parasite causes amebic dysentery and liver abscesses and results in the death of more than 70,000 people worldwide each year.

Using a high-throughput screen for drugs developed by the research team, they discovered that auranofin – a drug approved by the US Food and Drug Administration 25 years ago for rheumatoid arthritis – is very effective in targeting an enzyme that protects amebae from oxygen attack (thus enhancing sensitivity of the amebae to reactive oxygen-mediated killing).

The results of the work, led by Sharon L. Reed, MD, professor in the UCSD Departments of Pathology and Medicine and James McKerrow, MD, PhD, professor of Pathology in the UCSF Sandler Center for Drug Discovery, will be published in the May 20, 2012 issue of Nature Medicine.

Entamoeba histolytica cyst.

Entamoeba histolytica is a protozoan intestinal parasite that causes human amebiasis, the world’s fourth leading cause of death from protozoan parasites. It is listed by the National Institutes of Health as a category B priority biodefense pathogen.  Current treatment relies on metronidazole, which has adverse effects, and potential resistance to the drug is an increasing concern.

“Because auranofin has already been approved by the FDA for use in humans, we can save years of expensive development,” said Reed.  “In our studies in animal models, auranofin was ten times more potent against this parasite than metronidazole.”

In a mouse model of amebic colitis and a hamster model of amebic liver abscess, the drug markedly decreased the number of parasites, damage from inflammation, and size of liver abscesses.

“This new use of an old drug represents a promising therapy for a major health threat, and highlights how research funded by the National Institutes of Health can benefit people around the world,” said Reed.  The drug has been granted “orphan-drug” status (which identifies a significant, newly developed or recognized treatment for a disease which affects fewer than 200,000 persons in the United States) and UC San Diego hopes to conduct clinical trials in the near future.

Additional contributors to the study include first author Anjan Debnath, Shamila S. Gunatilleke  and James H. McKerrow, UCSF Sandler Center for Drug Discovery; Derek Parsonage and Leslie B. Poole, Wake Forest School of Medicine; Rosa M. Andrade, Chen He, Eduardo R. Cobo and Ken Hirata, UC San Diego School of Medicine; Steven Chen and Michelle R. Arkin, UCSF; Guillermina García-Rivera, Esther Orozco and Máximo B. Martínez, Instituto Politécnico Nacional, Mexico City; and Amy M. Barrios, University of Utah, Salt Lake City.

This work was supported by the Sandler Foundation and US National Institute of Allergy and Infectious Diseases grant 5U01AI077822-02, with additional support from R01 GM050389.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Findings mixed in India, Nepal, Pakistan and Bangladesh

Each year, more than 10 million girls under the age of 18 marry, usually under force of local tradition and social custom. Almost half of these compulsory marriages occur in South Asia. A new study suggests that more than two decades of effort to eliminate the practice has produced mixed results.

Child brides in Rayer Bazar, Dhaka, Bangladesh. Images courtesy of MH Kawsar.

Writing in the May 16, 2012 issue of Journal of the American Medical Association, Anita Raj, PhD, professor of medicine in the University of California, San Diego School of Medicine, and colleagues, report that marriage rates for girls under the age of 14 in India, Nepal, Pakistan and Bangladesh – the South Asian countries with the highest historical rates – have significantly declined since 1991. Conversely, the rate among girls aged 16 and 17 continues largely unchanged or, in the case of Bangladesh, has increased 36 percent.

Childhood marriage, which mostly involves girls, is widely condemned as a violation of individual human rights. Numerous studies have found that child brides are more likely to die young, suffer from serious health problems, live in poverty and remain illiterate.  

“There is a global effort to eliminate girl child marriage,” said Raj. “Our findings are heartening in terms of eliminating the practice among very young girls, but not among older girls. There needs to be a greater focus on prevention of marriage among later adolescents. If we cannot impact reduction of marriage in this age group, we’ll continue to see inadequate change on reduction of girl child marriage as a whole.”

Child brides in Rayer Bazar, Dhaka, Bangladesh. Images courtesy of MH Kawsar.

Raj and colleagues examined randomized cluster samples from multiple demographic, health and nutrition surveys taken between 1991 and 2007 in India, Nepal, Pakistan and Bangladesh, where the prevalence of girl child marriages has historically reached or exceeded 20 percent.

They found that the marriage prevalence rate for girls under age 14 decreased across the board during the time span studied: 45 percent in Bangladesh, 35 percent in India, 57 percent in Nepal and 61 percent in Pakistan. Reductions in other age groups, however, were less promising. Marriage of 16- and 17-year-old girls showed no decline over the past 20 years for any of the South Asian countries assessed; Bangladesh actually demonstrated a 36 percent increase in marriage of girls within this age group. Raj said Bangladesh’s significant increase in marriages among 16- and 17-year-old girls probably reflected a shift from younger aged groups.

Child brides in Rayer Bazar, Dhaka, Bangladesh. Images courtesy of MH Kawsar.

The factors influencing reduction in childhood marriage rates remain imperfectly understood. For example, Raj noted that the laws governing legal marriage age are not the same for the four countries studied. “Pakistan has a legal age of 16 for marriage while in India, it is 18,” she said, “but the percentage of females married as minors is greater for India than Pakistan, so we do not feel law has as much impact as social norms.”

More influential, perhaps, is the role of education, which Raj and colleagues are now studying. “There have been rigorous evaluations of interventions in Ethiopia and Malawi aimed at retaining girls in schools, with the result of delayed age at marriage. We need better understanding of the degree to which girl education can reduce risk for early marriage among girls in South Asia.”

Co-authors are Lotus McDougal, Joint Doctoral Program, UC San Diego-San Diego State University and Melanie L. A.  Rusch, PhD, Division of Global Public Health, UC San Diego School of Medicine.

Funding for this research came, in part, from the David and Lucile Packard Foundation.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Findings suggest possibility of boosting their health benefit 

For the first time, researchers at the University of California, San Diego have peered inside a living mouse cell and mapped the processes that power the celebrated health benefits of omega-3 fatty acids. More profoundly, they say their findings suggest it may be possible to manipulate these processes to short-circuit inflammation before it begins, or at least help to resolve inflammation before it becomes detrimental.
 
The work is published in the May 14, 2012 online Early Edition of the Proceedings of the National Academy of Sciences.

The therapeutic benefits of omega-3 fatty acids, which are abundant in certain fish oils, have long been known, dating back to at least the 1950s, when cod liver oil was found to be effective in treating ailments like eczema and arthritis.  In the 1980s, scientists reported that Eskimos eating a fish-rich diet enjoyed better coronary health than counterparts consuming mainland foods.

“There have been tons of epidemiological studies linking health benefits to omega-3 oils, but not a lot of deep science,” said Edward A. Dennis, PhD, distinguished professor of pharmacology, chemistry and biochemistry. “This is the first comprehensive study of what fish oils actually do inside a cell.”

The scientists fed mouse macrophages – a kind of white blood cell – three different kinds of fatty acid: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA). EPA and DHA are major polyunsaturated omega-3 fatty acids, essential to a broad range of cellular and bodily functions, and the primary ingredient in commercial fish oil dietary supplements. AA is a polyunsaturated omega-6 fatty acid prevalent in the human diet.

In high levels, fatty acids are toxic, so cells typically sequester them as phospholipids in their membranes. When stimulated, however, the fatty acids may be released, provoking a cascading inflammatory response. Acute or limited inflammation is, of course, a vital immunological response to physical damage or invasive pathogens. But chronic inflammation is harmful and a common element of almost every disease, from diabetes to cancer.

After supplementing the mouse macrophages with fatty acids, the scientists stimulated them to produce an inflammatory response. They discovered that omega-3 fatty acids inhibit an enzyme called cyclooxygenase (COX), which produces the prostaglandin hormones that spark inflammation. The action is similar to what happens when one takes an aspirin, which disrupts the COX-2 signaling pathway, thus reducing inflammation and pain.

On the other hand, Dennis and co-author Paul C. Norris, a graduate student in the chemistry and biochemistry department and the molecular pharmacology training program, discovered that omega-3 oils do not inhibit another group of enzymes called lipoxygenases (LOX), which are also produced by stimulated macrophages. One type of generated LOX enzyme in turn produces fat-signaling molecules called leukotrienes, which are pro-inflammatory. But Norris noted that LOX enzymes may also generate anti-inflammatory compounds called resolvins from EPA and DHA.

These observations, he said, are also helpful in identifying potential adverse effects from taking fish oil. Since omega-3 fatty acids possess overlapping functions with COX inhibitor drugs, with well-known side effects, using both in combination can produce unexpected consequences.

It is this parsing of what’s happening inside cells that Dennis called “ground-breaking.”

“We’ve been able to look inside a cell, see what fish oils do and determine that the process of inflammation at this level may be manipulatable,” he said. “Now, we need to learn if we can fine-tune that process so we can use omega-3 oils to reduce the production of pro-inflammatory prostaglandins and boost the production of anti-inflammatory resolvins.”

Funding for this research came, in part, from the LIPID MAPS Large Scale Collaborative Grant U54 GM069338 (Jean Chin and Sarah Dunsmore, program officers) and Grant R01 GM64611 (Jean Chin, program officer) from the National Institutes of Health; and the UC San Diego Graduate Training Program in Cellular and Molecular Pharmacology National Institutes of Health Grant T32 GM007752.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have identified a new biomarker and therapeutic target for pancreatic cancer, an often-fatal disease for which there is currently no reliable method for early detection or therapeutic intervention.  The paper will be published May 15 in Cancer Research.

Pancreatic ductal adenocarcinoma, or PDAC, is the fourth-leading cause of cancer-related death.  Newly diagnosed patients have a median survival of less than one year, and a 5-year survival rate of only 3 to 5 percent. Therefore, biomarkers that can identify early onset of PDAC and which could be viable drug targets are desperately needed.

"We found that a kinase called PEAK1 is turned on very early in pancreatic cancer,” said first author Jonathan Kelber, PhD, a postdoctoral researcher in the UCSD Department of Pathology and Moores Cancer Center.  “This protein was clearly detected in biopsies of malignant tumors from human patients – at the gene and the protein levels – as well as in mouse models.”

PEAK1 is a type of tyrosine kinase – an enzyme, or type of protein, that speeds up chemical reactions and acts as an “on” or “off” switch in many cellular functions.  The fact that PEAK1 expression is increased in human PDAC and that its catalytic activity is important for PDAC cell proliferation makes it an important candidate as a biomarker and therapeutic target for small molecule drug discovery.

In addition to showing that levels of PEAK1 are increased during PDAC progression, the scientists found that PEAK1 is necessary for the cancer to grow and metastasize.

“PEAK1 is a critical signaling hub, regulating cell migration and proliferation,” said Kelber. “We found that if you knock it out in PDAC cells, they form significantly smaller tumors in preclinical mouse models and fail to metastasize efficiently.”

The research team, led by principal investigator Richard Klemke, PhD, UCSD professor of pathology, studied a large, on-line data base of gene expression profiles to uncover the presence of PEAK1 in PDAC.  These findings were corroborated at the protein level in patient biopsy samples from co-investigator Michael Bouvet, MD, and in mouse models developed by Andrew M. Lowy, MD, both of the UCSD Department of Surgery at Moores Cancer Center.

While many proteins are upregulated in cancers of the pancreas, there has been limited success in identifying candidates that, when inhibited, have potential as clinically approved therapeutics. However, the researchers found that inhibition of PEAK1-dependent signaling sensitized PDAC cells to existing chemotherapies such as Gemitabine, and immunotherapies such as Trastuzumab.

“Survival rates for patients with pancreatic cancer remain low,” said Bouvet. “Therefore, earlier detection and novel treatment strategies are very important if we are going to make any progress against pancreatic cancer.  Since current therapies are often ineffective, our hope is that the findings from this research will open up a new line of investigation to bring a PEAK1 inhibitor to the clinic.”

Additional contributors to the study include Theresa Reno, Sharmeela Kaushal, Cristina Metildi,Tracy Wright, Konstantin Stoletov, Jessica M. Weems, Frederick D. Park, Evangeline Mose, UC San Diego; Yingchun Wang, Chinese Academy of Science, Beijing; and Robert M. Hoffman, UC San Diego and AntiCancer, Inc., San Diego. 

The study was supported by the National Institutes of Health. 

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Researchers at the Comprehensive Alzheimer’s Program at the University of California, San Diego School of Medicine have announced two new clinical trials for patients with either mild to moderate Alzheimer’s disease (AD) and one trial for Mild Cognitive Impairment.

“Two of these studies represent an exciting new approach to treating Alzheimer’s, focusing on improving memory in patients with early symptoms of impaired memory and possibly slowing down  the disease progression long before symptoms appear,” said Michael Rafii, MD, PhD, assistant professor of neurosciences and director of the Memory Disorders Clinic at UC San Diego .

All three are randomized, double-blind, placebo-controlled studies:

Click on the photo above for video of Michael Rafii, MD, PhD, discussing AD trials.

The first is a national clinical trial examining the effects of resveratrol – a compound found in red grapes or juice, red wine, chocolate, tomatoes and peanuts – on participants with mild to moderate dementia due to Alzheimer’s disease.   Pre-clinical and pilot clinical research studies suggest that resveratrol may prevent diabetes, act as a natural cancer fighter, ward off cardiovascular disease, and prevent memory loss, but there has been no large definitive study of its effects in humans.  

“The risk of all of these diseases increases with aging,” said Rafii.   “Most resveratrol studies showing any health benefits have been conducted in animal models such as mice, and with doses that far exceed intake from sipping wine or nibbling on chocolate. With this clinical trial, we hope to find out if daily doses of pure resveratrol can delay or alter memory deterioration and daily functioning in people with mild to moderate dementia due to Alzheimer’s.” 

The second trial is a phase-two study employing an immunotherapeutic drug developed by Roche called Gantenerumab to remove beta-amyloid, a protein that is deposited into plaques found in the brains of patients with Alzheimer's disease.  Beta-amyloid is neurotoxic and believed to be the main cause of neuronal degeneration in AD. This trial is for patients with what is called prodromal Alzheimer’s disease, or mild cognitive impairment that represents the earliest state of the disease.

The third study involves a drug called Crenezumab , which Rafii says has been shown to be one of the more potent amyloid-lowering compounds yet developed.  This drug, from Genentech, is a monoclonal antibody, which means that it very specifically binds only to beta-amyloid.

“By using antibodies against beta-amyloid we hope to reduce its neurotoxic effects on the brain,” Rafii said.  “There is a lot of evidence that beta-amyloid molecules cause damaging effects in the brain perhaps as much as ten years before they deposit to form plaques and result in symptoms of memory loss.  The aim of these two studies is to see if we can remove beta-amyloid before it causes damage and forms the plaques that result in Alzheimer’s.”

According to the National Institute of Aging, more than 5.3 million people in the United States are suffering from Alzheimer’s, and every 70 seconds, another person develops the disease.  Currently, there are no drugs to treat prodomal AD.

The UC San Diego research is sponsored by the Alzheimer’s Disease Cooperative Study through a grant from the National Institute on Aging, as well as by Hoffman La Roche and Genentech.  For more information on enrolling at the UC San Diego site, contact the Comprehensive Alzheimer’s Program at 858-246-1300 or email CAPmemory@ucsd.edu

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Controlled trial shows improved spasticity, reduced pain after smoking medical marijuana

A clinical study of 30 adult patients with multiple sclerosis (MS) at the University of California, San Diego School of Medicine has shown that smoked cannabis may be an effective treatment for spasticity – a common and disabling symptom of this neurological disease.

The placebo-controlled trial also resulted in reduced perception of pain, although participants also reported short-term, adverse cognitive effects and increased fatigue.  The study will be published in the Canadian Medical Association Journal on May 14.

Principal investigator Jody Corey-Bloom, MD, PhD, professor of neurosciences and director of the Multiple Sclerosis Center at UC San Diego, and colleagues randomly assigned participants to either the intervention group (which smoked cannabis once daily for three days) or the control group (which smoked identical placebo cigarettes, also once a day for three days).  After an 11-day interval, the participants crossed over to the other group.

“We found that smoked cannabis was superior to placebo in reducing symptoms and pain in patients with treatment-resistant spasticity, or excessive muscle contractions,” said Corey-Bloom.

Earlier reports suggested that the active compounds of medical marijuana were potentially effective in treating neurologic conditions, but most studies focused on orally administered cannabinoids. There were also anecdotal reports of MS patients that endorsed smoking marijuana to relieve symptoms of spasticity. 

However, this trial used a more objective measurement, a modified Ashworth scale which graded the intensity of muscle tone by measuring such things as resistance in range of motion and rigidity. The secondary outcome, pain, was measured using a visual analogue scale.  The researchers also looked at physical performance (using a timed walk) and cognitive function and – at the end of each visit – asked patients to assess their feeling of “highness.”

Although generally well tolerated, smoking cannabis did have mild effects on attention and concentration. The researchers noted that larger, long-terms studies are needed to confirm their findings and determine whether lower doses can result in beneficial effects with less cognitive impact.

The current study is the fifth clinical test of the possible efficacy of cannabis for clinical use reported by the University of California Center for Medicinal Cannabis Research (CMCR). Four other human studies on control of neuropathic pain also reported positive results.

“The study by Corey Bloom and her colleagues adds to a growing body of evidence that cannabis has therapeutic value for selected indications, and may be an adjunct or alternative for patients whose spasticity or pain is not optimally managed,” said Igor Grant, MD, director of the CMCR, which provided funding for the study.

Additional contributors include Tanya Wolfson, Anthony Gamst, PhD, Shelia Jin, MD, MPH, Thomas D. Marcotte, PhD, Heather Bentley and Ben Gouaux, all from UC San Diego School of Medicine. 

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

UC San Diego Nutrition experts launch year-long study of participants with Type 2

Diabetes affects nearly 24 million people in the United States, most with Type 2 diabetes, a disease which is often coupled with obesity.  Concerned by the increasing number of overweight Americans, nutrition experts with the UC San Diego School of Medicine are launching Take Charge, a research study analyzing the effectiveness of a commercial weight-loss program on participants with Type 2 diabetes who have a BMI of 25 – 45.

Cheryl Rock, PhD, RD

“We know that commercial weight loss programs can contribute to weight loss. Now we ask if they can have an impact on diabetes,” said Cheryl Rock, PhD, RD, professor in the Department of Family and Preventive Medicine at the UC San Diego School of Medicine.  “We want to find out if participants using a weight loss program do better than those who receive individualized dietary counseling with a registered dietitian.”

Rock and her team will work with primary care physicians throughout the San Diego community to enlist potential participants.  “This is about the health of our entire community,” said Rock.  “The problem of obesity is so great in that we need help on all fronts: medical, surgical and pharmaceutical.  And we want to know if science-based commercial weight loss programs can contribute to solving this national problem as well.”

Take Charge Participants must:

• Be 18 years old or older
• Be overweight
• Have Type 2 diabetes  
• Be willing to participate for one year
• Otherwise be in generally good physical and mental health
• Agree to take part in the diet, exercise and lifestyle counseling program

Participants will be randomly assigned to one of three groups:

• Group one will receive dietary counseling, including menu planning and exercise advice from a Registered Dietitian.
• The other two groups will receive dietary counseling at a commercial facility and receive prepackaged meals coinciding with the assigned diet.
• All study participants will receive follow up phone calls and/or emails from the study coordinator every few weeks throughout the course of the study. 
• In addition, the investigators want to look at the effects of treatment on:
  • Feelings and quality of life
  • Waist circumference
  • Cardiovascular fitness

The costs of all study procedures, examinations, and medical care that may be delivered as part of this study will be provided at no cost. Participants will be compensated for travel-related costs.  This study is funded by Jenny Craig, Incorporated. For more information on participation, please contact study coordinator, Angela Leone, MS, RD, UC San Diego Moores Cancer Center, 858-822-4792 or AFLeone@ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Research with mice reveals possible strategy to reverse fibrosis in liver and other organs

An international team of scientists, led by researchers at the University of California, San Diego School of Medicine, report that significant numbers of myofibroblasts – cells that produce the fibrous scarring in chronic liver injury – revert to an inactive phenotype as the liver heals. The discovery in mouse models could ultimately help lead to new human therapies for reversing fibrosis in the liver, and in other organs like the lungs and kidneys.

The work is published in the May 7, 2012 online Early Edition of the Proceedings of the National Academy of Sciences.

A photomicrograph of cirrhotic liver tissue, with extensive fibrotic scarring (stained blue).

“The take-away message is two-fold,” said David A. Brenner, MD, vice chancellor for Health Sciences, dean of the UC San Diego School of Medicine and senior author of the paper. “First, we’ve shown that liver fibrosis is markedly reversible and we now better understand how it happens. Second, we can start looking for ways to direct active myofibroblasts to stop producing scar, and become inactive. We can focus on developing drugs that promote cell change and regression. It raises the bar for prospective treatment tremendously.”

Liver fibrosis is the 12th leading cause of death in the United States. It is the result of chronic liver injury caused by such agents as the hepatitis B and C viruses, alcoholic liver disease and non-alcoholic steatohepatitis. The condition is manifested by extensive scarring of liver tissue and the organ’s progressive inability to filter body toxins. Liver fibrosis precedes the development of liver cancer. Often, the only treatment for end-stage liver fibrosis is an organ transplant. 

Fibrosis begins when infectious agents or excessive alcohol consumption trigger activation of hepatic stellate cells (HSCs), which normally act as quiescent storage units for nutrients like vitamin A in the liver. Once activated, these HSCs acquire characteristics of another cell type called myofibroblasts, which are characterized by their abundant production of extracellular matrix proteins such as collagen. These proteins accumulate as scar tissue, rendering the organ progressively dysfunctional.

