UC Davis professor is co-author of paper.

Worldwide increases in the incidences of asthma, allergies, infectious and cardiovascular diseases will result from a variety of impacts of global climate change, including rising temperatures, worsening ozone levels in urban areas, the spread of desertification and expansions of the ranges of communicable diseases as the planet heats up, the professional organization representing respiratory and airway physicians stated in a new position paper released today (March 14).

The paper is published online and in print in the Proceedings of the American Thoracic Society. The society is the professional organization for pulmonologists, thoracic surgeons and respiratory therapists, among others. It issued the position paper to help its members know how to respond to these changes with their patients and within their communities, and to add their voices to calls for international cooperation to respond to the existing and anticipated negative health effects of global warming.

While based in the United States, the 15,000-member society has members from around the globe. The position paper was written by a 10-member committee that included representatives from Europe, Asia, India, the Middle East and Africa.

“In these proceedings, we address such questions as how climate change may impact the distribution of respiratory disease worldwide, the impact of heat stress and adaptation, and how extreme heat affects the individual and the community,” said Kent Pinkerton, professor of pediatrics at the UC Davis School of Medicine and director of the UC Davis Center for Health and the Environment.

“Since my research focuses on environmental air pollution and its impact on the respiratory system, my biggest concern has been with issues of air quality,” said Pinkerton, who is co-author of the paper and the organizer of the workshop upon which it is based. “These include more smoke and particulate matter from more wildfires, which are known to increase in frequency as the climate warms, and the presence of airborne particles from dust storms caused by desertification.”

The position paper outlines a complex web of interrelated respiratory health effects from global climate change. For example, mold spores that previously only were seen in Central America have been found as far north as Vancouver, British Columbia, promoting increases in allergies and asthma, with climate-change conditions implicated. Infectious diseases common in the Mediterranean region now are being seen as far north as Scandinavia, as that area grows warmer.

“There are certain vector-borne diseases caused by certain types of parasites or organisms whose range has expanded and that has been associated with increases in temperature,” Pinkerton said.

Pinkerton said that some of the prospective respiratory health impacts from global climate change will be direct, such as more asthma due to increases in particulate matter in the atmosphere because of desertification, or increases in pollen because of more and extended plant blooms. But some will be indirect, Pinkerton said.

For example, greater concentrations of displaced populations following extreme weather events — such as hurricane Katrina or the Indonesian or Japanese tsunamis — could lead to increases in outbreaks of infectious diseases. The health impacts will, of course, be more serious for sensitive populations, he noted.

“There are individuals who will be much more susceptible to the effects of global climate change than will the members of the general population,” Pinkerton said. “In particular, we know that infants and young children, people with asthma or chronic obstructive pulmonary disease (COPD), and those who are elderly or who have compromised immune systems will have more difficulties when air quality is poorer.”

The position paper also categorizes the main issues that workshop participants deemed of key importance to respiratory health. The society placed heat-related disease resulting from increased frequency and severity of heat waves as the most serious and direct health risk of climate change. Higher surface temperatures, especially in developed urban areas, will promote the formation of greater amounts of ground-level ozone, exposure to which has been linked to exacerbations of asthma, lung cancer and acute lower-respiratory infections.

Public health measures should be developed to support vulnerable populations during specific climate-change related events, such as heat waves or severe air pollution episodes and other extreme weather events (e.g., extreme rainfall and floods) or rising sea levels and storm surges that challenge or threaten community infrastructure, Pinkerton said.

“Our greatest concern is infants, children, the elderly and other sensitive populations,” he said. “They will be the first to experience serious climate change-related health problems.”

The position paper was co-authored by William Rom, professor of medicine and environmental medicine at the New York University School of Medicine.

Initial two patients are nonagenarians.

James Carleton (left) of Redding and James Cook of Yuba City were Sacramento's first TAVR patients.

For James Carleton, tennis is a second career. He took up the sport in his late 50s and became a regular on the senior circuit. But when he collapsed on a court last year at age 91, he feared that second career might be over.

The general contractor from Redding was told he had aortic valve stenosis, a disease that reduces blood flow from the heart through the aortic valve to the rest of the body due to calcification, a prior infection or a birth defect.

People with aortic valve stenosis may not experience symptoms — such as chest pain, dizziness and fainting — until late in the course of the disease. Often, but not always, it is an age-related condition: It is estimated to affect about 2 to 4 percent of people over age of 65.

The traditional treatment is open-chest surgery to replace the damaged valve — an option that Carleton’s cardiologist did not recommend. He was instead referred to UC Davis, the only hospital in Sacramento currently offering a minimally invasive treatment recently approved by the U.S. Food and Drug Administration called transcatheter aortic valve replacement, or TAVR.

“For some, the disease is too advanced or they have other health issues that prevent them from being good candidates for surgery. For those patients, the disease is often fatal within a year,” said Jeffrey Southard, an assistant professor of cardiovascular medicine who, together with Cardiovascular Medicine Chief Reginald Low, leads the new TAVR program at UC Davis. “It is remarkable to have another lifesaving option that also restores quality of life more quickly than open-heart surgery.”

Carleton was evaluated at UC Davis and approved for the procedure, which took place Feb. 27. Working with a team of interventional cardiologists and cardiothoracic surgeons, Southard moved a tightly compressed new valve through a catheter inserted in Carleton’s femoral artery until it was positioned inside the diseased heart valve. A balloon was inflated to deploy the replacement valve. When the balloon was deflated, the new valve remained open, restoring normal blood flow.

“Ever since I became ill, I hoped to play tennis again with my family and in national level tournaments,” Carleton said. “Dr. Southard says I can start practicing in 10 days, which is simply amazing.”

Carleton was Southard’s second TAVR patient. His first, 90-year-old James Cook of Yuba City, had the procedure earlier on the same day. They were both discharged from the hospital March 1.

The UC Davis Cardiology Valve Clinic has a growing list of patients in inland Northern and central California who have been waiting for a nonsurgical treatment option for aortic valve stenosis.

“TAVR is one of many less-invasive procedures that are revolutionizing cardiac care and altering the course of cardiovascular diseases,” said Low. “UC Davis is committed to making sure that these opportunities are available as quickly as possible for patients in our region.”

For more information about TAVR or to request a referral to the clinic, call (916) 734-6500.

Cardiovascular medicine at UC Davis unites specialists and subspecialists who are passionate about providing the highest level of cardiac and blood-vessel care. In addition to being compassionate clinicians, they are national leaders in developing and testing the next generation of cardiac and vascular therapies, technologies and surgical techniques, and then making them available to patients worldwide. For information, visit www.ucdmc.ucdavis.edu/heart.

Improvement seen in patients with heart failure and type 2 diabetes in initial study.

Francisco Villarreal, UC San Diego

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, M.D., Ph.D., 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, M.D., 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, Ph.D., Theodore P. Ciaraldi, Ph.D., Alan S. Maisel, M.D., and Robert R. Henry, M.D., UC San Diego School of Medicine and VA San Diego Health System; Guy Perkins, Ph.D., Anne N. Murphy, Ph.D., Robert Naviaux, M.D., Ph.D., and Michael Hogan, Ph.D., UC San Diego School of Medicine; and Guillermo Ceballos, M.D., Ph.D., 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 Co.

Heat-sensitive proteins in different combinations distinguish temperatures, from a warm handshake to spicy foods.

Jie Zheng, UC Davis

The winter sun feels welcome, but not so a summer sunburn. Research over the past 20 years has shown that proteins on the surface of nerve cells enable the body to sense several different temperatures. Now scientists have discovered how just a few of these proteins, called ion channels, distinguish perhaps dozens of discrete temperatures, from mildly warm to very hot.

Researchers showed that the building blocks, or subunits, of heat-sensitive ion channels can assemble in many different combinations, yielding new types of channels, each capable of detecting a different temperature. The discovery, in cell cultures, demonstrates for the first time that only four genes, each encoding one subunit type, can generate dozens of different heat-sensitive channels.

“Researchers in the past have assumed that because there are only four genes, there are only four heat-sensitive channels, but now we have shown that there are many more,” said Jie Zheng, leader of the research and an associate professor of physiology and membrane biology at the UC Davis School of Medicine.

The research publishes today (March 2) in the Journal of Biological Chemistry.

Ion channels are pores in cell membranes. Their ability to open and close controls the flow of charged ions, which turns neuron signalling on or off — in this case to inform the body of the temperature the neuron senses.

The researchers found that when different subunits combine, the resultant hybrid, or heteromeric, channel can detect temperatures about midway between what the “parent” channels detect.

One of the channels they studied, called TRPV1, reacts to hot temperatures — about 100 degrees Fahrenheit. It is also responsible for the ability to sense spicy foods, such as chili peppers. A second channel, TRPV3, responds to temperatures of about 85 degrees. It also senses many food flavors, such as those found in rosemary, oregano, vanilla and cinnamon, that elicit a warm sensation.