However, if the source of the liver injury is successfully treated or eliminated, the liver can repair itself. In part, this is due to the activated HSCs undergoing apoptosis (programmed cell death) and being removed by other cells. But UC San Diego scientists say that, in tests using a mouse model, as many as half of all activated HSCs persist. They do not die, but rather revert to an inactive phenotype during fibrotic regression.

“After one month of regression, these cells have stopped producing collagen. They’ve upregulated some of the genes associated with quiescence and returned to their normal location in the liver,” said Tatiana Kisseleva, MD, PhD, an assistant research scientist and first author of the study.  

It’s not clear why these myofibroblasts survive. Also, scientists note the reverted myofibroblasts do not completely return to their original quiescent state. “They’re still more susceptible to repetitive injury than original quiescent HSCs,” said Kisseleva, who noted future tests will investigate whether additional reversion occurs with more time.

Kisseleva suggested the findings present another avenue for treating liver fibrosis, especially in possibly reverting fibrosis and cirrhosis, which accounts for roughly 27,000 deaths in the United States annually.

Fibrosis occurs in other organs as well, such as the kidneys and lungs, with comparable deadly effect. Recent studies indicate fibrotic reversibility in these organs as well. “Our findings are applicable to other fibrosing organs,” said Kisseleva. “Instead of killing damaged cells, we might be able to de-activate them and revert them to healthy originals.”

Co-authors of the study are Min Cong, Chunyan Jiang, Keiko Iwaisako, Brian Scott and Wolfgang Dillmann, Department of Medicine, UC San Diego; YongHan Paik, Department of Medicine,  UC San Diego and Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, South Korea; David Scholten, Department of Medicine, UC San Diego and Department of Medicine III, University Hospital Aachen, Germany; Thomas Moore-Morris and Sylvia M. Evans, Skaggs School of Pharmacy and Pharmaceutical Science, UC San Diego; Hidekazu Tsukamoto, Keck School of Medicine, University of Southern California.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

On May 3, 2012, Rady Children’s Hospital-San Diego and the UC San Diego School of Medicine launched the Center for the Promotion of Maternal Health and Infant Development. The new center, located on the campus of Rady Children’s Hospital at 7910 Frost Street in San Diego, will focus on identifying the best ways to optimize pregnancy outcomes and to improve the health of children in San Diego through groundbreaking research and patient care.

Under the direction of Kenneth Lyons Jones, MD and Christina Chambers, PhD, MPH, professors in the Department of Pediatrics at UC San Diego School of Medicine, the center will be home to a number of programs, projects and services including:

• The California Teratogen Information Service (CTIS) Pregnancy Health Information Line, a state-wide non-profit organization offering evidence-based clinical information about exposures during pregnancy and breastfeeding through its toll-free hotline, 800-532-3749, and website, CTISPregnancy.org.
• The Organization of Teratology Information Specialists (OTIS) Research Center, which conducts groundbreaking research on the safety of various medications and vaccines used for the treatment of conditions such as autoimmune diseases and asthma, and to prevent influenza,  meningitis and HPV infection in pregnant women throughout the U.S. and Canada.
• The National Children’s Study (NCS) San Diego which aims to examine the effects of environmental and genetic factors  on the growth, development, and long-term health of children, following them from before birth until age 21 years.
• A California study, called “Ready, Set, Go,” that aims to understand how a child’s learning and behavior may be affected by factors that happened before birth, including various environmental  agents which the mother came into contact with during her pregnancy, such as the kinds of food that she ate and how much alcohol she consumed.
• A Genetics/Dysmorphology outpatient clinic to evaluate children with birth defects.
• Maternal and fetal health education and training programs.

“We are excited about the opportunity this new Center brings to combine the talents of UC San Diego and Rady Children’s Hospital researchers and clinicians to improve the lives of women and children not only in the San Diego community, but across the country,” said Chambers.

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Media Contact: Nicole Chavez, 858-246-1745, ncchavez@ucsd.edu

NIH-Funded Study Finds Office Visit Alone Just as Effective

Invasive and costly tests commonly performed on women before surgery for stress urinary incontinence (SUI) may not be necessary, according to researchers at the University of California San Diego, School of Medicine and the Urinary Incontinence Treatment Network.  The study, supported by the National Institutes of Health (NIH), will be released online May 2 by the New England Journal of Medicine (NEJM).

Nager discusses study findings.

The study, which compared results after a combination of a preoperative check-up and bladder function tests to an office check-up alone, found that women who only had the office examination experienced equally successful outcomes after surgery.

“We wanted to know if invasive tests are really needed in women who have SUI, or if observation alone could achieve the same outcomes,” said study lead -author Charles Nager, MD, director of Urogynecology and Reconstructive Pelvic Surgery at UC San Diego Health System.  “The findings of our study argue that the tests provide no added benefit for surgical treatment success to patients.”

SUI affects up to 30 million American women and causes leakage of urine when coughing, laughing, sneezing, running or lifting heavy objects.  Bladder tests that use technology such as imaging, pressure monitors and muscle and nerve sensors, are commonly used on these women before surgery to characterize the degree of incontinence and to guide decisions about treatment options.  However, the tests are uncomfortable, costly and increase the risk of urinary tract infections.

In the study, half of a group of 630 women with uncomplicated SUI underwent a preoperative office evaluation with bladder function testing.  The other half had an office evaluation only.  The proportion of women who achieved treatment success was similar, 76.9 percent versus 77.2 percent, respectively, with no significant differences between groups in quality of life, patient satisfaction or voiding dysfunction – an inability to empty the bladder completely. 

UC San Diego School of Medicine researchers who participated in this study included Michael Albo, MD, and Emily Lukacz, MD.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

The Women’s Pelvic Medicine Center at UC San Diego Health System is the region’s first center designed exclusively for the diagnosis and treatment of pelvic floor disorders.  Since the program’s inception in 1998, women with complex conditions, such as incontinence and pelvic organ prolapse, have been treated through advanced medical therapies and minimally invasive surgical techniques.

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

Paul S. Viviano has accepted the position as the new CEO of UC San Diego Health System and associate vice chancellor for Health Sciences. His appointment was approved by the UC Board of Regents, and will commence June 1, 2012.

Paul Viviano, future CEO, UC San Diego Health System

“Mr. Viviano has a solid track record of strategic leadership and entrepreneurism that drives results,” said David Brenner, MD, vice chancellor for Health Sciences and dean of the School of Medicine at UC San Diego. “He has a hands-on philosophy of working with clinicians and researchers to insure outstanding patient care – exactly the kind of skills needed to elevate levels of innovation and quality as UC San Diego Health System grows.” 

Viviano is currently Chairman of the Board and CEO of Alliance Healthcare Services – the nation’s largest provider of advanced outpatient diagnostic imaging services and a national leader in delivery of radiation oncology services – where he has served since 2003.  During his tenure, he defined the strategic path, expanded the company’s technology platform, and optimized the investment value of the organization.

His prior positions include president and CEO of USC University Hospital and USC/Norris Cancer Hospital, a private research and teaching hospital staffed by faculty from the Keck School of Medicine at the University of Southern California.  USC/Norris is an NCI-designated comprehensive cancer center with more than 200 basic scientists, physicians and other Keck School of Medicine faculty members. 

Prior to his work at USC, Viviano served in various positions, including executive vice president and CEO of  the St. Joseph Health System in Orange, California, comprised of 14 acute hospitals, six medical practice foundations, three home-health agencies and multiple ambulatory clinics.

From 1985 to 1987, he was president and CEO of the 300-bed non-profit acute care facility Long Beach Community Hospital and, from 1980 to 1985, served as CEO of Los Alamitos Medical Center.

A Los Angeles native and UC alum, Viviano earned his master’s degree in public administration-public health at UCLA. He is a member of the Board of Trustees at Loyola Marymount University, where he also serves as chair of the governance committee, a member of the finance committee and chair of the Bioethics Institute.  He is also a board member and former chairman of the National Association for Quality Imaging, and will continue to serve as a member of the Board of Directors for Alliance HealthCare Services.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

In the online May 2 issue of the journal Cell Metabolism, researchers at the University of California, San Diego School of Medicine publish three distinct articles exploring:

• the complex interactions of lipids and inflammation in insulin resistance
• the roles of omega 3 fatty acids and a particular gene in fighting inflammation
• how elevated levels of a particular protein might delay the muscle-destroying effects of amyotrophic lateral sclerosis.

Type 2 diabetes has reached epidemic proportions around the world, fueled in large part by the equally alarming expansion of obesity as a global health problem. But while it’s well-known that obesity is the most common cause of insulin resistance – the primary metabolic abnormality in type 2 diabetes – researchers have only recently begun to effectively parse the underlying, complicated relationships between lipids (fats and related molecules essential to cell structure and function) and chronic tissue inflammation (a key cause of obesity-induced insulin resistance).

In a wide-ranging Perspective article published in Cell Metabolism, Christopher K. Glass, MD, PhD, a professor in the departments of Cellular and Molecular Medicine, and Medicine at the UC San Diego, and Jerrold M. Olefsky, MD, associate dean for Scientific Affairs and Distinguished Professor of Medicine at UC San Diego, survey where the science stands, describing, for example, the pro-inflammatory effects of saturated fatty acids and the anti-inflammatory benefits of omega 3 fatty acids. They also discuss how inflammation impacts lipid metabolism at the cellular, tissue, organ and whole-body levels. 

In a second, related article, Olefsky and colleague Da Young Oh, an assistant project scientist, discuss the critical role of a gene called GPR120 in inhibiting pro-inflammatory macrophages while simultaneously boosting the anti-inflammatory benefits of omega 3 fatty acids. They argue that new research highlights the importance of GPR120 as an attractive target for new drugs that could increase insulin sensitivity and, perhaps, have anti-obesity effects as well.

Finally, Don W. Cleveland, PhD, professor and chair of the Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research at UC San Diego and colleagues report the effects of elevated levels of a gene- regulating protein in mouse cells afflicted by a form of amyotrophic lateral sclerosis or ALS.

In humans, ALS is a progressive, adult-onset neurodegenerative disorder characterized by selective motor neuron and muscle loss that ultimately results in fatal paralysis. Among the key players in muscle function is a transcriptional activator protein called PGC-1alpha, which helps enhance various aspects of muscle cell function, including metabolism and mitochondrial biogenesis.

Cleveland and colleagues report that elevated levels of PGC-1alpha in the muscles of a mouse model of inherited ALS helps maintain health and function, though it does not extend survival time. The researchers suggest that increasing PCG-1alpha activity in muscle could be a new and attractive therapeutic target for maintaining, improving and extending physical abilities in ALS patients. 

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

William G. Bradley, Jr., MD, PhD, FACR, chairman of the Department of Radiology, was awarded the ACR Gold Medal, the highest honor of the American College of Radiology on April 22, during the ACR annual meeting and Chapter Leadership Conference held in Washington, D.C.   The ACR said of Bradley, “(He) is renowned for his endless dedication…to advance the science and cause of radiology locally, nationally and internationally.”  He founded the

William Bradley, Jr., MD, PhD
Dilip Jeste, MD

ACR’s MR Accreditation Program in 1992 and served as its chair for seven years.  He also chaired the ACR Commission of Neuroradiology and MRI from 1999 to 2005, and was vice president of its Board of Chancellors in 2005-06.  ACR noted his many accomplishments in pioneering developments in MR and publications, especially his influential co-editorship of Magnetic Resonance Imaging.

Dilip Jeste, MD, Estelle and Edgar Levi Chair on Aging and Distinguished Professor of Psychiatry and Neurosciences, has been selected to receive a 2012 NAMI Exemplary Psychiatrist Award from the National Alliance on Mental Illness (NAMI).  The awards are given to psychiatrists “who have made substantial contributions to NAMI Affiliate or NAMI State Organization activities,” and winners are recognized for their advocacy for access to care and research funding, community education programs or other NAMI priorities.  Jeste, nominated by San Diego NAMI, is director of the Stein Institute for Research on Aging and President-Elect of the American Psychiatric Association.  NAMI is organizing a special presentation honoring this year’s award winners on May 7, during the 2012 APA conference in Philadelphia. 

In addition, Neal Swerdlow, MD, PhD, professor of psychiatry, will receive the 2012 APA Award for Research at its Philadelphia conference.  APA notes that Swerdlow’s “demonstrated leadership and outstanding achievements in the field of psychiatry make him an outstanding recipient of this award.” Swerdlow is director of the UCSD Psychiatry Research Residency Track, and Deputy Director of the NIMH Consortium on the Genetics of Schizophrenia. His laboratories study the neurobiology of information processing and its deficiencies in schizophrenia, Tourette Syndrome and OCD. Swerdlow chaired the Tourette Syndrome Association Scientific Advisory Board, served on the San Diego NAMI Board of Directors and chaired their Medical Advisory Board. He is associate editor of Behavioral Neuroscience.

Victor Nizet, MD

The American Academy for Microbiology has announced that Victor Nizet, MD, has been elected as a 2012 Academy Fellow, an honor that recognizes those who have made significant contributions to the field of microbiology.  Nizet is a professor of pediatrics and pharmacy and Chief of the Division of Pediatric Pharmacology & Drug Discovery at UCSD’s School of Medicine and Skaggs School of Pharmacy & Pharmaceutical Sciences. His research seeks to discover novel treatment strategies for infectious diseases through understanding the fundamental mechanisms of bacterial pathogenesis and the innate immune system, with a special focus on human streptococcal and staphylococcal infections.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Study finds overweight teens who are satisfied with their bodies are less depressed, less prone to unhealthy behaviors

A study to be published in the June 2012 issue of Journal of Adolescent Health looking at the relationships between body satisfaction and healthy psychological functioning in overweight adolescents has found that young women who are happy with the size and shape of their bodies report higher levels of self-esteem.  They may also be protected against the negative behavioral and psychological factors sometimes associated with being overweight.

Kerri Boutelle, PhD

A group of 103 overweight adolescents were surveyed between 2004 and 2006, assessing body satisfaction, weight-control behavior, importance placed on thinness, self-esteem and symptoms of anxiety and depression, among other factors.

“We found that girls with high body satisfaction had a lower likelihood of unhealthy weight-control behaviors like fasting, skipping meals or vomiting,” said Kerri Boutelle, PhD, associate professor of psychiatry and pediatrics at the University of California, San Diego School of Medicine. Boutelle added that the positive relationship shown in this study between body a girl’s happiness with her body and her behavioral and psychological well-being suggests that improving body satisfaction could be a key component of interventions for overweight youth.

“A focus on enhancing self-image while providing motivation and skills to engage in effect weight-control behaviors may help protect young girls from feelings of depression, anxiety or anger sometimes association with being overweight,” said Boutelle. 

Additional contributors included first author Taya R. Cromley, PhD, of UCLA; Stephanie Knatz and Roxanne Rockwell, UC San Diego; and Dianne Neumark-Sztainer, PhD, MPH, RD and Mary Story, PhD, RD, University of Minnesota, Minneapolis.

This study was supported by a University of Minnesota Children’s Vikings Grant.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Steven Garfin, MD, Distinguished Professor and chair of the Department of Orthopaedic Surgery at UC San Diego Health System was named President of the International Society for the Advancement of Spine Surgery (ISASS) for 2012 to 2013.

ISASS assesses existing strategies and innovative ideas in clinical and basic sciences related to spine surgery to enhance patient care.

Steven Garfin, MD, Distinguished Professor and chair of the Department of Orthopaedic Surgery at UC San Diego Health System.

“Being named president of ISASS is an honor and a responsibility. Spinal surgery is an important part of the continuum of care for patients with spine related pains, injuries and deformities,” said Garfin, an international expert in complex spine reconstruction.  “Spinal surgeons gathering from countries around the world have much to learn from, and teach, each other.”

Increasingly, insurance companies are pushing back on authorization and funding for spine care.  Prior to the formation of ISASS, there was no academic group for spinal surgeons to speak on behalf of patient care as it relates solely to surgical procedures. 

“Much of the research done on spine related problems is performed in collaboration with surgeons and will progress better with a like-minded specialty group where questions can be openly discussed,”  said Garfin.  “We need to continue to focus on the advances in the field that bring real clinical benefits to patients.”

Garfin’s new position will expand awareness of UC San Diego’s academic, clinical and basic science endeavors.

“As surgeons from around the world come to UC San Diego to train and study, they will hopefully take home a positive message about our programs,” said Garfin. 

During his one-year term as president, Garfin will focus on the following areas:

• Continue ISASS’ growth and position the society as the primary educational resource for surgeons with new technologies and innovative solutions.
• Interact with members of the international spine surgery community to learn more about the successes and failures of new devices and techniques from patients and physicians.
• Address the causes of lower back pain, discover new diagnostic tools and develop strategies for fusion/motion preservation treatments in spinal disorders.

The Department of Orthopaedic Surgery at UC San Diego Heath System is dedicated to providing excellence in clinical care and research in musculoskeletal disorders, it is a pioneer in cartilage restoration and transplantation, and has leaders in joint replacement, hand and upper extremity surgery, trauma care, spine surgery and sports medicine.

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Media Contact: Michelle Brubaker, 619-543-6163, mmbrubaker@ucsd.edu

Jack E. Dixon, PhD, Vice President and Chief Scientific Officer of the Howard Hughes Medical Institute, and professor of pharmacology, cellular and molecular medicine, chemistry and biochemistry at the University of California, San Diego has been named a foreign member of the Royal Society.  Dixon is among 44 newly elected fellows and 8 new Foreign Members of the Royal Society, a fellowship of the world's most eminent scientists that is the oldest scientific academy in continuous existence.

Jack E. Dixon, PhD

Founded in 1660, Royal Society Fellows have included Isaac Newton, Charles Darwin, Ernest Rutherford, Albert Einstein, Dorothy Hodgkin, Francis Crick, James Watson and Stephen Hawking. Today there are approximately 1,500 Fellows and Foreign Members, including more than 80 Nobel Laureates. Foreign Members to the Royal Society are elected for life through a peer-review process on the basis of excellence in science. There are currently about 140 Foreign Members.

“Jack E. Dixon is one of the most influential biochemists of his generation. His elegant studies have radically advanced our understanding of cell signaling and the molecular basis of pathogenesis,” said the Royal Society in announcing his election on April 22.

Dixon was instrumental in the analysis of protein tyrosine phosphatases (PTPases.) He also discovered that the bacterium responsible for the plague or "black death," Yersinia pestis, harbors the most active PTPase yet described. This enzyme functions as a lethal weapon when injected into mammalian cells to block the immune response. This mechanism is now recognized as a widely used strategy for pathogenic bacteria to disarm the host's immune system.

A powerful advocate for scientific research, Dixon is also a member of the National Academy of Sciences and past president of the American Society for Biochemistry and Molecular Biology.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

UC San Diego researchers join CHP this morning to educate students and public

According to the California Department of Motor Vehicles (CADMV), distracted driving is on the rise due to an increase in the use of cell phones and other electronic devices and the increasing importance of these devices in individuals’ lives.  Studies have shown that phoning and driving increases the risk of crashes four-fold, with hands free and hand held devices equally dangerous.  Texting increases this risk 8-16 times.

A team of experts from UC San Diego's Trauma Epidemiology and Injury Prevention Research Center analyzed driving habits in college and university students in San Diego County. The team will share the results at a media conference along with the California Highway Patrol at 10 a.m., Tuesday, April 24, 2012, at the UC San Diego Medical Center in Hillcrest, near the Emergency entrance on Front Street.

“Distracted Driving is a highly prevalent behavior in college students who have misplaced confidence in their own driving skills and their ability to multitask,” said Linda Hill, MD, MPH, clinical professor in the Department of Family and Preventive Medicine at UC San Diego School of Medicine.  “Despite the known dangers, distracted driving has become an accepted behavior.”

“This study highlights the high prevalence of distracted driving in college students, including texting while driving, something we see first-hand each and every day,” said assistant chief Robert Clark, Border Division, California Highway Patrol.  “The demonstration of misplaced confidence in their own and others’ ability to multitask may lead to opportunities for us to educate and employ some risk abatement strategies.”

Nearly 5,000 students from University of California San Diego, San Diego State University, University of San Diego, CSU San Marcos and eight smaller colleges in the region completed the study.  The average age was 21 years old; 66 percent female; 83 percent were undergraduates; 17 percent graduates.

Distracted Driving Behaviors

• 78 percent reported driving while using a cell phone (talking or texting)
• 52 percent reported using hands free devices at least some of the time
• 47 percent said they use hands free at least 50 percent of the time
• Only 25 percent used hands free with high frequency
• 50 percent said they send texts while driving on freeway
• 60 percent said they send texts while in stop and go traffic or in city streets
• 87 percent send texts while at traffic lights
• Only 12 percent said they never text, not even at a traffic light

In addition to Hill, the UC San Diego research team included Jill Rybar, MPH, Tara Styer, MPH, and Ethan Fram.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Without p-tau protein present, impact of amyloid is “not significantly different from zero”

According to a new study, the neuron-killing pathology of Alzheimer’s disease (AD), which begins before clinical symptoms appear, requires the presence of both amyloid-beta (a-beta) plaque deposits and elevated levels of an altered protein called p-tau.

Without both, progressive clinical decline associated with AD in cognitively healthy older individuals is “not significantly different from zero,” reports a team of scientists at the University of California, San Diego School of Medicine in the April 23 online issue of the Archives of Neurology.

“I think this is the biggest contribution of our work,” said Rahul S. Desikan, MD, PhD, research fellow and resident radiologist in the UC San Diego Department of Radiology and first author of the study.  “A number of planned clinical trials – and the majority of Alzheimer's studies – focus predominantly on a-beta. Our results highlight the importance of also looking at p-tau, particularly in trials investigating therapies to remove a-beta. Older, non-demented individuals who have elevated a-beta levels, but normal p-tau levels, may not progress to Alzheimer’s, while older individuals with elevated levels of both will likely develop the disease.”