When the TRPV1 and TRPV3 subunits recombine, the heteromeric channel is tuned to about 92 degrees. Surprisingly, the study showed that the hybrid channel has an even higher chemical sensitivity than the channels that made it up.

Zheng and his colleagues also showed that channels made up of TRPV1 and TRPV3 subunits react to heat at a rate about midway between that of the two constituent channel subunits. But repeatedly exposing the hybrid channels to their target temperature boosted their response, a behavior called sensitization, which TRPV3 also exhibits.

“It says ‘I remember this temperature. I will make a really loud noise to tell the system that it is coming,’” Zheng said. The process allows the body to be more sensitive to temperature.

By contrast, TRPV1 typically responds the same way when repeatedly exposed to its target temperature — and sometimes even decreases its response, a process called desensitization. It helps the body to adapt to high temperature, Zheng explained.

The research builds on work the team published in 2007 demonstrating that the heat-sensitive subunits can combine to form heteromeric channels. However, at the time, scientists didn’t know how these channels respond to heat. The new work shows that the channels are indeed sensitive to different temperatures.

“Knowing that there are many distinct heat-sensing ion channels now opens the way to understand how neurons encode precise temperature information, an important process that allows us to enjoy the rich spectrum of temperature in life — a memorable warm handshake, a soothing shower and a cup of hot latte — and add vanilla flavor, please,” Zheng said. “It also may provide insights regarding the causes and potential treatments for temperature-sensitivity disorders, such as Raynaud’s syndrome.”

Raynaud’s syndrome is a condition that causes some areas of the body — such as fingers, toes, the tip of the nose and ears — to feel numb and cool in response to cold temperatures or stress. The cause is unknown.

The scientists introduced the genes for TRPV1 and TRPV3 channel subunits to cultured human kidney cells. They tagged the genes with fluorescent markers to confirm when the resulting proteins had combined to form a new channel complex.

Once functional channels were formed, the researchers used a glass pipette with a very fine tip to record ion channels’ responses to temperature changes.

In order to rapidly increase the temperature, they built an apparatus that allowed them to deliver an infrared laser beam to the cell. The method allowed them to heat the channel more than a thousand times faster than commercially available heating devices.

The collaborative research is funded by the National Institutes of Health, the American Heart Association and the Chinese government.

The UC Davis School of Medicine is among the nation’s leading medical schools, recognized for its research and primary-care programs. The school offers fully accredited master’s degree programs in public health and in informatics, and its combined M.D.-Ph.D. program is training the next generation of physician-scientists to conduct high-impact research and translate discoveries into better clinical care. Along with being a recognized leader in medical research, the school is committed to serving underserved communities and advancing rural health. For more information, visit UC Davis School of Medicine at medschool.ucdavis.edu.

UC Davis researchers recommend expanded fitness testing and outreach.

William Bommer, UC Davis

After years of increases in the rates of childhood obesity, a new UC Davis study shows that the increase slowed from 2003 to 2008 among California school children.

While encouraged by the results, the authors expressed concern about a group of youngsters currently driving the increase in obesity: children under age 10.

“Children who were obese entering the fifth grade remained obese in subsequent years as well, despite improvements in school nutrition and fitness standards,” said William Bommer, professor of cardiovascular medicine at UC Davis and senior author of the study. “And we suspect that this trend begins before kindergarten.”

Published in the February 2012 issue of the American Heart Journal, the results indicate a major turning point in efforts to reduce the impact of a chronic condition linked with a host of serious adult health issues that can begin in childhood, including heart disease, diabetes, breathing issues and some cancers.

Bommer served on a state task force that recommended standards to help protect K-12 children and teens from diseases related to sedentary living and unhealthy eating. As a result, new laws in 2005 expanded fitness programs, nutrition education and alternatives to high-fat, high-sugar foods and beverages in California schools.

Since 1996, California schools have reported to the state Department of Education the results of a variety of fitness and body composition evaluations for fifth, seventh and ninth graders. Body composition evaluations included body mass index — or BMI — measures, which determine if a child has a healthy weight or is overweight or obese. Data on all students from 2003 to 2008 were provided to Bommer to evaluate and gauge the success of the new standards. For the current study, he and his colleagues included data on a total of 6.3 million students for whom complete fitness test results and body composition evaluations were available.

There were some encouraging results. While childhood obesity is still on the rise (2 percent more children were overweight and obese in 2008 than in 2003), the rate of increase is slowing. National studies in prior decades showed annual increases in obesity among children and teens between 0.8 percent and 1.7 percent each year. For the current study, the rate of increase in California was an average of 0.33 percent per year.