The findings also underscore the importance of p-tau as a target for new approaches to treating patients with conditions ranging from mild cognitive impairment (MCI) to full-blown AD. An estimated 5.4 million Americans have AD. It’s believed that 10 to 20 percent of Americans age 65 and older have MCI, a risk factor for AD. Some current therapies appear to delay clinical AD onset, but the disease remains irreversible and incurable.

“It may be that a-beta initiates the Alzheimer's cascade,” said Desikan. “But once started, the neurodegenerative mechanism may become independent of a-beta, with p-tau and other proteins playing a bigger role in the downstream degenerative cascade. If that’s the case, prevention with anti-a-beta compounds may prove efficacious against AD for older, non-demented individuals who have not yet developed tau pathology.  But novel, tau-targeting therapies may help the millions of individuals who already suffer from mild cognitive impairment or Alzheimer's disease.”

The new study involved evaluations of healthy, non-demented elderly individuals participating in the ongoing, multi-site Alzheimer’s Disease Neuroimaging Initiative, or ADNI. Launched in 2003, ADNI is a longitudinal effort to measure the progression of mild cognitive impairment and early-stage AD.

The researchers studied samples of cerebrospinal fluid (CSF) taken from ADNI participants.

“In these older individuals, the presence of a-beta alone was not associated with clinical decline,” said Anders M. Dale, PhD, professor of radiology, neurosciences, and psychiatry at UC San Diego and senior author of the study. “However, when p-tau was present in combination with a-beta, we saw significant clinical decline over three years.”
 
A-beta proteins have several normal responsibilities, including activating enzymes and protecting cells from oxidative stress. It is not known why a-beta proteins form plaque deposits in the brain. Similarly, the origins of p-tau are not well understood. One hypothesis, according to Desikan, is that a-beta plaque deposits trigger hyperphosphorylation of nearby tau proteins, which normally help stabilize the structure of brain cells. Hyperphosphorylation occurs when phosphate groups attach to a protein in excess numbers, altering their normal functions. Hyperphosphorylated tau – or p-tau – can then exacerbate the toxic effects of a-beta plaque upon neurons.
 
The discovery of p-tau’s heightened role in AD neurodegeneration suggests it could be a specific biomarker for the disease before clinical symptoms appear. While high levels of another tau protein – t-tau – in cerebrospinal fluid have been linked to neurologic disorders, such as frontotemporal dementia and traumatic brain injury, high levels of p-tau correlates specifically to increased neurofibrillary tangles in brain cells, which are seen predominantly with AD.

“These results are in line with another ADNI study of healthy controls and MCI participants that found progressive atrophy in the entorhinal cortex – one of the areas of the brain first affected in AD –only in amyloid positive individuals who also showed evidence of elevated p-tau levels,” said Linda McEvoy, PhD, assistant professor of radiology and study co-author.

“One of the exciting dimensions of this paper was the combined use of cerebrospinal fluid markers and clinical assessments to better elucidate the neurodegenerative process underlying Alzheimer’s disease in individuals who do not yet show clinical signs of dementia,” added co-author James Brewer, MD, PhD, an associate professor of radiology and neurosciences at UC San Diego School of Medicine.  “We do not have an animal model that works very well for studying this disease, so the ability to examine the dynamics of neurodegeneration in living humans is critical.”

Nonetheless, the scientists say more research is needed. They note that CSF biomarkers provide only an indirect assessment of amyloid and neurofibrillary pathology and may not fully reflect the underlying biological processes of AD.

“This study highlights the complex interaction of multiple pathologies that likely contribute to the clinical symptomatology of Alzheimer’s disease,” said co-author Reisa Sperling, MD, a neurologist at Massachusetts General Hospital and Brigham and Women’s Hospital. “It suggests we may be able to intervene in the preclinical stages of AD before there is significant neurodegeneration and perhaps prevent the onset of symptoms.”

Other co-authors are Wesley K. Thompson, Department of Psychiatry; and Dominic Holland and Paul S. Aisen, Department of Neuroscience, UC San Diego School of Medicine.

Funding for this research came, in part, from the National Institutes of Health and the Alzheimer’s Disease Neuroimaging Initiative.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

People with nonalcoholic fatty liver disease (NALFD) who consume alcohol in modest amounts – no more than one or two servings per day – are half as likely to develop hepatitis as non-drinkers with the same condition, reports a national team of scientists led by researchers at the University of California, San Diego School of Medicine.

The findings are published in the April 19, 2012 online issue of The Journal of Hepatology.

Two forms of nonalcoholic fatty liver disease (NAFLD) are depicted in these images of liver biopsies from adults, taken from this study.  The first (top) shows nonalcoholic fatty liver only.  The second (bottom) shows nonalcoholic steatohepatitis (NASH), a more serious condition with potential to progress to cirrhosis. Images courtesy of Elizabeth Brunt, MD, of Washington University in Saint Louis.

NALFD is the most common liver disease in the United States, affecting up to one third of American adults. It’s characterized by abnormal fat accumulation in the liver. The specific cause or causes is not known, though obesity and diabetes are risk factors. Most patients with NAFLD have few or no symptoms, but in its most progressive form, known as nonalcoholic steatohepatitis or NASH, there is a significantly heightened risk of cirrhosis, liver cancer and liver-related death.

NALFD is also a known risk factor for cardiovascular disease (CVD). Patients with NAFLD are approximately two times more likely to die from coronary heart disease than from liver disease. The study’s authors wanted to know if the well-documented heart-healthy benefits of modest alcohol consumption outweighed alcohol’s negative effects.

“We know a 50-year-old patient with NAFLD has a higher risk of CVD,” said Jeffrey Schwimmer, MD, associate professor of clinical pediatrics at UC San Diego, director of the Fatty Liver Clinic at Rady Children’s Hospital-San Diego and senior author. “Data would suggest modest alcohol consumption would be beneficial (in reducing the patient’s CVD risk) if you don’t take liver disease into account. When you do take liver disease into account, however, the usual medical recommendation is no alcohol whatsoever.”

Schwimmer and colleagues discovered that the benefits of modest alcohol consumption were compelling, at least in terms of reducing the odds of patients with NAFLD from developing more severe forms of the disease. Patients with NASH are 10 times more likely to progress to cirrhosis, the final phase of chronic liver disease. Cirrhosis is the 12th leading cause of death in the U.S., killing an estimated 27,000 Americans annually.

“Our study showed that those people with modest alcohol intake – two drinks or less daily – had half the odds of developing NASH than people who drank no alcohol,” said Schwimmer. “The reasons aren’t entirely clear. It’s known that alcohol can have beneficial effects on lipid levels, that it increases ‘good’ cholesterol, which tends to be low in NAFLD patients. Alcohol may improve insulin sensitivity, which has a role in NAFLD. And depending upon the type of alcohol, it may have anti-inflammatory effects.”

The study also found that in patients with NAFLD, modest drinkers experienced less severe liver scarring than did lifelong non-drinkers.

The study did not evaluate the effects of different types of alcohol, such as beer or spirits. Schwimmer said to do so would require a much larger study. Also, the study’s findings do not apply to children. All of the participants in the study were age 21 and older.

The current paper is based on analyses of 600 liver biopsies of patient’s with NAFLD by a national panel of pathologists who had no identifying clinical information about the samples. The study excluded anyone who averaged more than two alcoholic drinks per day or who reported consuming five or more drinks in a day (binge-drinking) at least once a month. All of the patients were at least 21 years of age.

Schwimmer said the findings indicate patients with liver disease should be treated individually, with nuance.

“For a patient with cirrhosis or viral hepatitis, the data says even small amounts of alcohol can be bad. But that may not be applicable to all forms of liver disease. Forty million Americans have NAFLD. Physicians need to look at their patient’s overall health, their CVD risk, their liver status, whether they’re already drinking modestly or not. They need to put all of these things into a framework to determine risk. I suspect modest alcohol consumption will be an appropriate recommendation for many patients, but clearly not all.”

Co-authors are Winston Dunn, departments of Pediatrics and Medicine, UC San Diego and Gastroenterology and Hepatology, Department of Medicine, University of Kansas Medical Center; Arun J. Sanyal, Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University Medical Center; Elizabeth M. Brunt, John Cochran VA Medical Center, Saint Louis and Division of Gastroenterology, Saint Louis University School of Medicine; Aynur Unalp-Arida, Department of Epidemilogy, Johns Hopkins Bloomberg School of Public Health; Michael Donohue, Division of Biostatics and Bioinformatics, Department of Family and Preventive Medicine, UC San Diego; and Arthur J. McCullough, Department of Gastroenterology and Hepatology, Cleveland Clinic.

Funding for this research came, in part, from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development and the National Cancer Institute.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

UC San Diego Medical Center, located in Hillcrest, has been named one of the nation’s 100 Top Hospitals^® by Thomson Reuters. Ranked among the country’s major teaching hospitals, the Medical Center was also one of twelve hospitals to receive the Everest Award. This award honors hospitals that have achieved both the highest current performance and the fastest long-term improvement over a five-year period in Reuter’s national benchmarking study.

UC San Diego Medical Center named top hospital by Retuers.

“These honors reflect the extraordinary achievements of UC San Diego Health System teams that are dedicated to delivering the highest quality and most efficient care possible to all patients,” said Tom McAfee, MD, interim CEO, UC San Diego Health System. “Our goal is to deliver specialized lifesaving care based on an evidence-based model that can be replicated by hospitals nationwide.”

“Our Quality Council has actively pursued the strategic goals of achieving outstanding outcomes and preventing patient harm,” said Angela Scioscia, MD, CMO, UC San Diego Health System. “Performance improvement efforts have been deliberate to achieve what Thomson Reuter’s calls ‘balanced excellence.’ Most notable are our innovations in resuscitation services and training, prevention of health care associated infections, strategies to provide medication safely, and commitment to advancing and leveraging our clinical informatics.” 

The Thomson Reuters 100 Top Hospitals^® study evaluates performance in 10 areas: mortality; medical complications; patient safety; average patient stay; expenses; profitability; patient satisfaction; adherence to clinical standards of care; post-discharge mortality; and readmission rates for acute myocardial infarction (heart attack), heart failure, and pneumonia. The study has been conducted annually since 1993.

To conduct the 100 Top Hospitals study, Thomson Reuters researchers evaluated 2,886 short-term, acute care, non-federal hospitals. They used public information — Medicare cost reports, Medicare Provider Analysis and Review (MedPAR) data, and core measures and patient satisfaction data from the Centers for Medicare and Medicaid Services (CMS) Hospital Compare website. Hospitals do not apply, and winners do not pay to market this honor.

The winning hospitals were announced in the April 16 edition of Modern Healthcare magazine.

“This year, the concentration of 100 Top Hospitals award winners has shifted significantly, with Texas, Florida, and California housing the most winners,” said Jean Chenoweth, senior vice president at Thomson Reuters.  ”A major change in performance geographically is an encouraging indication that the bar for quality care has been raised once again.”

UC San Diego Health System has been nationally recognized by Thomson Reuters, The Leapfrog Group and University HealthSystem Consortium (UHC) as a leader in quality and safety initiatives. UC San Diego Medical Center in Hillcrest is focused on providing acute care services to the region. This location offers the areas only Regional Burn Center, Level 1 Trauma Center, Level III NICU and comprehensive AIDS/HIV services.

More information on this study and other 100 Top Hospitals research is available at www.100tophospitals.com

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Susan Ferro-Novick, PhD, professor in the Department of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine, and Herbert Levine, PhD, professor in the UC San Diego Department of Physics, have been elected to the American Academy of Arts and Sciences.

They join 218 other distinguished scientists, scholars, writers, civic leaders and businessmen in the 2012 class, which will be inducted at a ceremony Oct. 6, 2012 at the Academy’s headquarters in Cambridge, Mass.

Susan Ferro-Novick, PhD

Ferro-Novick, who is also a Howard Hughes Medical Institute investigator, studies how vesicles move and function within cells. Vesicles are sacs of membrane that carry cargo between organelles within a cell. Specifically, Ferro-Novick and colleagues are interested in how vesicles and organelles maintain their identity amid a constant flow of intracellular traffic. Her basic research is relevant to human disease. For example, a bone formation disorder called spondyloepiphyseal dysplasia tardia results from a mutation in a gene that encodes a subunit of a large multisubunit complex identified in the Ferro-Novick lab. This complex mediates several different trafficking events in the cell.

Herbert Levine, PhD

Levine is co-director of the UC San Diego Center for Theoretical Biological Physics. His work examines the physics of nonequilibrium processes, especially in the emergence of spatial patterns in extended systems, and covers issues arising in condensed matter physics, chemical physics and most recently biophysics.

The 232-year-old American Academy of Arts and Sciences is one of the nation’s most prestigious honorary societies, celebrating the contributions of members to science and technology, energy and global security, social policy, culture, humanities and education. The 2012 class includes James Drunckman, who developed influential theories of how citizens form political opinions; U.S. Secretary of State Hillary Rodham Clinton; Robert P. Colwell, chief architect of Intel’s Pentium microprocessors; actor Clint Eastwood; Amazon founder Jeffrey Bezos; recording artist Paul McCartney; composer Andre Previn; and philanthropist Melinda F. Gates.

Historical members include George Washington, Daniel Webster, Albert Einstein and Winston Churchill. Current membership includes more than 250 Nobel laureates and 60 Pulitzer Prize winners.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Karl Y. Hostetler, MD, has been selected as the recipient of the 2012 Gertrude Elion Memorial Lecture Award by the International Society of Antiviral Research.  Hostetler is a professor of medicine in the Divisions of Infectious Diseases and Endocrinology at the UC San Diego School of Medicine. Each year the award is given to a scientist of international repute who has made significant contributions to the field of antiviral research and to mentoring of young scientists. The award will be presented during the International Conference on Antiviral Research in Sapporo, Japan on April 16. 

Karl Hostetler, MD, UC San Diego School of Medicine

“I had the privilege of meeting Dr. Elion at Burroughs Wellcome early in my career while developing an alternate version of AZT,” said Hostetler. “I am deeply gratified to receive the 2012 Gertrude Elion Memorial Award on behalf of myself, my coworkers and the UC San Diego School of Medicine.”

Hostetler is an international expert in the design, synthesis and evaluation of novel orally active antivirals for poxviruses such as smallpox, monkeypox, cowpox, and ectromelia as well as for cytomegalovirus, herpes simplex, and other double stranded DNA viruses.   He has also advanced the discovery and development of high potency antiretrovirals for drug-resistant HIV. 

He is a founder of three biotech companies, Vical Inc., Triangle Pharmaceuticals, and Chimerix Inc., which are dedicated to developing lifesaving drugs in the treatment of serious viral infections and cancer.  Hostetler holds 43 U.S. patents and has published more than 160 peer-reviewed scientific articles.

Hostetler’s lecture will recount the discovery of novel antiviral agents using a patented lipid conjugation technique to create AIDS drugs which are more potent, active against a broad range of drug resistant HIV variants, and require infrequent dosing. 

“Dr. Elion discovered acyclovir, the first commercially successful antiviral, for which she received the Nobel Prize in 1988.  The development of this drug was followed by a large number of new antiviral agents which have profoundly improved the treatment of AIDS, hepatitis B and C,” said Hostetler.  

Hostetler received his undergraduate degree in chemistry from DePauw University in Greencastle, Indiana in 1961 and his medical degree from the Western Reserve University School of Medicine in Cleveland, Ohio in 1965. He completed his internship and residency in internal medicine at University Hospitals of Cleveland and a fellowship in endocrinology and metabolism at the Cleveland Clinic Foundation. He currently serves as Director of the Endocrinology Clinic at the San Diego VA Medical Center and is an associate member of the UC San Diego Moores Cancer Center.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

New Building is first LEED Gold certified acute care medical facility in San Diego Region
 
The UC San Diego Sulpizio Cardiovascular Center is the first hospital-based project in the region to receive LEED Gold certification from the United States Green Building Council (USGBC).  Representatives from the USGBC – San Diego Chapter recently presented a plaque to the building project and design team.
 
“I am extremely proud of this team and the UC San Diego Sulpizio Cardiovascular Center,” said Randy Leopold, LEED^®AP, director of Health Care Architectural Services, UC San Diego Facilities Design & Construction.  “The design decision we made from the beginning laid the foundation for our being able to pursue LEED certification.  This Gold level certification recognition is the jewel in our crown.”
 

UC San Diego's Randy Leopold and Doug Kot from USGBC-San Diego untie ribbon on LEED plaque at UC San Diego Sulpizio Cardiovascular Center.

LEED – Leadership in Energy and Environmental Design – promotes a “whole-building” approach to sustainability by recognizing performance in several key areas.  Though the Sulpizio Cardiovascular Center project began in 2005, prior to “LEED” guideline establishment, leadership at UC San Diego, along with the design and construction teams, believed in creating a building that was environmentally thoughtful. 
 
The facility design takes full advantage of the movement of the sun with shading devices and massing elements to minimize heat gain and reduce energy consumption.  The design also embraces the idea of blurring the lines between interior and exterior regions, to provide the facility with a “natural” feel that picks up on the stunning geography of the nearby coastal canyons. 
 
“It is no small task to achieve LEED certification after the design of the project was mostly complete,” said Doug Kot, Executive Director of the USGBC- San Diego Chapter.  “This team had established the right goals and accountability and was intuitively on their way toward building sustainability when we started working with them."
 
Kot went on to explain that the indoor environmental quality of UC San Diego Sulpizio Cardiovascular Center makes this building a superior facility for patients and staff.  “This building promotes good health by combining energy conservation techniques with the very best care available and that is what we are here to celebrate in this LEED project,” said Kot.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Scott M. Lippman, MD, chair of Thoracic/Head and Neck Medical Oncology at The University of Texas (UT) MD Anderson Cancer Center, has accepted the position of director of Moores Cancer Center at the University of California, San Diego, beginning May 1, 2012.

UC San Diego Moores Cancer Center, home to nearly 350 medical and radiation oncologists, cancer surgeons, and researchers, is one of only 41 National Cancer Institute (NCI)-designated comprehensive cancer centers in the country.  It is part of UC San Diego Health System, the San Diego region’s only academic health system.

UC San Diego Moores Cancer Center director, Scott Lippman, MD

“As the new director, Lippman will implement strong initiatives for ramping up the research-driven cancer therapy and prevention programs and clinical trials of the Moores Cancer Center,” said David A. Brenner, MD, vice chancellor for Health Sciences and dean of the School of Medicine at UC San Diego.  “His ultimate goal, and ours, is to facilitate the translation of novel discoveries from our world-class laboratories into personalized therapies.  I am confident that under Dr. Lippman’s leadership, research at Moores Cancer Center will benefit our patients and change standards of care for decades to come.”

Lippman currently holds the Charles A. LeMaistre Distinguished Chair in Thoracic Oncology and is professor of Cancer Medicine and Cancer Prevention at MD Anderson.  Lippman graduated from Johns Hopkins University School of Medicine, did his internship and residency training at Johns Hopkins Hospital and Harbor-UCLA Medical Center, and had hematology/medical oncology training at Stanford University and the University of Arizona. He is triple board-certified in internal medicine, hematology and medical oncology.

Lippman’s major fields of research are translational/molecular studies of cancer risk, molecular-targeted drug development and personalized therapy, with a long-standing record of funding from the NCI in these research areas, including recently as principal investigator of two program project (P01) grants and a Specialized Program of Research Excellence (SPORE). He is also leader of the Lung Cancer Program of the MD Anderson Cancer Center Support Grant and is co-investigator on the American Association for Cancer Research (AACR) Stand Up to Cancer (SU2C) project involving molecular studies of lung cancer.

Lippman will bring to UC San Diego Health Sciences more than 25 years of experience as principal investigator of translational research involving investigator-initiated clinical trials.  He has participated in the national leadership of clinical/translational research planning and development within the NCI Cooperative Group setting and currently sits on the National Institutes of Health (NIH) Clinical Trials/Translational Research Advisory Committee. He has served on several cancer center external advisory boards and major-trial steering committees, and has played a leadership role in major AACR and American Society of Clinical Oncology (ASCO) committees and programs.

In addition to extensive research and academic administrative responsibilities, Lippman plans to maintain an active clinical practice, including the accrual of new patients to clinical research protocols.  As a clinician, he is well-respected by his peers, with recognition in every major “Top Doctor” listing including recently in the U.S. News Top Doctors. 

Author of more than 300 publications in high-impact journals, including The New England Journal of Medicine, JAMA, PNAS, and The Lancet, and chapters in major medical textbooks, Lippman has received many awards, among them the ASCO-American Cancer Society Award, AACR Cancer Research and Prevention Foundation Award, and the ASCO Statesman Award, and he is an elected member of the prestigious Association of American Physicians.

His extensive record of extramural service includes serving on the Food and Drug Administration Oncologic Drugs Advisory Committee, NIH Clinical Oncology Study Section, and NIH Chemo/Dietary Prevention study section, which he currently chairs.  He has served on the editorial boards of several top-tier, peer-reviewed journals, including Cancer Research, Journal of the National Cancer Institute, and Journal of Clinical Oncology, and is editor-in-chief of the AACR journal Cancer Prevention Research.  He also has chaired major scientific meetings including AACR and Keystone meetings and has given keynote lectures at major international scientific meetings.  

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

On Monday, April 9, Santiago Horgan, MD, chief of minimally invasive surgery at UC San Diego Health System implanted the new FDA-approved LINX device in a 29-year old patient suffering from gastroesophageal reflux disease (GERD), a chronic digestive disease that can lead to severe inflammation, stricture, Barrett’s esophagus and esophageal cancer.

Santiago Horgan, MD, implants first LINX device since FDA approval.