In addition, while the results of fitness tests varied (abdominal strength and trunk extensor strength worsened overall, while upper body strength and flexibility improved overall), there was a significant increase in the percent of children with healthy aerobic capacity.

“This was particularly heartening, because cardiovascular and respiratory endurance directly correlate with reduced risks of heart disease and diabetes later in life, especially if it is maintained over time,” said Bommer.

One concern, however, was that students with lower aerobic capacity and upper body strength fitness scores and higher BMIs tended to live in counties with lower median household incomes (less than $40,000 per year) or with higher unemployment.

“We clearly need to do more to ensure that children, regardless of where they go to school, are benefiting from the recommended health standards,” said study lead author Melanie Aryana, a UC Davis researcher in cardiovascular medicine. “Expanding efforts to ensure that all California schools have the resources they need to make healthy changes will help.”

The team’s strongest recommendation related to reducing the trend toward early onset, persistent obesity among younger school children. This generation could eventually reverse recent advances in reducing heart disease risks and mortality, according to Bommer. He advises earlier fitness testing, including during preschool, to better monitor this increase together with interventions that specifically address unhealthy weight prior to age 10.

“Our study proves that nutrition and physical activity standards can help fewer children become obese during a critical time in their lives for establishing long-term healthy habits,” said Bommer. “But just imagine how much more we can do to reduce the impact of obesity if we are just as successful much earlier in children’s lives.”

In addition to Bommer and Aryana, Zhongmin Li, UC Davis associate professor of internal medicine, was a study co-author.

The UC Davis School of Medicine is among the nation’s leading medical schools, recognized for its research and primary-care programs. The school offers fully accredited master’s degree programs in public health and in informatics, and its combined M.D.-Ph.D. program is training the next generation of physician-scientists to conduct high-impact research and translate discoveries into better clinical care. Along with being a recognized leader in medical research, the school is committed to serving underserved communities and advancing rural health. For more information, visit UC Davis School of Medicine at medschool.ucdavis.edu.

Structural brain aging associated with lack of omega-3 acids in diet.

Fish and omega-3

FINDINGS:
A new study by UCLA researchers shows that a diet lacking in omega-3 fatty acids, which are commonly found in fish, may cause your brain to age faster and lose some of its memory and thinking capabilities. The research demonstrated that people with lower levels of omega-3 fatty acids have lower brain volumes — equivalent to approximately two years of structural brain aging.

Study evaluates 965 heart disease patients for depression.

Mary Whooley

Patients with heart disease who took cholesterol-lowering statins were significantly less likely to develop depression than those who did not, in a study by Mary Whooley, M.D., a physician at the San Francisco VA Medical Center (SFVAMC) and a professor of medicine at the University of California, San Francisco.

The study was published electronically in the Journal of Clinical Psychiatry.

Whooley and her research team evaluated 965 heart disease patients for depression, and found that the patients who were on statins were significantly less likely to be clinically depressed than those who were not. They then followed the 776 patients who were not depressed – 520 who were using statins and 256 who were not – for an additional six years. Of those taking statins, 18.5 percent developed depression, compared with 28 percent of those not on the drugs. Put another way, the patients who took statins were 38 percent less likely to develop depression than patients who did not.

As the study went on, said Whooley, the difference between the two groups became more pronounced, with the patients on statins becoming less likely to develop depression and the patients not on statins becoming more likely to become depressed over time.

“This would suggest that statins may have some kind of long-term protective effect against depression, perhaps by helping to prevent atherosclerosis in the brain, which can contribute to depressive symptoms,” Whooley said.

She also noted that statins have positive effects on the endothelium – the inner lining of the blood vessels – keeping blood vessels less rigid and therefore better able to adapt to the body’s changing needs. “The exact mechanism is not known, however, and requires further study,” she said.

Whooley cautioned that it is possible that patients who take statins “are just healthier overall than those who don’t, and somehow we’re not accounting for that in our analysis, even though we adjusted for factors such as smoking, physical activity and cholesterol levels.”

If statins are definitively proven to protect against depression, said Whooley, they could be used to reduce the burden of depressive symptoms in patients with heart disease and, by extension, improve cardiovascular outcomes in depressed patients. Whooley has shown in previous studies that heart disease patients with depression are less likely to exercise and take medication, thus increasing their risk for heart attack, stroke, and other cardiovascular events.