“The multi-center clinical trial results clearly showed that the magnetic device is highly effective in treating GERD and the painful burning that results from this progressive condition,” said Horgan, an international expert in treating esophageal disease. “Unlike drugs that suppress stomach acids, this flexible device corrects the anatomy and immediately addresses the actual source of reflux.”

The LINX system is composed of a series of titanium beads, each with a magnetic core, that are connected to form a ring shape. It is implanted at the lower esophageal sphincter (LES), a circular band of muscle that closes the last few centimeters of the esophagus and prevents the backward flow of stomach contents.

The LINX device is designed to prevent acid reflux but allow for digestion.

“This device has changed my life,” said Gina Brickell, one of the first recipients of the LINX device. “I suffered from GERD for years. Now I can eat what I want, when I want, and where I want.”

The FDA approved the LINX Reflux Management System in March 2012. Horgan and his surgical team have implanted more than 20 of the devices during the clinical trial phase, representing the most surgeries in the second phase of procedures that led to FDA approval.

The LINX device is an option for patients who do not respond to dietary and lifestyle measures. The device can be placed during a 20-30 minute minimally invasive surgery. Patients may leave the hospital the same day after brief observation.

Click on the above image to watch video of Horgan discussing LINX technique for GERD.

Magnetic Resonance Imaging (MRI) tests are prohibited if you have received the LINX Reflux Management System.

The LINX Reflux Management System is manufactured by Torax Medical Inc. in St. Paul, Minn.

To learn more about eligibility for the LINX device at UC San Diego Health System, please call 619-471-0447.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Researchers at the University of California, San Diego and Veterans Affairs San Diego Healthcare System have shown that elevated pulse pressure may increase the risk of cerebrovascular disease (CVD) in older adults with Alzheimer’s disease (AD).  Their study has been published in the early online edition of Journal of Alzheimer's Disease in advance of the June 5 print publication.

The findings may have treatment implications, since some antihypertensive medications specifically address the pulsatile component of blood pressure.  Pulse pressure (PP) – the difference between systolic and diastolic pressure – is one measure of the pulsatile component of blood pressure.  PP increases substantially with age, partially due to hardening of the arteries.

Hypertension is a common risk factor for AD, but the use of antihypertensive medications to prevent dementia has had mixed results.  Most studies examining the effects of blood pressure on the risk of AD have focused on standard measures of blood pressure, the systole and diastole readings.  However, scientists theorized that PP elevation may impair the clearance of beta amyloid – a hallmark of AD – from the brain.  Other studies have suggested that PP elevation may contribute to AD risk indirectly by increasing the risk of CVD.

The researchers, led by Mark W. Bondi, PhD, of VA San Diego Healthcare System and UC San Diego Department of Psychiatry, looked at 65 patients who later met the criteria for AD at autopsy.  These patients were examined before death for relationships among blood pressure and neuropathologic markers.  More than half of them were found, at autopsy, to have CVD. 

“The association between PP and CVD was independent of dementia severity and the presence of other vascular risk factors,” said Bondi. “Interestingly, standard measures of blood pressure were not significantly associated with the presence of CVD.”

The study suggests several conclusions: that elevated blood pressure in older adults with AD is related to CVD but not AD pathology; that CVD may be more closely associated with PP than systolic or diastolic pressure; and that, in AD patients, PP elevation may be influencing cognition through effects on CVD. 

The study’s first author, Daniel A. Nation, PhD, of the VA San Diego Healthcare System, concluded the findings offer possible treatment implications. “Antihypertensive treatments targeting the pulsatile component of blood pressure may reduce the vascular contribution to cognitive impairment in AD patients or in individuals at risk of AD.”

Additional contributors include Lisa Delano-Wood, PhD, Christina E. Wierenga, PhD and Amy J. Jak, PhD, VA San Diego and UC San Diego Department of Psychiatry; Katherine J. Bangen, PhD, UC San Diego Department of Psychiatry; Lawrence A. Hansen, MD, UC San Diego Departments of Neurosciences and Pathology; Douglas R. Galasko, MD, VA San Diego and UC San Diego Department of Neurosciences; and David P. Salmon, PhD, UC San Diego Department of Neurosciences.

The study was supported by the Alzheimer’s Association and the National Institute of Health.

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Media contacts: Debra Kain, 619-543-6163, ddkain@ucsd.edu; Cynthia Butler, 858-552-4373, Cynthia.Butler@va.gov

The first atlas of the surface of the human brain based upon genetic information has been produced by a national team of scientists, led by researchers at the University of California, San Diego School of Medicine and the VA San Diego Healthcare System. The work is published in the March 30 issue of the journal Science.

Genetic clustering map of brain, left lateral view.

The atlas reveals that the cerebral cortex – the sheet of neural tissue enveloping the brain – is roughly divided into genetic divisions that differ from other brain maps based on physiology or function. The genetic atlas provides scientists with a new tool for studying and explaining how the brain works, particularly the involvement of genes.

“Genetics are important to understanding all kinds of biological phenomena,” said William S. Kremen, PhD, professor of psychiatry at the UC San Diego School of Medicine and co-senior author with Anders M. Dale, PhD, professor of radiology, neurosciences, and psychiatry, also at the UC San Diego School of Medicine.

According to Chi-Hua Chen, PhD, first author and a postdoctoral fellow in the UC San Diego Department of Psychiatry, “If we can understand the genetic underpinnings of the brain, we can get a better idea of how it develops and works, information we can then use to ultimately improve treatments for diseases and disorders.”

The human cerebral cortex, characterized by distinctive twisting folds and fissures called sulci, is just 0.08 to 0.16 inches thick, but contains multiple layers of interconnected neurons with key roles in memory, attention, language, cognition and consciousness.

Other atlases have mapped the brain by cytoarchitecture – differences in tissues or function. The new map is based entirely upon genetic information derived from magnetic resonance imaging (MRI) of 406 adult twins participating in the Vietnam Era Twin Registry (VETSA), an ongoing longitudinal study of cognitive aging supported in part by grants from the National Institutes of Health (NIH). It follows a related study published last year by Kremen, Dale and colleagues that affirmed the human cortical regionalization is similar to and consistent with patterns found in other mammals, evidence of a common conservation mechanism in evolution. 
 
“We are excited by the development of this new atlas, which we hope will help us understand aging-related changes in brain structure and cognitive function now occurring in the VETSA participants,” said Jonathan W. King, PhD, of the National Institute on Aging, part of the NIH.     

The atlas plots genetic correlations between different points on the cortical surface of the twins’ brains. The correlations represent shared genetic influences and reveal that genetic brain divisions do not map one-to-one with traditional brain divisions that are based on structure and function. “Yet, the pattern of this genetic map still suggests that it is neuroanatomically meaningful,” said Kremen.

Kremen said the genetic brain atlas may be especially useful for scientists who employ genome-wide association studies, a relatively new tool that looks for common genetic variants in people that may be associated with a particular trait, condition or disease.  

Co-authors of the study are Wes Thompson, Matthew S. Panizzon, UCSD Department of Psychiatry; E.D. Gutierrez, UCSD Department of Cognitive Science; Terry L. Jernigan, UCSD departments of Psychiatry and Cognitive Science; Lisa T. Eyler and Amy J. Jak, UCSD Department of Psychiatry and VA San Diego Healthcare System; Christine Fennema-Notestine, UCSD department of Psychiatry and Radiology; Michael C. Neale, Virginia Commonwealth University; Carol E. Franz, UCSD Department of Psychiatry and UCSD Center for Behavioral Genomics; Michael J. Lyons and Michael D. Grant, Boston University; Bruce Fischl, Harvard Medical School and Massachusetts General Hospital; Larry J. Seidman, Harvard Medical School; and Ming T. Tsuang, UCSD Department of Psychiatry, VA San Diego Healthcare System, UCSD Center for Behavioral Genomics.

In addition to the NIH, funding for this research came from the VA San Diego Center of Excellence for Stress and Mental Health. VETSA is also supported by the VA Cooperative Studies Program.

Disclosure: Anders M. Dale is a founder and equity-holder in CorTechs Laboratories, Inc. and serves on its Scientific Advisory Board.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Katherine Hepburn famously said of her slim physique: “What you see before you is the result of a lifetime of chocolate.” New evidence suggests she may have been right.

Beatrice Golomb, MD, PhD, associate professor in the Department of Medicine at the University of California, San Diego, and colleagues present new findings that may overturn the major objection to regular chocolate consumption: that it makes people fat. The study, showing that adults who eat chocolate on a regular basis are actually thinner that those who don’t, will be published online in the Archives of Internal Medicine on March 26.

Beatrice Golomb, MD, PhD (right).

The authors dared to hypothesize that modest, regular chocolate consumption might be calorie-neutral –in other words, that the metabolic benefits of eating modest amounts of chocolate might lead to reduced fat deposition per calorie and approximately offset the added calories (thus rendering frequent, though modest, chocolate consumption neutral with regard to weight). To assess this hypothesis, the researchers examined dietary and other information provided by approximately 1000 adult men and women from San Diego, for whom weight and height had been measured.

Click on the photo (above) for video of Golomb discussing this research.

The UC San Diego findings were even more favorable than the researchers conjectured. They found that adults who ate chocolate on more days a week were actually thinner – i.e. had a lower body mass index – than those who ate chocolate less often. The size of the effect was modest but the effect was “significant” –larger than could be explained by chance.  This was despite the fact that those who ate chocolate more often did not eat fewer calories (they ate more), nor did they exercise more. Indeed, no differences in behaviors were identified that might explain the finding as a difference in calories taken in versus calories expended.

“Our findings appear to add to a body of information suggesting that the composition of calories, not just the number of them, matters for determining their ultimate impact on weight,” said Golomb. “In the case of chocolate, this is good news –both for those who have a regular chocolate habit, and those who may wish to start one.”

Additional contributors to the study include Sabrina Koperski and Halbert L. White, PhD, of UC San Diego. 

Funding for this study was provided by the National Institutes of Health.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Repeated stress triggers the production and accumulation of insoluble tau protein aggregates inside the brain cells of mice, say researchers at the University of California, San Diego School of Medicine in a new study published in the March 26 Online Early Edition of the Proceedings of the National Academy of Sciences.

The aggregates are similar to neurofibrillary tangles or NFTs, modified protein structures that are one of the physiological hallmarks of Alzheimer’s disease. Lead author Robert A. Rissman, PhD, assistant professor of neurosciences, said the findings may at least partly explain why clinical studies have found a strong link between people prone to stress and development of sporadic Alzheimer’s disease (AD), which accounts for up to 95 percent of all AD cases in humans.

“In the mouse models, we found that repeated episodes of emotional stress, which has been demonstrated to be comparable to what humans might experience in ordinary life, resulted in the phosphorylation and altered solubility of tau proteins in neurons,” Rissman said. “These events are critical in the development of NFT pathology in Alzheimer’s disease.”

Exposing mice to 14 days of repeated stress resulted in an accumulation of insoluble phosphorylated tau protein aggregates in brain cells, visualized in this electron micrograph.

The effect was most notable in the hippocampus, said Rissman, a region of the brain linked to the formation, organization and storage of memories. In AD patients, the hippocampus is typically the first region of the brain affected by tau pathology and the hardest-hit, with substantial cell death and shrinkage.

Not all forms of stress are equally threatening. In earlier research, Rissman and colleagues reported that acute stress – a single, passing episode – does not result in lasting, debilitating long lasting changes in accumulation of phosphorylated tau. Acute stress-induced modifications in the cell are transient, he said, and on the whole, probably beneficial.

“Acute stress may be useful for brain plasticity and helping to facilitate learning. Chronic stress and continuous activation of stress pathways may lead to pathological changes in stress circuitry. It may be too much of a good thing.”  As people age, perhaps their neuronal circuits do too, he said, becoming less robust and perhaps less capable of completely rebounding from the effects of stress.

“Age is the primary, known risk factor for Alzheimer’s disease. It may be that as we age, our neurons just aren’t as plastic as they once were and some succumb.”
  
The researchers observed that stress cues impacted two key corticotropin-releasing factor receptors, suggesting a target for potential therapies. Rissman noted drugs already exist and are in human trials (for other conditions) that modulate the activity of these receptors.

“You can’t eliminate stress. We all need to be able to respond at some level to stressful stimuli. The idea is to use an antagonist molecule to reduce the effects of stress upon neurons. The stress system can still respond, but the response in the brain and hippocampus would be toned down so that it doesn’t result in harmful, permanent damage.”

Co-authors of the paper are Michael A. Staup and Allyson Roe Lee, UCSD Department of Neurosciences; Nicholas J. Justice, Baylor College of Medicine; and Kenner C. Rice NIDA/NIH, Wylie Vale and Paul E. Sawchenko, The Salk Institute for Biological Studies.

The authors dedicate this work to long time mentor and colleague, Dr. Wylie Vale, whose years of pioneering work deciphering and describing the stress system were fundamental to this paper. Vale passed away earlier this year at the age of 70.

Funding for this research came, in part, from the National Institutes of Health, the Alzheimer’s Art Quilt Initiative; the Alzheimer’s Association; the Foundation for Medical Research and the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Genetic studies find dysregulation in pathways that govern development of the prefrontal cortex in young patients with autism

A study led by Eric Courchesne, PhD, director of the Autism Center of Excellence at the University of California, San Diego School of Medicine has, for the first time, identified in young autism patients genetic mechanisms involved in abnormal early brain development and overgrowth that occurs in the disorder.  The findings suggest novel genetic and molecular targets that could lead to discoveries of new prevention strategies and treatment for the disorder. 

Eric Courchesne, PhD, UC San Diego Autism Center for Excellence.

The study to be published on March 22 in PLoS Genetics uncovered differences in gene expression between brain tissue from young (2 to14 years old) and adult individuals with autism syndrome disorder, providing important clues why brain growth and development is abnormal in this disorder.

Courchesne first identified the link between early brain overgrowth and autism in a landmark study published by the Journal of the American Medical Association (JAMA) in 2003.  Next, he tested the possibility that brain overgrowth might result from an abnormal excess of brain cells.  In November 2011, his study, also published in JAMA, discovered a 67 percent excess of brain cells in a major region of the brain, the prefrontal cortex – a part of the brain associated with social, communication and cognitive development.

“Our next step was to see whether there might be abnormalities of genetic functioning in that same region that might give us insight into why there are too many cells and why that specific region does not develop normally in autism,” said Courchesne.

In the new study, the researchers looked towards genes for answers, and showed that genetic mechanisms that normally regulate the number of cortical neurons are abnormal. “The genes that control the number of brain cells did not have the normal functional expression, and the level of gene expression that governs the pattern of neural organization across the prefrontal cortex is turned down.  There are abnormal numbers and patterns of brain cells, and subsequently the pattern is disturbed,” Courchesne said. “This probably leads to too many brain cells in some locations, such as prefrontal cortex, but perhaps too few in other regions of cortex as well.”

In addition, the scientists discovered a turning down of the genetic mechanisms responsible for detecting DNA defects and correcting or removing affected cells during periods of rapid prenatal development.

Autism is a highly heritable neurodevelopmental disorder, yet the genetic underpinnings in the brain at young ages have remained largely unknown.  Until now, few studies have been able to investigate whole-genome gene expression and genotype variation in the brains of young patients with autism, especially in regions such as the prefrontal cortex that display the greatest growth abnormality.

Scientists – including co-first authors Maggie Chow, PhD, and Tiziano Pramparo, PhD, at UC San Diego – identified abnormal brain gene expression patterns using whole-genome analysis of mRNA levels and copy number variations from 33 autistic and control postmortem brain samples.  They found evidence of dysregulation in the pathways that govern cell number, cortical patterning and cell differentiation in the young autistic prefrontal cortex.  In contrast, in adult patients with autism, the study found that this area of the brain shows dysregulation of signaling and repair pathways.

“Our results indicate that gene expression abnormalities change across the lifespan in autism, and that dysregulated processes in the developing brain of autistic patients differ from those detected at adult ages,” said Courchesne. “The dysregulated genetic pathways we found at young ages in autism may underlie the excess of neurons – and early brain overgrowth – associated with this disorder.”

Additional contributors include co-senior authors Nicholas J. Schork, PhD, biostatistician at The Scripps Research Institute in La Jolla, CA, and Anthony Wynshaw-Boris, professor of pediatrics at UC San Francisco; Mary E. Winn and Sarah Murray, The Scripps Research Institute; Lauren Weiss and Haim Belinson, UC San Francisco; Jian-Bing Fan and Craig April, Illumina, Inc.; Cynthia Carter Barnes, Hai-Ri Li and Xiang-Dong Fu, UC San Diego.

The research was supported by funds from the Simons Foundation, The Peter Emch Family Foundation, Autism Speaks, the Thursday Club Juniors and the UCSD-NIH Autism Center of Excellence.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

15 Years of Healing San Diego’s Underserved
 
On Saturday, March 31, the UC San Diego Student-Run Free Clinic Project will host its annual fundraiser and awards ceremony. The event will be held at the UC San Diego Price Center Ballroom on the La Jolla campus. Funds raised during this event help provide free medical, dental, pharmacy, acupuncture, legal and social services  to San Diego’s working poor and homeless. More than 2,000 San Diegans rely on its comprehensive integrative health services every year. 

Ellen Beck, MD, UC San Diego Student-Run Free Clinic Project.

“For more than 15 years, the UC San Diego Student-Run Free Clinic Project has helped people of all ages and backgrounds access high-quality health care, regardless of their ability to pay,” said Ellen Beck, MD, clinical professor in the Department of Family and Preventive Medicine at UC San Diego School of Medicine. “The patients we assist have fallen through the gaps in San Diego’s ragged safety net and cannot afford health insurance.”
 
The Student-Run Free Clinic Project is run by 200 UC San Diego School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences students under the supervision of 100 licensed professionals including physicians, pharmacists, dentists, lawyers and social workers. The project has four clinical sites throughout the region: Baker Elementary in Southeast San Diego, First Lutheran Church Downtown, Pacific Beach United Methodist Church, and Golden Avenue Elementary in Lemon Grove. 

“Since our launch in 1997, we have had the support of incredible community partners, a passionate group of students and the blessing of the UC San Diego School of Medicine,” said Beck. “On our first night, in the basement of a church, we saw 10 patients. The number has grown and grown.”

Click on the above photo to watch video of the clinic in action.

Since its inception, more than 35,000 clinic visits have taken place offering transdisciplinary health care services, including specialty care for cardiovascular, ophthalmologic and psychiatric needs. Prescriptions, lab work, and related services are available at no charge. More than 85 percent of the patients have chronic conditions in need of ongoing care.

“It is important to point out that this is underserved medicine, not charity care,” said Beck. “For example, our dental services are not poverty dentistry where teeth are pulled, but restorative. We believe that toothlessness leads to joblessness, so we provide solutions like dentures that take care of the medical need and improve a person’s employment opportunities.”

The Student-Run Free Clinic Project serves as a model of care for other U.S. cities. The program runs an onsite Fellowship in Underserved Health Care, the first in the country. More than 140 faculty and health professionals have completed the national training and started more than 15 other student-run free clinic projects across the country.

“The medical students are taught a humanistic approach to care,” said Beck. “This is a mindset that they use every day and we hope will carry into their future medical practices. We teach them how to preserve their passion and sense of respect for all patients. All you have to do is see the students in action to know that they are exceptional in their approach.”
 
Beck said that the greatest challenge for the Student-Run Free Clinic Project is that operational expenses have increased while previously  available funding from federal and state sources have decreased. Beck estimates that the clinic provides the community an equivalent of $1.6 million in free medications, and several million in donated services.
 
“Many of the families who come to us are in crisis or on the verge of homelessness. Some are simply struggling financially and need help with basic health needs. We are here to serve all, but need the support of the community to do so.”
 
Beck is a recipient of the 2010 James Irvine Foundation Leadership award. She was recently honored as a WebMD Magazine 2011 Health Hero.
 
For more information on the fundraising dinner and award celebration on March 31, please call 858-534-6160 or visit http://meded.ucsd.edu/freeclinic/benefit_dinner.php

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Only academic facility on West Coast to receive certification

UC San Diego Moores Cancer Center has one of the first oncology practices in the nation to be recognized by the Quality Oncology Practice Initiative (QOPI^®) Certification Program, an affiliate of the American Society of Clinical Oncology (ASCO).  The QOPI^® Certification Program is a new initiative to certify oncology practices that meet rigorous standards for high-quality cancer care. 

UC San Diego Moores Cancer Center

“This award shows our commitment to voluntarily participating in a program that certifies the quality of cancer care at Moores Cancer Center,” said Barbara Parker, MD, medical director, Oncology Services, UC San Diego Moores Cancer Center.  “We value peer-review certification and understand the benefits of using standardized processes to improve the quality of care for our patients.”

QOPI is a voluntary, self-assessment and improvement program launched by ASCO in 2006 to help hematology-oncology and medical oncology practices assess the quality of the care they provide to patients. Through the QOPI program, practices abstract data from patients’ records up to twice per year and enter this information into a secure database. UC San Diego Moores Cancer Center is one of 23 academic and community centers receiving the inaugural certification. More than 580 oncology practices have registered in the QOPI program.
 
“Increasingly educated patients and families demand accountability and the highest standards from cancer care providers,” said Douglas W. Blayney, MD, immediate past president of ASCO. “The QOPI certification will allow oncologists in the community to be at the forefront of cancer care, and to be recognized for their quality. The Certification Program will help practices determine whether they are providing the best treatment and care possible to their patients, and demonstrates a commitment to excellence and ongoing quality improvement in the hematology-oncology outpatient practice.” 

“UC San Diego Health System is focusing on quality as an institutional initiative,” said Steven Plaxe, MD, PhD, director, Gynecologic Oncology and chair of UC San Diego Moores Cancer Center’s Quality Committee.  “For our oncology practice to be recognized by the distinguished leadership of ASCO for our initiatives confirms that we are providing excellent cancer care.”