Statins are the most commonly prescribed medication in the world, according to the study authors. “They are relatively safe, and generally well-tolerated,” said Whooley.

Co-authors of the study are Christian Otte, M.D., of Charite´ University Medical Center, Berlin, Germany, and Shoujun Zhao, Ph.D., of SFVAMC and UCSF.

The study was supported by funds from the Department of Veterans Affairs, the National Heart, Lung and Blood Institute, the Robert Wood Johnson Foundation, the American Federation for Aging Research, the Ischemia Research and Education Foundation and the National Alliance for Research in Schizophrenia and Depression. Some of the funds were administered by the Northern California Institute for Research and Education.

NCIRE – the Veterans Health Research Institute – is the largest research institute associated with a VA medical center. Its mission is to improve the health and well-being of veterans and the general public by supporting a world-class biomedical research program conducted by the UCSF faculty at SFVAMC.

SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.

UC Davis research highlights role of elevated levels of Toll-like receptors on cells.

Ishwarlal Jialal, UC Davis

UC Davis scientists have uncovered a key suspect in the destructive inflammation that underlies heart disease and diabetes. The new research shows elevated levels of a receptor present on leucocytes of the innate immune response in people at risk for these chronic diseases. The receptors are the body’s first line of defense against infectious invaders, and they trigger a rush of cytokines, the body’s aggressive immune soldiers, into the bloodstream.

The research, published today (Feb. 22) in the journal Diabetes Care, studied individuals diagnosed with metabolic syndrome — a cluster of cardio-metabolic risk factors linked to many life-threatening diseases. Metabolic syndrome is found in about a third of American adults and people in other industrialized countries.

The syndrome is a high-risk obesity state as previously shown by diabetes expert Ishwarlal Jialal and his team at the UC Davis Medical Center. It increases the risk of developing diabetes at least five-fold and heart disease by two- to four-fold. Jialal, professor of pathology and laboratory medicine at UC Davis Health System, also led the new study.

The receptors, or sensors, on cells are called Toll-like receptors (TLRs), and the Nobel Prize was awarded last year for discoveries that showed they initiate the swift innate immune response to infections. But the inflammation they trigger can also be harmful. In mice it has been shown that two TLRs — TLR2 AND TLR4 — are important in the development of both diabetes and heart disease.

These receptors are present in many cells, but they are most abundant on monocytes, a type of white blood cell that plays a central role in the inflammation response to invading microbes. They can be triggered by pathogen products or signals from dying cells and saturated fatty acid.

The UC Davis research focused on TLR2 and TLR4. For the study, researchers evaluated 90 individuals between the ages of 21 and 70, of whom 49 had at least three features characteristic of metabolic syndrome. These included hypertension, low HDL-cholesterol, high triglycerides and obesity, as evidenced by increased waist circumference, or a glucose level between 101-125 mg/dl but not indicative of diabetes. Members of the control group had no more than two such markers. People with atherosclerosis, diabetes, inflammatory or malignant disease, and other disorders were excluded to study the receptor function without confounding variables, and to gain insights into nascent or early metabolic syndrome prior to complications.

Comparisons of the blood of participants from both groups showed that the metabolic syndrome group exhibited significantly higher levels of both messenger RNA and cell-surface receptor proteins TLR2 and TLR4, increased levels of the master switch of inflammation in the nucleus, and a much higher concentration of immune soldiers in the blood, such as cytokines, that create inflammation.

All of these abnormalities were independent of obesity, suggesting they are due to the metabolic-syndrome environment. The levels of both free fatty acids and the product of gram-negative bacteria endotoxin also were increased in the blood of individuals with metabolic syndrome at least two- and three-fold respectively, and explained in part the TLR4 increase.

The research suggests that suppressing TLR activity with weight loss and with diet, exercise and drugs targeted specifically at these receptors, might prove effective in treating heart disease, diabetes and other conditions linked to metabolic syndrome.

Jialal pointed out that not all obese people suffer from the constellation of symptoms that make up metabolic syndrome, and in fact, about 30 percent of obese people are at low risk for metabolic complications, according to one key study. But since research shows increased inflammation in obese people, the Toll-like receptor and monocyte findings may help define individuals at high risk for obesity.

Jialal’s research group reported last year that monocytes and related macrophages were present in the fat of individuals with metabolic syndrome and that their fat was more inflamed. The new finding shows that the Toll-like sentinel proteins might be directing an increase in this activity, and that the inflammatory agents are making it into the bloodstream, from where they can go to any part of the body, including fat, liver and heart.