QOPI analyzes individual practice data and compares these to more than 80 evidence-based and consensus quality measures. The information is then provided in reports to participating practices.  Individual practices are also able to compare their performance to data from other practices across the country. Based on this feedback, doctors and practices can identify areas for improvement.  

The QOPI Certification Program provides a three-year certification for outpatient hematology-oncology practices that meet standards for quality cancer care.

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Becker’s Hospital Review issues annual list of 70 “great” hospitals and health systems

UC San Diego Moores Cancer Center is the only San Diego hospital to be featured in Becker’s Hospital Review list of “70 Hospitals and Health Systems with Great Oncology Programs.” The full list in available online: www.beckershospitalreview.com

UC San Diego Moores Cancer Center

“We are pleased to be listed with our nation’s very best cancer centers,” said Thomas Kipps, MD, PhD.  “Moores Cancer Center is truly motivated to provide the best of both worlds – cancer research and the ability to bring the most advanced and most effective treatments directly to the bedside.”

According to review editors for Becker's Hospital Review, the hospitals and health systems on the list are “considered leaders in cutting-edge cancer treatment, prevention and research” and were chosen “based on clinical accolades, quality care and contributions to the field of oncology.”  Ten California hospitals made the list, five of which are University of California based medical centers.

To develop the list, Becker’s analyzed data from sources including The U.S. News & World Report, HealthGrades, American Nurses Credentialing Center, the National Cancer Institute and the American College of Surgeons. After examining national rankings and reviews, the editorial team performed additional research into each hospital. The result is a list of 70 hospitals from around the country that have demonstrated “continual innovation in treatments and services, patient-centered care, and the achievement of clinical milestones and groundbreaking discoveries.”

According to the editors, “(These) hospitals and systems serve as anchors of health within their community by providing cutting-edge oncology treatment and groundbreaking research. Though these hospitals may differ in size or location, everyone has expressed the vision to eliminate cancer and is working vehemently towards that goal.”

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Brain stimulation surgery for patients with Parkinson’s disease; promoting liver health on a national level; leading one of the nation’s top ALS clinics; and designing a law that protects the rights of students with epilepsy: these are significant reasons why four UC San Diego School of Medicine doctors were honored during the 18th annual Combined Health Agencies Health Hero Awards breakfast on March 15 at The Prado in Balboa Park.

Each year, the Combined Health Agencies’ 24 health non-profit members each choose a person or company that works daily to improve the lives of local residents affected by chronic illness. This year, four winners who were recognized were UC San Diego physicians David Barba, MD, Rohit Loomba, MD, William Mobley, MD, PhD, and Howard Taras, MD.

Since 2005, Barba, clinical professor of surgery in the Division of Neurological Surgery at UC San Diego Health System, has been involved with the Parkinson’s Association of San Diego. He routinely performs brain stimulation surgery on many patients with Parkinson’s disease and has demonstrated his leadership by organizing a sold-out patient symposium securing top quality speakers in the field. Barba is currently establishing a UC San Diego system for those working on Parkinson’s research to be in direct contact with each other.

The American Liver Foundation considers Loomba, assistant professor of clinical medicine in the Division of Gastroenterology and the Division of Epidemiology in the Department of Family and Preventive Medicine, a collaborative partner as he serves on the National Board of Directors, and the non-profit local Speakers Bureau promoting prevention and care.

As Chair of the Department of Neurosciences at UC San Diego School of Medicine, Mobley garners national support from physicians and clinicians to join the UC San Diego ALS and Motor Neuron Treatment and Research Center team to raise the level of care and treatment of patients with ALS in San Diego. Through Mobley’s reputation and expertise, the ALS Clinic is quickly becoming known as a place where patients can receive the best care possible in their fight against what is commonly known as Lou Gehrig's disease.

Taras, professor of pediatrics in the Division of Child Development and Community Health, is being recognized by the Epilepsy Foundation for his instrumental work in the passing of SB 161, a bill signed into law in 2011 that protects the rights of students with epilepsy. He has testified numerous times at California State Legislative hearings and spent hundreds of hours educating legislators and the public about the issue of emergency seizure rescue medications. Through this legislation, life-saving medication can be administered to students at school to prevent further brain damage or death.

“We are humbled by the service of these physicians and grateful to have UC San Diego Health System in our community,” said Susan Day, president of Combined Health Agencies.

This year’s event is possible by the generous support of community sponsors UC San Diego Health System, PhRMA, GlaxoSmithKline, Johnson & Johnson, BIOCOM, Rady Children’s Hospital-San Diego, Sonnenberg & Company CPAs, and The San Diego Business Journal.

Combined Health Agencies has been United Way's health partner in the United Way/CHAD Campaign since 1974. As a federation of 24 local health charities, Combined Health Agencies is focused on improving the quality of life for individuals and families who are faced with chronic health conditions.

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Media Contact: Melanie Peters, 619-543-6163, mopeters@ucsd.edu

A study by researchers at the University of California, San Diego School of Medicine and The University of Minnesota indicates that a parent’s weight change is a key contributor to the success of a child’s weight loss in family-based treatment of childhood obesity.  The results were published today in the advanced online edition of the journal Obesity.

“We looked at things such as parenting skills and styles, or changing the home food environment, and how they impacted a child’s weight,” said Kerri N. Boutelle, PhD, associate professor of pediatrics and psychiatry at UC San Diego and Rady Children’s Hospital-San Diego.  “The number one way in which parents can help an obese child lose weight?  Lose weight themselves.  In this study, it was the most important predictor of child weight loss.”

Recent data suggests that 31 percent of children in the United States are overweight or obese, or between four and five million children.  Current treatment programs generally require participation by both parents and children in a plan that combines nutrition education and exercise with behavior therapy techniques.

“Parents are the most significant people in a child’s environment, serving as the first and most important teachers,” said Boutelle “They play a significant role in any weight-loss program for children, and this study confirms the importance of their example in establishing healthy eating and exercise behaviors for their kids.”

The researchers looked at eighty parent-child groups with an 8 to 12-year-old overweight or obese child, who participated in a parent-only or parent + child treatment program for five months. 

The study focused on evaluating the impact of three types of parenting skills taught in family-based behavioral treatment for childhood obesity, and the impact of each on the child’s body weight: the parent modeling behaviors to promote their own weight loss, changes in home food environment, and parenting style and techniques (for example, a parent’s ability to help limit the child’s eating behavior, encouraging the child and participating in program activities).

Consistent with previously published research, parent BMI change was the only significant predictor of child’s weight loss. 

The researchers concluded that clinicians should focus on encouraging parents to lose weight to help their overweight or obese child in weight management.

For more information about weight loss programs for children and adolescents at UC San Diego, visit www.obesitytreatment.ucsd.edu or email Kidsweight@ucsd.edu.

Additional contributors to the study include Guy Cafri, UCSD Child and Adolescent Services Research Center, and Scott J. Crown, University of Minnesota. 

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Tracking the genetic pathway of a disease offers a powerful, new approach to drug discovery, according to scientists at the University of California, San Diego School of Medicine who used the approach to uncover a potential treatment for prostate cancer, using a drug currently marketed for congestive heart failure. Their findings are published in the current online issue of the Proceedings of the National Academy of Sciences.

“The science of genomics – the study of all of the genes in a person and how these genes interact with each other and the environment – has revealed many fundamental aspects of biology, including the mechanisms of diseases like cancer. But it has not yet been truly exploited to find new medicines to treat those diseases,” said Xiang-Dong Fu, PhD, professor of cellular and molecular medicine and senior author of the PNAS paper.

Fu, with colleagues at UC San Diego and elsewhere, describe a unique screening strategy that compares genes associated with specific disease phenotypes (traits) with small molecules capable of intervening with disease-linked gene-expression events. The high-throughput process, capable of analyzing large numbers of genes and drugs simultaneously, emphasizes investigation of the entire genetic pathway of the disease against a large set of internal controls, rather than its limited phenotype or any particular molecular or cellular target.

Historically, drug discovery has been driven by phenotype- or target-based methodologies.

“For 50 years, the standard phenotype approach emphasized the final outcome without worrying about the mechanism,” said Fu. “The process has produced some very good drugs, but researchers often didn’t know exactly how or why the drug worked. Aspirin is an example. It’s been around for more than a century, but we still don’t understand the mechanism in great detail.”

More recently, many drug designers have focused upon targeting particular components of a disease, such as a vital molecule or receptor involved in the pathogenic process. The approach has a stronger, more rational scientific basis, said Fu, but remains beset by two fundamental difficulties: “You can create a drug that disrupts a specific disease target, but you also run the risk of causing unforeseen, adverse side effects that might be worse than the disease. Second, there are many places inside of a cell that are essentially ‘undruggable.’ They are difficult, if not impossible, to intervene with.”

The new approach attempts to avoid these problems by emphasizing investigation of the genetic pathways associated with disease processes and how they might be altered to produce a healthful benefit.

“The idea is to identify the genetic troublemakers associated with a disease and then find a way to contain them, not crush them,” said Fu. “No gene was ever designed to cause disease. The goal is to find new drugs or ways to convert these genes or the affected cells back to a normal state. In many disease paradigms, you don’t want to kill cells. You want to modify them to become healthy again.”

While the idea of conducting multi-target screenings is not new, the technology to do so has been limited.  Deep sequencing, said Fu, is ideally suited for the purpose.  

To illustrate the efficacy of their high-throughput, gene-sequencing approach, Fu and colleagues applied the strategy to prostate cancer, which sometimes becomes resistant to standard antiandrogen hormone therapy. The scientists found that Peruvoside, a cardiac glycoside, strongly inhibits both androgen-sensitive and androgen-resistant prostate cancer cells without triggering severe side effects. Interestingly, a related cardiac glycoside called Digoxin has been used to treat congestive heart failure. A large epidemiological study found protective effects against prostate cancer on patients treated with Digoxin, compared to control cohorts.

“High-throughput genetic sequencing and screening allows you to look deeply into cells and analyze millions of molecules at the same time. The technology is constantly improving and getting cheaper. We think it’s a promising strategy for drug discovery,” said Fu. 

Co-authors include Hairi Li, Dong Wang, Jinsong Qiu, Yu Zhou, UCSD Department of Cellular and Molecular Medicine; Hongyan Zhou and Sheng Ding, Gladstone Institute of Cardiovascular Disease; Xianqiang Li, Signosis, Inc.; and Michael G. Rosenfeld, Howard Hughes Medical Institute, UCSD Department of Medicine.

Funding for this research came, in part, from the Prostate Cancer Foundation and the National Human Genome Research Institute.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

When you think of Botox injections, you probably think of getting rid of unwanted wrinkles around the eyes or forehead, but recently the US Food and Drug Administration (FDA) approved using the injections to help patients with neurological conditions who suffer from incontinence, or an overactive bladder. 

Botox injections paralyze the bladder muscle to prevent contractions that cause urgency to urinate or leak.  Although medications and behavioral modifications are treatment options, many patients, especially the elderly, do not respond to these methods and need a more aggressive approach.

Charles Nager, MD, co-director of the UC San Diego Women’s Pelvic Medicine Center at UC San Diego Health System.

“About 80 percent of patients with neurological conditions, such as spinal cord injuries, Parkinson’s disease and multiple sclerosis, see improvement after about a week, and the results can last four to nine months,” said Charles Nager, MD, co-director of the UC San Diego Women’s Pelvic Medicine Center at UC San Diego Health System.

Incontinence is the seventh condition, including chronic migraines and underarm sweating, that Botox has been approved to treat since the drug first arrived on the market as a wrinkle reducer in 2002. 

The outpatient procedure uses a local numbing gel, followed by 15 to 20 injections in different areas of the bladder muscle. 

“It can really be life changing for someone with severe incontinence issues,” said Nager who also serves as director of Urogynecology and Reconstructive Pelvic Surgery in the Department of Reproductive Medicine at UC San Diego. 

UC San Diego Health System is currently recruiting for a clinical trial to test Botox injections versus sacral nerve stimulation as incontinence treatment options.

Sacral nerve stimulation uses small, electrical impulses to the nerves that control urination.  The impulses are generated by a small device surgically placed under the skin.  Attached to the device is a thin, electrode-tipped wire that passes under the patient’s skin, carrying impulses to the sacral nerve.  The surgery is an outpatient procedure done under local anesthesia.

Patients involved in the clinical trial are required to have tried two drugs that previously failed to treat their incontinence issues. 

For more information on the upcoming clinical trial, please visit: health.ucsd.edu/clinicaltrials

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Might the “Twinkie defense” have a scientific foundation after all? Researchers at the University of California, San Diego School of Medicine have shown – by each of a range of measures, in men and women of all ages, in Caucasians and minorities – that consumption of dietary trans fatty acids (dTFAs) is associated with irritability and aggression.

The study of nearly 1,000 men and women provides the first evidence linking dTFAs with adverse behaviors that impacted others, ranging from impatience to overt aggression. The research, led by Beatrice Golomb, MD, PhD, associate professor in the UC San Diego Department of Medicine, has been published online by PLoS ONE.

Dietary trans fatty acids are primarily products of hydrogenation, which makes unsaturated oils solid at room temperature. They are present at high levels in margarines, shortenings and prepared foods.  Adverse health effects of dTFAs have been identified in lipid levels, metabolic function, insulin resistance, oxidation, inflammation, and cardiac health.

The UC San Diego team used baseline dietary information and behavioral assessments of 945 adult men and women to analyze the relationship between dTFAs and aggression or irritability.  The survey measured such factors as a life history of aggression, conflict tactics and self-rated impatience and irritability, as well as an “overt aggression” scale that tallies recent aggressive behaviors. Analyses were adjusted for sex, age, education, and use of alcohol or tobacco products.

“We found that greater trans fatty acids were significantly associated with greater aggression, and were more consistently predictive of aggression and irritability, across the measures tested, than the other known aggression predictors that were assessed,” said Golomb. “If the association between trans fats and aggressive behavior proves to be causal, this adds further rationale to recommendations to avoid eating trans fats, or including them in foods provided at institutions like schools and prisons, since the detrimental effects of trans fats may extend beyond the person who consumes them to affect others.”

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Patients seeking a weight-loss surgery that does not require an implanted device or permanent change to their anatomy, have a new clinical trial option at UC San Diego Health System. Santiago Horgan, MD, chief of minimally invasive surgery, and his team, now offer gastric plication, a novel surgery that folds the stomach into a smaller, more compact size.

Santiago Horgan, MD, chief of minimally invasive surgery, UC San Diego Health System.

“This minimally invasive surgery is a new choice for patients who are more than 30 pounds overweight,” said Horgan, director of the UC San Diego Bariatric Metabolic Institute. “By folding the stomach, we can reduce the volume by 70 percent. Patients can expect to lose up to 2 pounds per week following the procedure.”

Horgan compares gastric plication, a way to fold the stomach into a new functional form, to the art of origami. Gastric plication is potentially reversible and is performed laparoscopically. During a one-hour procedure, one to five small incisions are made in the abdomen to reach the stomach to place the folds. Depending on the size of the patient’s stomach, one or two folds are created with non-absorbable sutures.

Click here to watch video of the surgery.

Horgan’s team now offers gastric plication for weight loss.

“After surgery, with a smaller stomach size, a patient feels fuller faster and is likely to have an actual decrease in appetite,” said Horgan. “If, for some reason, we need to return the stomach to its original size, we can do so. Also, since the patient’s anatomy is not rerouted, the patient does not have severe food restrictions.”

Horgan said that, in addition to weight loss, many surgery patients see an associated benefit in reducing their blood pressure, diabetes and depression medications. These long-term results are a product of a combination of surgery, healthy eating and exercise.

Horgan is a pioneer in minimally invasive surgery for the treatment of obesity.

Gastric plication offers a short hospitalization of one to two days with a return to normal activities in one week. Candidates must have a BMI of at least 27.

The UC San Diego Bariatric Metabolic Institute is dedicated to the science of developing and offering an array of surgical and non-surgical weight loss techniques that are customized to the patient’s individual needs. A team of internationally recognized surgeons and specialists provide patients a comprehensive long-term plan to improve their health and lifestyle. Learn more at bmi.ucsd.edu.

This clinical trial surgery was performed by Horgan as well as Garth Jacobsen, MD, and Nikolai A. Bildzukewicz, MD, of UC San Diego Health System.

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Media Contact: Jackie Carr, 619-543-6163, jcarr@ucsd.edu

Researchers Say Results Show Need for Additional Breastfeeding Support and Education

Researchers at the California Teratogen Information Service (CTIS) Pregnancy Health Information Line, a statewide non-profit organization based at the University of California, San Diego School of Medicine, have found women exposed to certain antidepressants during pregnancy were significantly less likely to breastfeed their babies compared to unexposed women. The results of the study were recently published online in The Journal of Human Lactation.

The study uses data obtained by counselors at the CTIS Pregnancy Health Information Line, a toll-free service offering evidence-based clinical information about exposures during pregnancy and breastfeeding.  It focused on 466 pregnant women who contacted the CTIS Pregnancy Health Information Line over a ten year period with questions about a wide variety of exposures and, after being counseled, agreed to participate in a follow-up study of their pregnancy outcome.

The study specifically examines breastfeeding choices of women exposed to selective serotonin reuptake inhibitor (SSRI) antidepressants at the time of delivery, compared to those who discontinued use of antidepressants earlier in pregnancy, as well as to those women who report not taking antidepressants at all. The results showed women exposed to an SSRI anytime in pregnancy were about 60 percent less likely to initiate breastfeeding than women who took no antidepressant.

“While the benefits of breastfeeding an infant are very clear, this study suggests that women who are taking antidepressants in pregnancy are not engaging in this behavior as often as we would like to see,” said Christina Chambers PhD, MPH, professor of pediatrics at UC San Diego School of Medicine, CTIS program director, and co-author of the study. “Whether this is due to the mother’s fear of harming her baby by breastfeeding while taking the medication, or due to the mother’s depression itself is unclear.” According to Chambers, regardless of the reason for breastfeeding choice, the study suggests that women who have depressive disorders and/or take antidepressants in pregnancy may require additional encouragement and support when making the choice to breastfeed an infant.
 
Questions or concerns about antidepressants or any other exposure during pregnancy or breastfeeding can be directed to the CTIS Pregnancy Health Information Line at 800-532-3749 or via instant message counseling at CTISPregnancy.org. Outside of California, please call the Organization of Teratology Information Specialists (OTIS) at 866-626-6847.

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Media Contact: Nicole Chavez, 858-246-1745, ncchavez@ucsd.edu

Researchers at the University of California, San Diego, the Medical University of South Carolina, the University of Cincinnati, and American Life Science Pharmaceuticals of San Diego have validated the protease cathepsin B (CatB) as a target for improving memory deficits and reducing the pathology of Alzheimer’s disease (AD) in an animal model representative of most AD patients.  The study has been published in the online edition of the Journal of Alzheimer’s Disease.

According to investigator Vivian Y. H. Hook, PhD, professor of the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences and professor of neurosciences, pharmacology and medicine at the UCSD School of Medicine, the study is important because it could lead to new therapeutics that improve the memory deficits of AD.

Abnormal accumulation of brain amyloid-β peptides (Aβ) is thought to cause the memory loss and amyloid plaque pathology of AD.  Aβ peptides are “cut” out from a larger protein called the amyloid precursor protein (APP) by an enzymatic “scissor” called β-secretase, and aggregate to form plaques in the brain regions responsible for memory.  Inhibiting the β-secretase “scissors” from “cutting” the APP with a drug would reduce brain Aβ levels and thereby improve memory deficits and reduce amyloid plaque pathology.  The vast majority of AD patients have wild-type (WT) β-secretase activity and thus the WT β-secretase has been a target of great interest for a long time.

Another protease, BACE1, has long been thought to be the β-secretase involved in AD pathology, because deleting that gene from animal models reduces brain Aβ and plaque pathology.  However, deleting the BACE1 gene was reported to make memory deficits worse in a transgenic model having WT β-secretase activity.

Hook and colleagues set off to find a WT β-secretase target, which improves memory deficits while reducing amyloid plaque pathology.  In the current paper, the researchers show that CatB is such a target because deleting that gene in a transgenic mouse model having WT β-secretase activity improves memory deficits and reduces amyloid plaque, which develop in this model, mimicking that found in AD.  In contrast, deleting the BACE1 gene in that transgenic model had no effect on memory deficits or pathology. 

Co-authors of the study were Gregory Hook, PhD, of American Life Science Pharmaceuticals in San Diego, and Mark Kindy of the Medical University of South Carolina, as well as the Ralph H. Johnson VA Medical Center, and Applied Neurotechnology, Inc., in Charleston, SC; Jin Yu and Hong Zhu, Medical University of South Carolina; and Salim S. El-Amouri, Cincinnati Children’s Hospital Medical Center, University of Cincinnati.

G. Hook is an employee and has equity in American Life Science Pharmaceuticals (ALSP); V. Hook is chair of ALSP’s scientific advisory board and holds equity in the company, and Kindy holds equity in Applied Neurotechnology, relationships disclosed to their institutions.

The study was supported in part by grants from the National Institute on Aging of the National Institutes of Health, the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Silencing it impairs tumor growth, making ROR1 a potential therapeutic target

A team of scientists at the University of California, San Diego Moores Cancer Center has identified a novel protein expressed by breast cancer cells – but not normal adult tissues – that could provide a new target for future anti-cancer drugs and treatments.

Thomas Kipps, MD, PhD

Led by Thomas J. Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research and Interim Director of the UC San Diego Moores Cancer Center, the scientists found that the tumor cells of patients with breast cancer frequently express the Receptor-tyrosine-kinase-like Orphan Receptor 1, or ROR1.  They found that silencing expression of ROR1 impaired the growth and survival of human breast cancer cells.  The findings are published in the March 5 online issue of PLoS One.

ROR1 was first identified in the early 1990s and labeled an orphan receptor because its purpose was unknown. Subsequent work found that ROR1 is expressed at high levels during embryogenesis, during which time it plays an important role in regulating embryonic muscle and skeletal development. During fetal development, however, the expression of this protein is turned off.  Normal cells and tissues in adults do not typically express ROR1.

Cancer cells, however, are a different matter.

“Cancer cells tend to acquire features of less differentiated cells,” said Kipps, interim director of the UC San Diego Moores Cancer Center and a professor of medicine in the UC San Diego School of Medicine. “They often can be found to have features of embryonic cells.”

In recent years, Kipps and others have become increasingly interested in the role of ROR1 plays in the growth of cancer – and whether the protein might provide new options for stopping development of the disease. In 2008, for example, Kipps and colleagues reported that patients with leukemia treated with whole-cell vaccines could generate antibodies that reacted with their leukemia cells and the leukemia cells of other patients, but not with normal cells.  They identified that such antibodies could target ROR1, accounting for the specificity of these antibodies in reacting with cancer cells.  They identified another protein that could interact with ROR1 to stimulate the growth and/or survival of leukemia cells and that antibodies generated against ROR1 could block this function.

The discovery that ROR1 functions similarly in breast cancer heightens hopes. When the protein was silenced in human breast cancer cells, the cancer cells had slower rates of growth in the laboratory and in animal studies.

“There was a qualitative difference,” said Kipps. “When ROR1 was knocked down, it took away some of the growth advantage enjoyed by cancer cells. Their capacity to survive also was impaired.  This could affect the capacity of the cancer cells to survive treatment with other anti-cancer agents or generate tumors altogether.”

The researchers report that expression levels of ROR1 correlate with the severity of at least some forms of breast cancer. The most aggressive cancers were the ones more likely to express ROR1. “That suggests ROR1 could be a good target for treating the most aggressive kinds of breast cancer, particularly the ones that lack expression of hormone receptors or the marker HER2/neu, which already can be targeted by monoclonal antibodies,” Kipps said.

The discovery of ROR1’s role in both blood and breast cancers also suggests it might have a similar function in other forms of cancer, a possibility Kipps said researchers will pursue.

Funding for this research came, in part, from the National Institutes of Health and the Leukemia and Lymphoma Society of America.

Co-authors of the paper are Suping Zhang, Liguang Chen, Bing Cui, Han-Yu Chuang, Jianqiang Yu, Jessica Wang-Rodriguez, Li Tang, George Chen and Grzegorz W. Basak, all at the UC San Diego Moores Cancer Center.

The article can be found online at http://dx.plos.org/10.1371/journal.pone.0031127

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

UC San Diego Telemedicine partners with Tri-City Medical Center NICU

An innovative telemedicine program connecting neonatal specialists from UC San Diego Medical Center and Tri-City Medical Center’s Neonatal Intensive Care Unit (NICU) will allow experts to collaborate, diagnose and treat some of San Diego County’s tiniest, most difficult cases.  Using a real-time, two-way audio/video connection will – in many situations – eliminate the need for Tri-City to transport their patients. However, in cases where further care is needed, this program allows for coordinated care and a transfer to the NICU at UC San Diego Medical Center.

Frank Mannino, MD, discusses this innovation in patient care (click photo to watch).

“This partnership allows us to produce a faster diagnosis and better chance for our hospital’s youngest and most vulnerable patients to continue to be cared for close to home and loved ones,” explained Hamid Movahhedian, MD, FAAP, Tri-City NICU Medical Director, chief, division of Neonatology, and vice chair of Pediatrics.
 
“In addition to allowing earlier diagnoses, we will be able to use this program in a host of ongoing educational programs, and support UC San Diego Health System’s and Tri-City Medical Center’s goal of continuously improving the overall quality of patient care,” said Neil Finer, MD, director of Neonatal Medicine, UC San Diego Health System. “We look forward to a close and productive working relationship with Tri-City Medical Center.”

The innovative telemedicine program is the first of its kind in the San Diego region allowing physicians, nursing staff and other health care professionals to collaboratively participate in cutting edge care of these patients and families, as well as learn various diagnoses first hand by participating in the live video stream.

Since 2009, UC San Diego’s enterprise-wide telemedicine program has fostered discussions with in-house specialists and specialty departments, as well as interested partners in the county, state, national and world-wide health care community who need subspecialty consultative care.  A key feature of the program is that its core workflow, checklists and deployment strategies can be integrated into most any UC San Diego department’s clinical strategic plan. 

“The power of telemedicine is extraordinary, allowing our NICU specialists to be available at a moment’s notice to help provide expert care for these smallest and most fragile of patients.  We are ecstatic to be part of the solution for such a critical care need,” explained Brett C. Meyer, MD, medical director of UC San Diego’s enterprise-wide Telemedicine Program “When a complex case arises our partners at Tri-City can request a consult and can contact us using the camera system.  Our specialists can not only contribute to the care, but with telemedicine they are, in essence, virtually present in the room with the patient to render assistance.”

The NICU at Tri-City Medical Center cares for 500 to 600 premature infants each year in its 20-bed nursery, the largest in North County. Opened in 1986, it is the only Level III NICU in North County, providing the highest level of neonatal care and most advanced technology available in the region.

The partnership is made possible through Proposition 1D Bond funds awarded to UC San Diego which will cover telemedicine equipment costs and maintenance.   A grant from Tri-City Hospital Foundation will cover credentialing expenses for UC San Diego physicians participating in the program.

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Media Contacts: Kim Edwards, UC San Diego Health System, 619-543-6163, kedwards@ucsd.edu; Tarcy Connors, Tri-City Medical Center, 760-492-3333, ConnorsTR@TCMC.com  

March 10 Conference Honors National Women and Girls HIV/AIDS Awareness Day

In observance of National Women & Girls HIV/AIDS Awareness Day, the UC San Diego AIDS Research Institute (ARI) and Center for AIDS Research (CFAR) are sponsors of “A Woman’s Voice/Una Voz de Mujer,” San Diego’s annual women’s HIV/AIDS conference.

The event will take place on Saturday, March 10 from 8 a.m. to 6 p.m. at the Hilton San Diego Bayfront, and is presented by the CARE Partnership, a collaboration of San Diego-area HIV/AIDS service providers and community members.

“A Woman’s Voice/Una Voz de Mujer” is free to women living with HIV/AIDS and $50 for all others.  It is the only local conference focusing on HIV-positive women and their families, reaching more than 200 women with medical updates, educational workshops, and presentations specific to women and HIV/AIDS.

“We are proud to continue our sponsorship of ‘A Woman’s Voice,’” said Douglas D. Richman, MD, director of the ARI and CFAR. “By supporting this nurturing and stigma-free environment, we believe that essential conversations can begin, testing strategies can be improved, and the ratio of HIV-positive women who know their status and are in excellent care will be increased. “

Community member Acintia Wright, who was diagnosed with HIV in 1995, attended the conference in the past and plans on attending again this year.

“What I like most about the conference is seeing the people who have come through this journey and can still smile about life,” said Wright. “It’s inspiring to see the collaboration of agencies with booths of information all around the conference. I love the educational workshops that are held throughout the day, and the service we receive is so uplifting.”

AIDS is now the leading cause of death among African-American women ages 25 to 44 and the fifth leading cause of death for all women in this age group. For more information, including registration information, call 619-702-4186.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Improvements seen in patients with heart failure and type 2 diabetes in initial study

A small clinical trial led by researchers at UC San Diego School of Medicine and VA San Diego Healthcare System (VASDHS) found that patients with advanced heart failure and  type 2 diabetes showed improved mitochondrial structure after three months of treatment with epicatechin-enriched cocoa. Epicatechin is a flavonoid found in dark chocolate. 

The results of this initial study has led to the implementation of larger, placebo-controlled clinical trial at UC San Diego School of Medicine and VASDHS to assess if patients with heart failure and diabetes show improvement in their exercise capacity when treated with epicatechin-rich cocoa.

The study published this week by the journal Clinical and Translational Science looked at five profoundly ill patients with major damage to skeletal muscle mitochondria. Mitochondria are structures responsible for most of the energy produced in cells.  These “fuel cells” are dysfunctional as a result of both type 2 diabetes and heart failure, leading to abnormalities in skeletal muscle. In patients with heart failure and diabetes abnormalities in both the heart and skeletal muscle result in impaired functional capacity.  These patients often complain of shortness of breath, lack of energy and have difficulty walking even short distances.  

The trial participants consumed dark chocolate bars and a beverage with a total epicatechin content of approximately 100 mg per day for three months.  Biopsies of skeletal muscle were conducted before and after treatment. After the three-month treatment, the researchers looked at changes in mitochondria volume and the abundance of cristae, which are internal compartments of mitochondria that are necessary for efficient function of the mitochondria, and measurable by electron microscopy.

“The cristae had been severely damaged and decreased in quantity in these patients,” said one of the senior investigators, Francisco J. Villarreal, MD, PhD of UC San Diego’s Department of Medicine’s Division of Cardiology. “After three months, we saw recovery – cristae numbers back toward normal levels, and increases in several molecular indicators involved in new mitochondria production.”

The results, which mimicked earlier studies showing improvement in skeletal and heart muscle function in animal models after treatment with epicatechin, were promising enough to prompt the larger study.

The principal investigator of this trial was Pam R. Taub, MD, assistant professor of medicine at UC San Diego and the VA San Diego Healthcare System. Taub will be leading the new clinical trial at UC San Diego that will enroll normal sedentary subjects as well as patients with heart failure/diabetes who will be treated with placebo, or epicatechin-rich chocolate.

Patients who would like more information about the clinical trial can call 858-552-8585, extension 3866.

Additional contributors to the published study include Israel Ramirez-Sanchez, PhD, Theodore P. Ciaraldi, PhD, Alan S. Maisel, MD, and Robert R. Henry, MD, UC San Diego School of Medicine and VA San Diego Health System; Guy Perkins, PhD, Anne N. Murphy, PhD, Robert Naviaux, MD, PhD and Michael Hogan, PhD, UC San Diego School of Medicine; and Guillermo Ceballos, MD, PhD, Escuela Superior de Medicina del Instituto Politécnico Nacional, Mexico City.

The study was supported in part by grants from the National Institutes of Health, American College of Cardiology and The Hershey Company.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Directly injected viral vector, Toca 511, is designed to spread through brain cancer cells and kill them while leaving healthy cells unharmed

UC San Diego Moores Cancer Center researchers and surgeons are among the first in the nation to treat patients with recurrent brain cancer by directly injecting an investigational viral vector into their tumor. The treatment is being developed by a local San Diego Company, Tocagen Inc.

The Toca 511 virus replicates by budding and spreads through tumor tissue.

“This clinical trial targets glioblastoma – one of the deadliest forms of brain tumor,” said principal investigator Santosh Kesari, MD, PhD, director of neuro-oncology in the Moores Cancer Center and in the Department of Neurosciences at the University of California, San Diego.  “Clinical trials of investigational therapies such as this may lead to new treatment options for patients battling this deadly disease.”
 
The current standard of care for a newly diagnosed, high-grade glioma includes surgically removing as much of the tumor as possible, followed by radiation therapy and chemotherapy.  Despite these measures, the tumor usually recurs making this trial a high priority.

The surgical procedure involves directly injecting the viral vector into the brain tumor.

The trial is investigating the use of Toca 511 (vocimagene amiretrorepvec), for injection in combination with Toca FC (flucytosine), extended-release tablets.  Toca 511 is a retroviral replicating vector (RRV) that is designed to deliver a cytosine deaminase (CD) gene selectively to cancer cells. After allowing time for the administered Toca 511 to spread through the cancerous tumor those cancer cells expressing the CD gene can convert flucytosine into the anti-cancer drug 5-fluorouracil (5-FU).  In this study, patients receive cycles of oral Toca FC monthly for up to six months.
 
“This may provide a way to destroy the cancer cells without disrupting delicate neurocircuitry,” explained surgeon scientist Clark Chen, MD, PhD, director of stereotactic and radiosurgery, UC San Diego Moores Cancer Center and an investigator on the study.  Chen administered Toca 511 into the first patients who have participated in this clinical trial at UC San Diego. “We fused the patient’s CT scan to their MRI and used neuro-navigation software to calculate exactly where in the tumor we needed to place the injection of Toca 511. The patients were given the injection and discharged from the hospital the day after the procedure.”

Co-investigator Bob Carter, MD, PhD, chief of the Division of Neurosurgery at UC San Diego Medical Center and Moores Cancer Center, noted that this novel agent is the culmination of years of multi-disciplinary efforts.  “Tocagen’s investigational therapy, Toca 511 & Toca FC, is a representative example of the culmination of many technological advances that have come to pass during the last three decades,” said Carter.  “It is a convergence of years of hard work by dedicated public and private practitioners in many different fields – including molecular biologists, basic scientists, virologists, physicists, mathematicians, surgeons, computer scientists, manufacturing experts, regulatory experts, and oncologists.”

Kesari discusses Tocagen clinical trial (click photo to view).

For Kesari, whose doctoral thesis focused on viral therapy for brain tumors, this has been a passion for 20 years.  “I started this kind of research two decades ago, and to see a new technology like Toca 511 advance from bench to bedside completes the circle.  This is the moment physician-researchers live for.”

“This trial is an exciting realization of the ability to help our patients that comes from outstanding science combined with innovative thinking and the desire to deliver compassionate care,” said William C. Mobley, MD, PhD, chair of the Department of Neurosciences at the UC San Diego School of Medicine.  “At UC San Diego, we are intent upon transforming the care of patients with disorders of the brain.”

Participants in this clinical trial must be 18 years or older; have a single, recurrent Grade three or four glioma and have had prior surgery and chemoradiation.

For more information please visit www.tocagen.com/clinicaltrials or www.clinicaltrials.gov and search for “Toca 511.” 

Study coordinator: Ryan Kim, 858-822-7937, rykim@ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

FDA-approved non-surgical technology alters heart tissue that triggers atrial fibrillation

UC San Diego Sulpizio Cardiovascular Center is now offering patients with atrial fibrillation the breakthrough benefits of heat energy, or radio frequency waves, to irreversibly alter heart tissue that triggers an abnormal heart rhythm or arrhythmia. The THERMOCOOL® SF Catheter is an FDA-approved outpatient procedure for an early-stage form of the condition called paroxysmal atrial fibrillation, when recurring symptoms are unresponsive to medicine. Patients typically experience rapid heartbeats that can lead to debilitating fatigue, dizziness, fainting or shortness of breath if left untreated.

Gregory Feld, MD

“Atrial fibrillation has a devastating impact on more than 2.7 million Americans, yet for many patients unresponsive to medication, traditional treatment options are limited,” said    Gregory Feld, MD, professor of medicine at University of California, San Diego and Director of the Cardiac Electrophysiology Program at UC San Diego Sulpizio Cardiovascular Center. “This catheter ablation technology is the latest treatment alternative for patients dealing with the disabling effects of cardiac arrhythmias, such as paroxysmal atrial fibrillation. This is a viable option for patients who do not benefit from their first medication.”

Atrial fibrillation causes the upper heart chambers to beat rapidly and uncontrollably, and is characterized by disorganized electrical activity in the heart. This results in an irregular pulse, and sometimes a “fluttering” feeling in the chest. An episode can last just seconds, or occur for minutes, hours or even days. Paroxysmal atrial fibrillation is an early-stage form of the condition, where episodes occur repeatedly but stop on their own, often in a few hours or less.

Performed by an electrophysiologist (EP), catheter ablation is a non-surgical procedure that addresses the underlying cause of arrhythmias. In real time, the clinician first pinpoints the source of irregular electrical activity using a 3-D mapping system, similar to a GPS device in your car. Guided by this map, the clinician directs a specialized catheter through the heart to the source of the abnormal electrical impulses. A small electrode in the tip of the catheter generates radio frequency waves that have enough heat to alter targeted areas of heart tissue. This process blocks the electrical impulses that can cause heart rhythm disorders.

Unlike traditional catheter technologies, the THERMOCOOL® SF catheter uniformly delivers a cooling saline solution through the catheter, allowing for cooling of the entire catheter tip. Thus, the tip temperature does not rise significantly during ablation, which reduces the risk for clotting, and enhances treatment safety.

This outpatient procedure takes approximately two-to-four hours, with some patients returning home the next day. The result is either a long-term reduction in the number of arrhythmias experienced and the severity of symptoms, or a permanent return to a more normal heart rhythm.

Atrial fibrillation is growing in prevelance. Up to 12 million Americans will have the condition by 2050. While not life-threatening, atrial fibrillation is a leading cause of stroke among people 65 years and older. 

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Understanding how RNA binding proteins control the genetic splicing code is fundamental to human biology and disease – much like editing film can change a movie scene. Abnormal variations in splicing are often implicated in cancer and genetic neurodegenerative disorders.

RNAs wound in a knot and bound by hnRNP proteins illustrates the intractable problem of RNA regulation addressed by Huelga et al.

In a step toward deciphering the “splicing code” of the human genome, researchers at the University of California, San Diego School of Medicine have comprehensively analyzed six of the more highly expressed RNA binding proteins collectively known as heterogeneous nuclear ribonucleoparticle (hnRNP) proteins.
 
This study, published online Feb 16 in Cell Press’ new open-access journal Cell Reports, describes how multiple RNA binding proteins cooperatively control the diversity of proteins in human cells by regulating the alternative splicing of thousands of genes. 

In the splicing process, fragments that do not typically code for protein, called introns, are removed from gene transcripts, and the remaining sequences, called exons, are reconnected.  The proteins that bind to RNA are important for the control of the splicing process, and the location where they bind dictates which pieces of the RNA are included or excluded in the final gene transcript -- in much the same fashion that removing and inserting scenes, or splicing, can alter the plot of a movie.

“By integrating vast amounts of information about these key binding proteins, and making this data widely available, we hope to provide a foundation for building predictive models for splicing and future studies in other cell types such as embryonic stem cells,” said principal investigator Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine and the Institute for Genomic Medicine at UC San Diego, and a visiting professor at the Molecular Engineering Laboratory in Singapore. “If we can understand how these proteins work together and affect one another to regulate alternative splicing, it may offer important clues for rational drug design.”

The data sets highlighted in this study – derived from genome-wide methods including custom-designed splicing-sensitive microarrays, RNA sequencing and high-throughput sequencing to identify genome-wide binding sites (CLIP-seq) -- map the functional binding sites for six of the major hnRNP proteins in human cells.

“We identified thousands of binding sites and altered splicing events for these hnRNP proteins and discovered that, surprisingly these proteins bind and regulate each other and a whole network of other RNA binding proteins, suggesting that these proteins are important for the homeostasis of the cell,” said first author, NSF fellow Stephanie C. Huelga.

According to the UCSD researchers, the genes specifically targeted by the RNA binding proteins in this study are also often implicated in cancer. Yeo added that of the thousands of genomic mutations that appear in cancer, a vast majority occur in the introns that are removed during splicing; however, intronic regions are where regulatory hnRNP proteins often bind.

“Our findings show an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells.  The orchestration of RNA binding proteins is not only important for the homeostasis of the cell, but – by mapping the location of binding sites and all the regulatory places in a gene – this study could reveal how disruption of the process leads to disease and, perhaps, a way to intervene.”

Additional contributors to the study include Anthony Q. Vu, Justin D. Arnold, Tiffany Y. Liang, Patrick P. Liu and Bernice Y. Yan, UCSD Cellular and Molecular Medicine; John Paul Donohue, Lily Shiue and Manuel Ares, Jr., UC Santa Cruz; Shawn Hoon and Sydney Brenner, A*STAR, Singapore. 

The study was funded in part by grants from the National Institutes of Health and the UC San Diego Stem Cell Research Program.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Writing in the February 17, 2012 issue of the journal Cell, researchers at the Ludwig Institute for Cancer Research, the University of California, San Diego School of Medicine and the Toronto Western Research Institute peel away some of the enduring mystery of how zygotes or fertilized eggs determine which copies of parental genes will be used or ignored.

A five-day-old human blastocyst.

In developing humans and other mammals, not all genes are created equal – or equally used. The expression of certain genes, known as imprinted genes, is determined by just one copy of the parents’ genetic contribution. In humans, there are at least 80 known imprinted genes. If a copy of an imprinted gene fails to function correctly – or if both copies are expressed – the result can be a variety of heritable conditions, such as Prader-Willi and Angelman syndromes, or diseases like cancer.

In the Cell paper, a team of scientists, led by Bing Ren, PhD, head of the Laboratory of Gene Regulation at the Ludwig Institute for Cancer Research at UC San Diego, describe in greater detail how differential DNA methylation in the two parental genomes set the stage for selective expression of imprinted genes in the mouse. Differential DNA methylation is essential to normal development in humans and other higher organisms. It involves the addition of hydrocarbon compounds called methyls to cytosine, one of the four bases or building blocks of DNA. Such addition alters the expression of different genes, boosting or suppressing them to help direct embryonic growth and development.

The process is sometimes called epigenetic regulation. Epigenetics is the study of factors influencing inheritance beyond the genes themselves. “DNA is just half the story,” said Ren, who also heads the San Diego Epigenome Center, one of four centers established by the National Institutes of Health to focus on epigenetics research.

“Understanding how these limited imprinted regions control regulation can help us better understand how certain diseases happen,” said Ren, a professor of cellular and molecular medicine in the UC San Diego School of Medicine. “That can help us develop better diagnostic tools for detecting genetic abnormalities and perhaps learn how to predict whether something bad will happen.”

Using a deep sequencing, high-throughput screening technology developed by Joseph Ecker at the Salk Institute for Biological Studies, Ren and colleagues found parent-of-origin specific DNA methylation imprints at 1,952 dinucleotide sequences in the mouse genome. The imprinted sequences formed 55 discrete clusters that included virtually all of the known germline differentially methylated regions and 23 previously unknown regions.

“That suggests it’s a very accurate tool,” said Wei Xie, first author of the paper and a postdoctoral researcher in Ren’s laboratory.

The researchers also found a unique type of methylation in the brain that was previously only seen in embryonic cells. “At this point we do not know what the significance of this modification is in the brain, but it is very specific, suggesting that it correlates to an important biological function” said Cathy L. Barr, PhD, a senior scientist at the Toronto Western Research Institute, the Hospital for Sick Children and co-author of the paper.  

Funding for this research came, in part, from the Krembil Seed Development Fund, an Applied Biosystems (Life Technologies) 10K Genome award, the Ludwig Institute for Cancer Research, the NIH Epigenomics Roadmap Project and the National Human Genome Research Institute.

Co-authors are Audrey Kim, Feng Yue and Ah Young Lee, Ludwig Institute for Cancer Research; James Eubanks, Toronto Western Research Institute, Toronto; and Emma L. Dempster, Toronto Western Research Institute, Toronto and Institute of Psychiatry, Kings College London.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Sudden Cardiac Arrest (SCA) is the leading cause of death in the United States.  This form of heart attack kills 325,000 people every year, representing one death every two minutes. Almost all SCA victims die before they even reach a hospital. To identify a drug that paramedics can use in the field, UC San Diego Health System has opened a clinical trial to evaluate two medications to help restore the heart beat.

UC San Diego Health System

“Only five percent of sudden cardiac arrest victims survive their heart attack,” said Daniel Davis, MD, UC San Diego Director of Resuscitation Science in the Department of Emergency Medicine. “For more than 30 years we’ve been looking for an anti-arrhythmic drug to treat ventricular tachycardia, or what we call shockable rhythm, but we have not found a drug that consistently improves patient outcomes. This clinical trial will help us determine if either the drugs amiodarone or lidocaine may help prevent death.”

This NIH-funded clinical trial consists of three study arms to compare lidocaine, amiodarone and a placebo. The primary objective is to determine if survival is improved with a new formulation of amiodarone and to determine if amiodarone or lidocaine is more effective. The drugs are delivered by injection.

“If there is clear evidence that lidocaine or amiodarone works better in saving lives, we hope to end the study early to incorporate the drug into everyday treatment practice,” said Davis. “This effort could help save dozens of lives each year in San Diego and hundreds across California.”

Currently in San Diego there is no anti-arrhythmic being used by paramedics to treat patients. Either cardiopulmonary resuscitation or the use of a defibrillator to shock the heart into normal rhythm, are the only two treatment options.

Click on the image above to watch Davis discuss the trial.

This clinical trial will be conducted under “Exemption from Informed Consent” guidelines, which have been approved by the U.S. Department of Health and Human Services and the Food and Drug Administration.  This means that the drug will be administered by paramedics to patients whose hearts have stopped beating. If a family member is present, they will be informed of the study and given the option of refusing participation.

“A patient in cardiac arrest is not capable of communication. Nor is it realistic to identify and contact family members in a timely fashion who can consent on their behalf,” said Davis. “When a patient is in critical need of rapid medical treatment, the priority is to provide treatment. Every second counts to save the heart and brain.”

The trial will launch in Spring 2012.  More than 3,000 patients will be enrolled over the course of three to four years in ten different sites across North America.

This clinical trial is part of The Resuscitation Outcomes Consortium (ROC) which was created to conduct clinical research in the areas of cardiopulmonary resuscitation and traumatic injury.  ROC consists of 10 Regional Clinical Centers and a Data and Coordinating Center that will provide the necessary infrastructure to conduct multiple collaborative trials to aid rapid translation of promising scientific and clinical advances to improve resuscitation outcomes.  Trials may evaluate existing or new therapies as well as clinical management strategies such as novel hemorrhage control strategies and alternative methods of delivering CPR or defibrillation.

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Media Contacts: Jackie Carr, jcarr@ucsd.edu, or Salvador Rivera, s3rivera@ucsd.edu, 619-543-6163

Gazing into your lover’s eyes isn’t only romantic; it also releases a brain chemical called oxytocin that strengthens social bonds in a variety of species.  For some people who suffer from depression, the so-called “hormone of love” might hold out hope. Researchers at the UC San Diego School of Medicine are conducting a clinical trial to study whether oxytocin – the brain hormone released with touches, hugs, or when a mother and her newborn baby bond – might help patients with depression.

Click on the above photo for video of Dr. MacDonald discussing the "love hormone."

“In humans, oxytocin is released when they hug or experience other pleasant physical touch, and it plays a part in the human sexual response cycle,” said Kai MacDonald, MD, assistant clinical professor of psychiatry at UC San Diego School of Medicine.

MacDonald went on to explain that oxytocin appears to change the brain signals related to social recognition via facial expressions, perhaps by changing the firing of the amygdala, the part of the brain that plays a primary role in the processing of important emotional stimuli.  In this way, oxytocin in the brain may be a potent mediator of human social behavior. 

“That’s why oxytocin is sometimes called ‘the love hormone,’” said MacDonald.  “It’s said that the eyes are the window to the soul…they certainly are the window to the emotional brain.  We know that the eye-to-eye communication, which is affected by oxytocin, is critical to intimate emotional communication for all kind of emotions – love, fear, trust, anxiety.”

UC San Diego researchers have previously discovered that oxytocin may help patients with schizophrenia, and MacDonald and colleague David Feifel, MD, PhD, UCSD professor of psychiatry, are now enrolling participants to examine its role in clinical depression. 

“Studies of blood levels and genetic factors in depressed patients point to the possibility that this natural hormone might play a part in helping clinical depression,” said MacDonald.  “Previously, studies of healthy individuals have shown that intranasal doses of oxytocin reduce activation of brain circuits involved in fear, increase levels of eye contact, and increase both trust and generosity,” MacDonald said. “Interestingly, people given oxytocin don’t report feeling any different, but they act differently.”

Early clinical data also indicates oxytocin may help women with anxiety disorders. 

“A hug or a touch that causes a release of this hormone might somehow change brain signals,” MacDonald said.  “We want to see if we can harness this response to help patients who suffer from depression.”

For more information on the clinical trial, contact 1-866-550-UCSD.    

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu  

Of 190 million obese Americans, approximately 10-15 percent engage in harmful binge eating. During single sittings, these over-eaters consume large servings of high-caloric foods. Sufferers contend with weight gain and depression including heart disease and diabetes. A new clinical trial, called Regulation of Food Cues, at UC San Diego Health System, aims to treat binge eating by helping participants to identify real hunger and to practice resistance if the stomach is full.

Kerri Boutelle, PhD, associate professor in the department of psychiatry at UC San Diego School of Medicine.

“Most weight-loss treatments for obese adults focus very little on the reduction of binge eating,” said Kerri Boutelle, PhD, principal investigator and associate professor in the department of psychiatry at UC San Diego School of Medicine. “With this study we use a variety of techniques to train the brain to identify and respond to hunger and cravings and to learn resistance to highly craved foods.”

The one-year study will recruit 30 participants who will undergo weekly 60–90 minute sessions held over 12 weeks. Participants will learn how food cravings originate, how to detect and monitor true hunger, how emotional factors influence eating habits, and how to manage cravings and impulses to eat.  

“Binge eaters often consume food in response to their environment, even when they are not hungry. This could be a response to watching TV, long commutes, sitting on the couch, time of day, even loneliness,” said Boutelle, who is also a licensed clinical psychologist. “The goal is to reduce cravings to overeat by up to 50 percent.”

Click on the image above to watch Boutelle discuss the Food Cue Trial.

Teaching obese people to recognize hunger signals is based upon the principles of behavioral psychology, which has proven effective in treating conditions such as anxiety and bulimia. Boutelle and her team have developed a treatment model that shows that binge eating often results from response to environmental food cues. Exposure-based treatments help eaters improve their sensitivity to hunger and fullness and reduce their sensitivity to the sight and smell of food.

Similar programs aimed at overweight youths have yielded promising results and an ability to maintain reductions in binge eating at six and 12 months after treatment.

Participants who join the study will be asked to complete interviews and surveys before and after treatment groups. In addition, they will complete food logs in which they will be asked to monitor levels of hunger and fullness as well as cravings.

To learn more about this clinical trial, please call 858-405-0263.

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Media Contacts: Jackie Carr or Debra Kain, 619-543-6163, ddkain@ucsd.edu

Scientists at the University of California, San Diego have developed a new method for making scaffolds for culturing tissue in three-dimensional arrangements that mimic those in the body. This advance, published online in the journal Advanced Materials, allows the production of tissue culture scaffolds containing multiple structurally and chemically distinct layers using common laboratory reagents and materials.

According to the UC San Diego researchers, this process is more affordable and widely feasible than previous methods that required expensive equipment and expertise.

The new approach is remarkably simple: solutions of the components of each layer, including polymers, are mixed with varying concentrations of a common inert reagent to control density. The solutions are layered so that the difference in density segregates each solution, and then polymerized so that they form a gel. The structure of each layer can be altered by varying the concentration of polymers, and the discreteness of the transition between layers can be altered by allowing the solutions to diffuse.

Lead author Jerome Karpiak, graduate student in the UCSD Biomedical Sciences Program, said, “We’re excited about the relevance of this method to tissue engineering. Since it offers such straightforward spatial control over structure and composition of stratified tissue scaffolds, including cell type and density, this technology could help the field move much faster.” Tissues cultured in vitro to mimic those in the body can potentially provide an alternative to transplantation for injured or degenerated tissue. 

“We believe this approach will vastly broaden the number of labs capable of culturing complex tissue,” said Adah Almutairi, PhD, assistant professor at the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, the Department of Nanoengineering and the Materials Science and Engineering Program at the UCSD Jacobs School of Engineering.  “Because manipulation of structure and concentrations of signal molecules is much easier in this system than in intact organisms, it holds great potential to advance the study of development and disease.” For example, this method may offer a novel approach to study how surrounding molecules affect the growth of axons in neurodevelopmental disorders.

Additional researchers included Yogesh Ner, PhD.  Research was funded in part by the National Institutes of Health Director’s New Innovator program and King Abdulaziz City of Science and Technology.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Kim E. Barrett, PhD, professor of medicine and dean of graduate studies at the University of California, San Diego, will become president-elect of the American Physiological Society (APS).  APS is the nation’s premier nonprofit organization devoted to fostering education, scientific research, and dissemination of information in the physiological science – the study of how molecules, cells, tissues and organs function to create health or disease.

Kim Barrett, PhD

Barrett, former Editor-in-Chief of the American Journal of Physiology: Cell Physiology, will assume her new duties at the APS annual meeting being held April 21-25, 2012, in San Diego. 

A native of the United Kingdom, Barrett received her BSc and PhD degrees from the Department of Chemistry at University College London. Following a post-doctoral fellowship at the National Institutes of Health, she joined the faculty of UC San Diego School of Medicine in 1985 and became a professor of medicine in 1996.

Her research interests center on the normal and abnormal biology of the intestinal epithelium and their relevance to digestive diseases. She has received a number of honors for her research, including the degree of Doctor of Medical Science, honoris causa, by Queens University, Belfast, Ireland. She is a former awardee of the science-based Henry Pickering Bowditch and Horace Davenport Lectureships sponsored by the APS.  She is also the recipient of the 2012 Bodil M. Schmidt-Nielsen Distinguished Mentor and Scientist Award.

In 2006, Barrett was appointed Dean of Graduate Studies at UC San Diego where she oversees the recruitment, academic advancement and climate for more than 4,000 masters degree and doctoral students. She also guides the development of new graduate programs and planning for an anticipated 50 percent growth in the graduate population at UC San Diego over the next 10 to12 years. In addition to her long-standing interest in student development and mentoring, she has been actively involved in the issue of women’s status in academia and served as the Chair of the APS’ Committee on Women in Physiology.

The elections come as the APS celebrates its 125th anniversary. The Society is the first society in the biomedical sciences field, with more than 10,500 members.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

One of few clinical trial sites, worldwide

Jim Black is fighting the meanest, most aggressive, most common kind of brain tumor in the United States: recurrent glioblastoma multiforme (GBM).  In the United States, each year, approximately 10,000 patients are affected by GBM.  Now, a novel investigational device – available only at clinical trial sites – is offering new hope to these patients.

The non-invasive procedure – called Tumor Treating Fields (TTF) – is delivered using a portable device – called the NovoTTF-100A System made by Novocure.  The TTF procedure uses alternating electrical fields to disrupt the rapid cell division exhibited by cancer cells. 
 

Santosh Kesari, MD, PhD, director of Neuro-Oncology at UC San Diego Moores Cancer Center.

“Patients with recurrent GBM present a significant treatment challenge,” said Santosh Kesari, MD, PhD, director of Neuro-Oncology at UC San Diego Moores Cancer Center.  “The initial clinical research for the approval trial demonstrated that, compared to patients who were treated with chemotherapy, patients treated with NovoTTF achieved comparable survival times, had fewer side effects, and reported improved quality of life.”

On average, a patient with GBM survives less than 15 months with optimal treatment and only three to five months without additional effective treatment.  The TTF procedure may provide physicians with a fourth treatment option in addition to surgery, radiation therapy and chemotherapy.

TTFs inhibit tumor growth by causing cancerous cells to die.  The TTF procedure is delivered using non-invasive, insulated transducer arrays (electrodes) that are placed directly on the skin in the region of the tumor.  The hat-like collection of electrodes connects to a portable device which is slightly thicker than a laptop and weighs about six pounds.  The device sends a low intensity, alternating electric field into the tumor which prevents the cells from dividing and spreading and causes cancer cells to die. 

The most commonly reported side effect from NovoTTF is a mild-to-moderate scalp rash, beneath the electrodes.  The FDA-approved device is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.

“When all other options have been exhausted, patients are willing to do just about anything to keep the tumor at bay,” said Kesari.  “This device gives them an opportunity to fight back, to feel like they are taking an active, hands-on role in their own treatment, and provides tremendous hope.”

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Research to Prevent Blindness (RPB) has awarded a grant of $100,000 to the Department of Ophthalmology at the University of California, San Diego School of Medicine to support research into the causes, treatment, and prevention of blinding eye diseases.  The research will be directed by Robert N. Weinreb, MD, Chairman of the Department of Ophthalmology and Director of the Shiley Eye Center.

UC San Diego Shiley Eye Center

RPB is the world’s leading voluntary organization supporting eye research.  Since 1984, the organization has awarded grants totaling $3,065,000 to the UC San Diego School of Medicine.  Over the past 28 years, this funding has supported research in glaucoma, cornea and retinal diseases.

“These funds are particularly invaluable for enhancing our ability to conduct the most impactful vision research,” said Weinreb.  “They will facilitate existing research, support cross-disciplinary investigative programs and assist in the translation of our research to prevent and cure blindness.”

Since it was founded in 1960, RPB has channeled hundreds of millions of dollars to medical institutions throughout the United States for research into all blinding eye diseases.  For information on RPB, RPB-funded research, eye disorders and the RPB Grants Program, go to rpbusa.org.

Based at the Shiley Eye Center, the UC San Diego Ophthalmology Department includes a complement of outstanding clinicians who provide comprehensive and specialized eye care for the full spectrum of diseases of the eye.  During the past decade, departmental teams of clinicians and scientists have translated their research to improve management of a variety of vision-impairing conditions including glaucoma, macular degeneration, ophthalmic plastic surgery, childhood eye disease, diabetic eye disease, and cataracts. 

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Media contact: Karen Anisko, 858-534-8017, kanisko@ucsd.edu

A team led by researchers at the University of California, San Diego School of Medicine reports that newly discovered mutations in an evolved assembly of genes cause Joubert syndrome, a form of syndromic autism.

The findings are published in the January 26 online issue of Science Express.

Image using an electron microscope shows a cilium growing from a neuron. (Gleeson lab)

Joubert syndrome is a rare, recessive brain condition characterized by malformation or underdevelopment of the cerebellum and brainstem.  The disease is due specifically to alterations in cellular primary cilia – antenna-like structures found on most cells. The consequence is a range of distinct physical and cognitive disabilities, including poor muscle control, and mental retardation. Up to 40 percent of Joubert syndrome patients meet clinical criteria for autism, as well as other neurocognitive disorders, so it is considered a syndromic form of autism.

The cause or causes of Joubert syndrome are not well-understood. Researchers looked at mutations in the TMEM216 gene, which had previously been linked to the syndrome. However, only half of the expected Joubert syndrome patients exhibit TMEM216 gene mutations; the other half did not. Using genomic sequencing, the research team, led by Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego, broadened their inquiry and discovered a second culprit: mutations in a neighboring gene called TMEM138.

“It is extraordinarily rare for two adjacent genes to cause the same human disease,” said Gleeson.  “The mystery that emerged from this was whether these two adjacent, non-duplicated genes causing indistinguishable disease have functional connections at the gene or protein level.”

Through evolutionary analysis, the scientists concluded that the two TMEM genes became joined end-to-end approximately 260 million years ago, about the time some amphibians began transitioning into land-based reptiles. The connected genes evolved in tandem, becoming regulated by the same transcription factors.

 “Prior to this transition, the two genes had wildly different expression levels,” said Jeong Ho Lee, MD, PhD, and first author of the study.  “Following this transition, they became tightly co-regulated.  Moreover, we found that the two encoded proteins coordinate delivery of factors key for cilia assembly.”

Gleeson said the findings suggest the human genome has evolved to take advantage of fortuitous ancestral events like gene translocations to better coordinate gene expression by assembling into specific modules. When these modules are disrupted, however, neurodevelopmental diseases may result. 

This research was funded, in part, by the Simons Foundation, the American Philosophical Society, the National Institutes of Health and the Howard Hughes Medical Institute.

Co-authors are Jennifer L. Silhavy, Ji Eun Lee, Lihadh Al-Gazali, Sophie Thomas, Erica E. Davis, Stephanie L. Bielas, Kiley J. Hill, Miriam Iannicelli, Francesco Brancati, Stacey B. Gabriel, Carsten Russ, Clare V. Logan, Saghira Malik Sharif, Christopher P. Bennett, Masumi Abe, Friedhelm Hildebrandt, Bill H. Diplas, Tania Attié-Bitach, Nicholas Katsanis, Anna Rajab, Roshan Koul, Laszlo Sztriha, Elizabeth R. Waters, Susan Ferro- Novick, Geoffrey C. Woods, Colin A. Johnson, Enza Maria Valente, and Maha S. Zaki.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

UC San Diego Moores Cancer Center researchers examine role of diet and exercise

An active lifestyle and a healthy diet can help you feel more energetic, control your weight, help you sleep better, and reduce your risk of many diseases.  Researchers at UC San Diego Moores Cancer Center are interested in discovering the effects of innovative diet and exercise programs on breast cancer survivors, as well as women who are ‘at risk’ for breast cancer.

“It’s like anything else in life; you have to really want it (weight loss),” said participant Lorri Maida, who is enrolled in the Healthy Eeating & Living Program (HELP) Study.  “Portion control, phone counseling and some kind of daily exercise are really working for me.”

STUDY DETAILS for BREAST CANCER SURVIVORS

The ENERGY Study – Exercise and Nutrition to Enhance Recovery and Good Health for You – explores the role of diet and exercise in female breast cancer survivors who are at risk for recurrence.

• 4-year study
• 21 years of age or older
• Overweight
• Diagnosed with Stage I-III breast cancer within the previous 5 years and have completed their initial treatment
• Willing and able to attend group meetings and maintain contact with investigators for two years
• Able to be physically active
• NOT currently enrolled in another nutrition or weight loss study

For more Information on ENERGY, please contact 858-822-2779 or hbarkai@ucsd.edu or visit energytrial.ucsd.edu

The REACH FOR HEALTH Study is testing how the treatments of lifestyle intervention and the drug called metformin, which is used to treat diabetes, affect breast cancer survival.

• 6-month study
• Overweight  
• Diagnosed with Stage I-IIIA
• Not scheduled for or currently undergoing chemotherapy
• Able to communicate dietary and physical activity data via telephone
• If taking statins, tamoxifen, or aromatase inhibitors; able and willing to remain on treatment for 6-month study period

For more detailed information on participating in REACH FOR HEALTH, call 858-822-6799 or contact Jesica Oratowski Coleman at joratowski@ucsd.edu.

STUDY DETAILS for THOSE ‘AT RISK’ (never had breast cancer)

The HELP Study – Health Eating & Living Program for Weight Control – aims to reduce breast cancer risk in postmenopausal women through lifestyle change, using Internet-enhanced telephone counseling intervention.

• 2-year study
• Women between the ages of 45 to 70
• Overweight
• Want to increase their physical activity and improve their diet
• Must have high-speed Internet access

For more information on participating in the HELP Study, contact 858-822-2895, healthyeating@ucsd.edu or visit healthyeatingucsd.org

The MENU Study – Metabolism, Exercise and Nutrition – examining the difference between three diets of differing composition on weight loss and cancer biomarkers.

• 1-year study
• Healthy, overweight women
• Over 21 years of age
• BMI (body mass index) higher than 30, less than 40
• Willing and able to participate in clinic visits, group sessions, and telephone and Internet communications at specified intervals
• Able to provide data through questionnaires and by telephone
• Willing to allow blood collections
• No known allergy to tree nuts
• Able to be physically active

For more information on the MENU study please contact Elizabeth Quitana, MS, RD at 858-822-6162, elquintana@ucsd.edu

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

First-ever feat provides new method to understand cause of disease, develop drugs

Led by researchers at the University of California, San Diego School of Medicine, scientists have, for the first time, created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer’s disease (AD), using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder.

Stem-cell-derived neurons, made from patients with Alzheimer’s disease, provide a new tool for unraveling the mechanisms underlying the neurodegenerative disease. In this image, DNA is shown in blue, dendrites and cell bodies in red and endosomal markers Rab5 and EEA1 in green and orange, respectively.

“Creating highly purified and functional human Alzheimer’s neurons in a dish – this has never been done before,” said senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program. “It’s a first step. These aren’t perfect models. They’re proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it.”

The feat, published in the January 25 online edition of the journal Nature, represents a new and much-needed method for studying the causes of AD, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.

“We’re dealing with the human brain. You can’t just do a biopsy on living patients,” said Goldstein. “Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory.”

Goldstein and colleagues extracted primary fibroblasts from skin tissues taken from two patients with familial AD (a rare, early-onset form of the disease associated with a genetic predisposition), two patients with sporadic AD (the common form whose cause is not known) and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated into working neurons.

The iPSC-derived neurons from the Alzheimer’s patients exhibited normal electrophysiological activity, formed functional synaptic contacts and, critically, displayed tell-tale indicators of AD. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder.

With the in vitro Alzheimer’s neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done.

“The differences between a healthy neuron and an Alzheimer’s neuron are subtle,” said Goldstein. “It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results.”

The researchers have already produced some surprising findings. “In this work, we show that one of the early changes in Alzheimer’s neurons thought to be an initiating event in the course of the disease turns out not to be that significant,” Goldstein said, adding that they discovered a different early event plays a bigger role.

The scientists also found that neurons derived from one of the two patients with sporadic AD exhibited biochemical changes possibly linked to the disease. The discovery suggests that there may be sub-categories of the disorder and that, in the future, potential therapies might be targeted to specific groups of AD patients.

Though just a beginning, Goldstein emphasized the iPSC-derived Alzheimer’s neurons present a huge opportunity in a desperate fight.  “At the end of the day, we need to use cells like these to better understand Alzheimer’s and find drugs to treat it. We need to do everything we can because the cost of this disease is just too heavy and horrible to contemplate. Without solutions, it will bankrupt us – emotionally and financially.”

Funding for this research came, in part, from the California Institute for Regenerative Medicine, the Weatherstone Foundation, the National Institutes of Health, the Hartwell Foundation, the Lookout Fund and the McDonnell Foundation.

A patent application has been filed on this technology by the University of California, San Diego.  For more information, go to: techtransfer.universityofcalifornia.edu/NCD/22199.html

Co-authors are Mason A. Israel and Sol M. Reyna, Howard Hughes Medical Institute and UCSD Department of Cellular and Molecular Medicine and UCSD Biomedical Sciences Graduate Program; Shauna H. Yuan, Howard Hughes Medical Institute and UCSD Department of Cellular and Molecular Medicine and UCSD Department of Neurosciences; Cedric Bardy and Yangling Mu, The Salk Institute for Biological Studies; Cheryl Herrera, Howard Hughes Medical Institute and UCSD Department of Cellular and Molecular Medicine; Michael P. Hefferan, UCSD Department of Anesthesiology; Sebastiaan Van Gorp, Department of Anesthesiology, Maastricht University Medical Center, Netherlands; Kristopher L. Nazor, Department of Chemical Physiology, The Scripps Research Institute; Francesca S. Boscolo and Louise C. Laurent, UCSD Department of Reproductive Medicine; Christian T. Carson, BD Biosciences; Martin Marsala, UCSD Department of Anesthesiology and Institute of Neurobiology, Slovak Academy of Sciences, Slovakia; Fred H. Gage, The Salk Institute of Biological Studies; Anne M. Remes, Department of Clinical Medicine, Neurology and Clinical Research Center, University of Oulu, Finland; and Edward H. Koo, UCSD Department of Neurosciences.

About Alzheimer’s disease
An estimated 5.4 million Americans have Alzheimer’s disease, according to the Alzheimer’s Association. Two-thirds are women. By 2050, as many as 16 million Americans are projected to have the disease. In 2011, the economic cost of caring for Alzheimer’s patients exceeded $183 billion, projected to rise to $1.1 trillion by 2050. Alzheimer’s is the sixth leading cause of death in the United States, killing more than 75,000 Americans annually. Currently, there are no drugs to prevent, alter or cure the disease. 

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

Researchers at the University of California, San Diego School of Medicine have created a new generation of fast-acting fluorescent dyes that optically highlight electrical activity in neuronal membranes. The work is published in this week’s online Early Edition of the Proceedings of the National Academy of Sciences.

The ability to visualize these small, fast-changing voltage differences between the interior and exterior of neurons – known as transmembrane potential – is considered a powerful method for deciphering how brain cells function and interact.

However, current monitoring methods fall short, said the study’s first author Evan W. Miller, a post-doctoral researcher in the lab of Roger Tsien, PhD, Howard Hughes Medical Institute investigator, UC San Diego professor of pharmacology, chemistry and biochemistry and 2008 Nobel Prize co-winner in chemistry for his work on green fluorescent protein.

“The most common method right now monitors the movement of calcium ions into the cell,” said Miller. “It provides some broad indication, but it’s an indirect measurement that misses activity we see when directly measuring voltage changes.”

Leech neurons stained with voltage-sensitive dye.

The new method employs dyes that penetrate only the membrane of neurons, either in in vitro cells cultured with the dye or, for this study, taken up by neurons in a living leech model. When the dyed cells are exposed to light, neuronal firing causes the dye momentarily to glow more brightly, a flash that can be captured with a high-speed camera.

“One of the tradeoffs with using voltage-sensing dyes in the past is that when they were reasonably sensitive to voltage changes, they were slow compared to the actual physiological events,” said Miller. “The new dye gives big signals but is much faster and doesn’t perturb the neurons. We essentially see no lag time between the optical signal and electrodes (used to double-check neuronal activity).”

The new method provides a wider view of neuronal activity, said Miller. More importantly, it makes it possible for neuroscientists to do accurate, single trial experiments. “Right now, you have to repeat experiments with cells, and then average the results, which is physiologically less relevant and meaningful.”

For Tsien, the new dyes address a career-long challenge.

“These results are the first demonstration of a new mechanism to sense membrane voltage, which is particularly satisfying to me because this was the first problem I started working on as a graduate student in 1972, with little success back then,” said Tsien. “Later, we devised indirect solutions such as calcium imaging or dyes that gave big but slow responses to voltage. These techniques have been very useful in other areas of biology or in drug screening, but didn’t properly solve the original problem. I think we are finally on the right track, four decades later.”

Funding for this research came, in part, from the Howard Hughes Medical Institute, the National Institutes of Health, including the National Institute of Neurological Disorders and Stroke and the National Institute of Biomedical Imaging and Bioengineering.

Co-authors are John Y. Lin, Department of Pharmacology, UC San Diego; E. Paxon Frady, Neurosciences Graduate Group, UC San Diego; Paul A. Steinbach, Department of Pharmacology, UC San Diego and Howard Hughes Medical Institute; William B. Kristan, Jr., Division of Biological Sciences, UC San Diego.

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Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu

UC San Diego Health System has received approval to acquire the Nevada Cancer Institute (NVCI), the official cancer institute of the state of Nevada, as an affiliate health care provider. The expansion represents a partnership between California and Nevada in offering lifesaving cancer care to patients through expert diagnosis, novel treatments and clinical trials.

Tom McAfee, MD, CEO, UC San Diego Health System

“We are proud to have Nevada Cancer Institute join UC San Diego Health System,” said Tom McAfee, MD, interim CEO of UC San Diego Health System and dean of clinical affairs. “As a world-class health system for cancer and surgical care, UC San Diego is fulfilling its mission of caring for patients locally, nationally, and around the world.”

Nevada Cancer Institute is a nonprofit organization committed to fighting cancer by offering the best in early detection, high-quality patient care, education and prevention. The Institute has treated more than 17,000 patients since opening in 2005, and offers novel treatment strategies through clinical trials, as well as Hope Coach, a mobile mammography unit. Its state-of-the-art flagship treatment center is a four-story, 142,000-square-foot facility in the Summerlin area of Las Vegas. NVCI also operates a patient clinic at University Medical Center. The Institute is accredited by The Joint Commission, and has earned the organization’s Gold Seal of Approval for quality and safety in health care facilities.

UC San Diego NVCI is a state-of-the-art, 142,000 sq. ft. facility.

“In light of health care reform, innovative partnerships between states and their health systems will be key to increasing access to specialized care while managing health care costs,” said McAfee. “Both Stanford University and Cleveland Clinic have pursued this strategy to care for neurological patients outside of their local areas. UC San Diego Health System is advancing this approach for the full spectrum of cancers, a strength of our clinical enterprise.”

Plans for UC San Diego NVCI include the recruitment of medical and surgical oncologists, as well as beginning a national search for a physician-scientist to serve as director of the institute. Insight Oncology, a management services organization, will assist with the integration of the two organizations and provide operational oversight of the flagship facility.

UC San Diego NVCI

Nevada patients will continue to see their current physician, now with the advantage of potentially qualifying for a wider range of clinical trials. UC San Diego NVCI hopes to partner with the local medical community and develop collaborations that best serve the needs of local doctors and their patients.

UC San Diego Health System purchased NVCI with clinical revenue generated by its hospitals. No state funding was utilized. All philanthropic support for NVCI will be specifically reserved for the Nevada facility and its patients.

In February 2011, UC San Diego Health System acquired San Diego Cancer Center as part of its regional strategy to expand cancer care into the north coastal community of San Diego with locations in Encinitas and Vista. The health system has also opened a radiation oncology site in South Bay, multi-specialty clinics in Murrieta, part of Riverside County, a comprehensive liver clinic in Henderson, Nevada, and telemedicine clinics throughout the state of California.

UC San Diego Health System is comprised of UC San Diego Medical Center in Hillcrest, and UC San Diego Thornton Hospital, Moores Cancer Center, Shiley Eye Center, and Sulpizio Cardiovascular Center in La Jolla, as well as other primary and specialty practices of UC San Diego Medical Group. UC San Diego Moores Cancer Center is home to nearly 350 medical and radiation oncologists, cancer surgeons, and researchers. It is one of only 40 National Cancer Institute-designated comprehensive cancer centers in the country, and the only one in the region - a rare honor distinguishing exceptionally high achievement in research, clinical care, education and community outreach and partnerships.

In early 2012, UC San Diego Health System will break ground on the Jacobs Medical Center. The state-of-the-art, 10-story facility will be home to four hospitals: the existing Thornton Hospital, the Hospital for Cancer Care, Hospital for Women and Infants, and Hospital for Advanced Surgery. The specialized center will offer 245 beds and 14 operating rooms including a 4-OR intraoperative imaging suite.

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Media Contacts: Jackie Carr, 619-543-6163, jcarr@ucsd.edu; Hilarie Grey, 702-822-5601, hgrey@nvcancer.org

Rick Hanson, PhD, author of the book Buddha’s Brain and founder of the Wellspring Institute for Neuroscience and Contemplative Wisdom, will present his lecture "Taking in the Good: Helping Children Build Inner Strength and Happiness”  at the UC San Diego Medical Center Auditorium on Friday, February 3. The lecture will kick off UC San Diego’s inaugural “Bridging the Hearts and Minds of Youth: Mindfulness in Clinical Practice, Education and Research” conference.

Hanson, a prolific writer and lecturer, maintains a clinical practice in San Rafael, Calif., and serves as a trustee for Saybrook University. He is considered an authority on self-directed neuroplasticity, the art of reshaping the brain through contemplative practice, and is a featured blogger for The Huffington Post and Psychology Today. His writings and teachings focus on “the essential inner skills of personal well-being, psychological growth, and contemplative practice.”

Steven Hickman, PsyD, associate clinical professor in the UC San Diego School of Medicine departments of Psychiatry and Family and Preventive Medicine, and director of the UCSD Center For Mindfulness (UCSD CFM) says about Hanson’s lecture, “this is a great opportunity to help clients, parents, friends and others understand the profound impact of contemplative practice on the developing minds of our children and ourselves.”

This “Bridging the Hearts and Minds of Youth: Mindfulness in Clinical Practice, Education and Research” conference is co-presented by UCSD CFM and Stressed Teens and will be held at the Catamaran Resort Hotel in San Diego, February 4 and 5. 

Tickets for the Hanson lecture are $15, pre-registration is encouraged.  To register for the lecture or the conference, visit the UCSD CFM website, cme.ucsd.edu/bridging/, or call 858-334-4636.

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Media Contact: Melanie Peters, 619-543-6163, mopeters@ucsd.edu

17 individuals in U.S. recognized for major contributions to science

The National Academy of Sciences (NAS) will honor 17 individuals with awards in recognition of their extraordinary scientific achievements in a wide range of fields spanning the physical, biological, and social sciences. Among them is Larry R. Squire, PhD, Distinguished Professor of Psychiatry, Neurosciences, and Psychology at the University of California, San Diego School of Medicine, and research career scientist at VA Medical Center, San Diego. 

Larry Squire, PhD

Squire, a resident of Del Mar, California, is the recipient of the National Academy of Sciences Award for Scientific Reviewing.  A leader in the field of memory and foremost expert in the anatomical and functional basis of mammalian memory, Squire is honored for “his prolific and comprehensive reviews on memory research, for his seminal books that are standards in the field, and critical reviews of books on neuroscience.”

The prize of $10,000, presented this year in the field of neuroscience, recognizes excellence in scientific reviewing. The award is supported by Annual Reviews, the Institute for Scientific Information, and The Scientist in honor of J. Murray Luck.

Squire and 16 other NAS award recipients will be honored in a ceremony on Monday, April 30, during the National Academy of Sciences’ 149th annual meeting.

The National Academy of Sciences is a private, nonprofit institution that was established under a congressional charter signed by President Abraham Lincoln in 1863. It recognizes achievement in science by election to membership, and – along with the National Academy of Engineering, Institute of Medicine, and National Research Council – provides science, technology, and health policy advice to the federal government and other organizations.

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Media Contact: Debra Kain, 619-543-6163, ddkain@ucsd.edu

Smoking is a major public health issue and quitting is the single most important thing smokers can do to improve their health.  In the 2012 edition of the prestigious Annual Review of Public Health, researchers at the University of California, San Diego School of Medicine have reviewed the landscape of smoking cessation over the past 20 years.  During this time period, there have been improvements in pharmaceutical medications to aid cessation, and free telephone cessation coaching has become available in every state.  However, recent trends in smoking cessation are troubling to tobacco control researchers.

John Pierce, PhD

“For the past decade, attempts to quit smoking have increased, but the proportion of people who become successful quitters has gone down” said John P. Pierce, PhD, professor of Family and Preventive Medicine and director of Population Sciences at UC San Diego Moores Cancer Center.  “Widespread dissemination of cessation services has not led to an increase in the probability that a quit attempt will be successful." 

The problem does not appear to be with the cessation services themselves. “Randomized trials continue to demonstrate that innovations in cessation assistance, such as the new text-to-quit service, increase success rates among smokers motivated to be part of clinical studies,” said Sharon Cummins, PhD, director of Evaluation with the California Smokers Helpline and a co-author on the study.  “Indeed, one study showed that heavier smokers are much more likely to quit successfully when a doctor actively monitors the quit attempt, pharmaceutical aids are used, and the smoker receives multiple coaching calls from a quitline service”.

The number of people who quit smoking successfully has stalled in the United States at every age.

However, recent evidence suggests that part of the problem may lie in how cessation aids are marketed by pharmaceutical companies:  many such ads suggest that quitting smoking may be as simple as putting on a patch.  It appears that younger smokers in particular are now more likely to underestimate the amount of work needed in order to quit smoking successfully. 

Traditionally, the majority of smokers who quit successfully have done so without assistance, and recent data suggests that this has not changed.  However, current national policy discourages unassisted quitting, advising clinicians to make sure smokers who want to quit do so with pharmaceutical assistance.  This policy may undermine smokers’ belief in their ability to quit on their own.

Pierce and colleagues noted that some of the earliest texts in psychology – written more than 100 years ago – include chapters on breaking habits such as smoking.  In 1890, William James laid out a series of maxims that were widely recognized then and that still hold true today:  smokers need to make a strong resolution to change; they need to act quickly on that resolution; they will be more successful if they make a personal commitment to another to be successful; and finally, it is important to understand the danger of having even a single cigarette during a quit attempt.

The researchers suggest that policy makers join those in academia for a serious review of tobacco cessation policy.

In addition to Pierce, the UC San Diego Moores Cancer Center research team included Sharon E. Cummins, PhD, Martha M. White, Aimee Humphrey and Karen Messer, PhD.
 
Funding support for this study was provided by the Tobacco-Related Disease Research Program (TRDRP). 

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Media Contact: Kim Edwards, 619-543-6163, kedwards@ucsd.edu

Results Show No ‘Safe’ Period For Drinking Alcohol In Pregnancy

Researchers at the California Teratogen Information Service (CTIS) Pregnancy Health Information Line, a state-wide non-profit organization based at the University of California, San Diego, have found new links between the timing of alcohol consumption during pregnancy and certain characteristics of Fetal Alcohol Syndrome (FAS). The results will be published in the April 2012 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View (online version).

The study uses data obtained by counselors at the CTIS Pregnancy Health Information Line, a toll-free service offering evidence-based clinical information about exposures during pregnancy and breastfeeding.  It focuses on 992 California women who contacted the CTIS Pregnancy Health Information Line between 1978 and 2005 with questions about a wide variety of exposures and, after being counseled, agreed to participate in a follow-up study of their pregnancy outcome. The study specifically examines the timing of the mother's reported alcohol exposure in relation to known physical features of Fetal Alcohol Syndrome (FAS). Importantly, all infants in the study, whether identified as exposed to alcohol or not, received a special screening for birth defects by Kenneth Lyons Jones, MD, chief of the Division of Dysmorphology/Teratology at the Department of Pediatrics and CTIS Medical Director.

The physical features of Fetal Alcohol Syndrome can be very subtle and not easily recognizable, particularly in newborns. These features include a smooth upper lip with thin/smooth red portion of the lip, short eye openings, smaller head size, and reduced birth weight and length.

Researchers found that every pattern of higher prenatal alcohol consumption (no matter the timing in pregnancy) was associated with an increased risk of having an underweight infant or one with a reduced birth length. However, there were also significant associations between higher alcohol consumption in the second half of the first trimester and certain facial features of FAS, in addition to lower birth weight and length. “For every one drink increase in the average number of drinks consumed daily, there was a 25 percent increased risk for smooth upper lip, a 22 percent increased risk for thin red portion of the upper lip border, a 12 percent increased risk for small head size, a 16 percent increased risk for reduced birth weight, and an 18 percent increased risk for reduced birth length,” said Haruna Sawada Feldman, PhD, MPH, CHES, post-doctoral student and lead author of the study.

“These findings show that drinking alcohol between week seven and 12 of pregnancy are clearly associated with a risk for FAS facial features, as well as a decrease in birth weight and length,” said Christina Chambers PhD, MPH, professor of pediatrics at UC San Diego and CTIS program director.  “However, this should not be misinterpreted to mean that drinking during weeks 1 through 7 is safe. This study only looked at data that included live births. It does not include women who had miscarriages or stillbirths possibly resulting from early alcohol exposure,” she explained. “If anything, this further supports the idea that there is no designated ‘safe’ period for drinking alcohol in pregnancy, and that discontinuing alcohol consumption as soon as possible, and, ideally, prior to pregnancy is the best approach to preventing FAS.”

Questions or concerns about alcohol or any other exposure during pregnancy or breastfeeding can be directed to the CTIS Pregnancy Health Information Line at 800- 532-3749 or via instant message counseling at CTISPregnancy.org. Outside of California, please call the Organization of Teratology Information Specialists (OTIS) at 866-626-6847.

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Media contact: Nicole Chavez, 619- 294-6262, ncchavez@ucsd.edu
Spanish language interviews are available

Cell phones aren’t just for talking any more.  Surfing the web, storing music and posting to Facebook have all contributed to the near-mandatory use of a cell phone.  How about using that cell phone to lose weight?  Researchers with Calit2’s Center for Wireless and Population Health Systems (CWPHS) and the Department of Family and Preventive Medicine, at University of California, San Diego are expanding a previous study aimed at finding out if cell phone technology can help with weight loss. 

For one year, researchers with the “ConTxt” study will evaluate the use of cell phone text messages to remind participants to make wise nutritional choices throughout the day.  Participants randomized to the intervention conditions will also be given tailored messages for weight loss and lifestyle changes as well as a pedometer to monitor their daily activity. 

“ConTxt is an innovative, yet straightforward approach to getting people to monitor their diet and physical activity,” says CWPHS project principal investigator Kevin Patrick, MD, MS, professor of Family and Preventive Medicine, UC San Diego School of Medicine.  “We are trying to make this as pain free as possible.  People won’t stick to something that’s too difficult and they’re all multi-tasking anyway.  We’re doing this study to increase what we know about using the cell phone to get messages to busy people on the go.”

Who Can Participate?

ConTxt is recruiting more than 300 participants who meet these criteria:

• Men and women
• 21 to 60 years of age
• Overweight or moderately obese with Body Mass Index (BMI) of 27-39.9
• Own a cell phone capable of sending and receiving picture and text messages
• English and Spanish speaking participants that reside in San Diego county

Strategy

As a part of tailoring of the program, surveys completed during baseline visit will help assess the participant’s lifestyle, for example, assessing nearby grocery stores, finding opportunities for physical activity and possibly enlisting the support of friends or family. 

The intervention is designed to send “prompts,” text or picture messages, with specific suggestions or tips regarding diet and improving lifestyle habits.   “I