The research is funded by the American Diabetes Association.

UC Davis Health System is improving lives and transforming health care by providing excellent patient care, conducting groundbreaking research, fostering innovative, interprofessional education and creating dynamic, productive partnerships with the community. The academic health system includes one of the country’s best medical schools, a 631-bed acute-care teaching hospital, an 800-member physician’s practice group and the new Betty Irene Moore School of Nursing. It is home to a National Cancer Institute-designated cancer center, an international neurodevelopmental institute, a stem cell institute and a comprehensive children’s hospital. Other nationally prominent centers focus on advancing telemedicine, improving vascular care, eliminating health disparities and translating research findings into new treatments for patients. Together, they make UC Davis a hub of innovation that is transforming health for all. For more information, visit healthsystem.ucdavis.edu.

UC Irvine-led finding could explain why air pollution models underestimate organic aerosols.

Barbara Finlayson-Pitts, UC Irvine

Airborne gases get sucked into stubborn smog particles from which they cannot escape, according to findings by UC Irvine and other researchers published today in the Proceedings of the National Academy of Sciences.

The results could explain a problem identified in recent years: Computer models long used by the U.S. Environmental Protection Agency, California air regulators and others significantly underestimate organic aerosols – the major component of smog particles. Such pollution blocks views of mountains and has been linked to everything from asthma to heart attacks. It is also the largest unknown in climate change calculations.

“You can’t have a lot of confidence in the predicted levels right now,” said lead author Veronique Perraud, assistant project scientist to pioneering UCI air chemist Barbara Finlayson-Pitts. “It’s extremely important, because if the models do a bad job of predicting particles, we may be underestimating the effects on the public.”

An independent expert who reviewed the research for PNAS agreed.

“The conclusions are highly significant,” said Purdue University atmospheric chemist Paul Shepson. “This paper should – and, I expect, will – have a big impact. We’ve known for nearly a decade that there’s a huge difference between what’s in the models and what’s actually in the air. Thanks to this paper, we have a much better idea of why.”

Scientists at UCI, a U.S. Department of Energy laboratory and Portland State University combined pinene, a common ingredient in household cleaners such as Pine Sol and outdoor emissions, with oxides of nitrogen and ozone to mimic smog buildup.

Models used by regulators for decades have assumed that organic aerosols in such pollution form liquid droplets that quickly dissolve potentially unhealthy gases. But the new work found that once gases are sucked into a particle, they get buried deeper and deeper.

“They check in, and they don’t check out. They cannot escape. The material does not readily evaporate and may live longer and grow faster in total mass than previously thought,” Finlayson-Pitts said. “This is consistent with related studies showing that smog particles may be an extremely viscous tar.”

Perraud noted that broader study needs to be done: “The next logical step is to straighten the models out. We need enough follow-up data to do so.”

Sophisticated tools made it easier to pinpoint the exact characteristics of chemical compounds in air. The scientists used a 26-foot-long “aerosol flow tube” at the AirUCI unit and a one-of-a-kind, 900-pound instrument known as SPLAT (a single particle laser ablation time-of-flight mass spectrometer) at the Pacific Northwest National Laboratory.

Co-authors are Emily Bruns, Wayne Chang, Donald Dabdub, Michael Ezell, Stanley Johnson and Yong Yu of UCI; M. Lizabeth Alexander and Alla Zelenyuk of PNNL; Dan Imre of Imre Consulting; and James F. Pankow of Portland State University. Funding was provided by the U.S. Department of Energy and the National Science Foundation.

About the University of California, Irvine: Founded in 1965, UCI is a top-ranked university dedicated to research, scholarship and community service. Led by Chancellor Michael Drake since 2005, UCI is among the most dynamic campuses in the University of California system, with nearly 28,000 undergraduate and graduate students, 1,100 faculty and 9,000 staff. Orange County’s second-largest employer, UCI contributes an annual economic impact of $4 billion. For more UCI news, visit www.today.uci.edu.

Berkeley Lab researchers find new evidence on how cholesterol gets moved from HDLs to LDLs.

Optimized negative-staining EM of CETP shows the protein’s banana shape

Researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) have found new evidence to explain how cholesteryl ester transfer protein (CETP) mediates the transfer of cholesterol from “good” high density lipoproteins (HDLs) to “bad” low density lipoproteins (LDLs). These findings point the way to the design of safer, more effective next generation CETP inhibitors that could help prevent the development of heart disease.

Gang Ren, a materials physicist and electron microscopy expert with Berkeley Lab’s Molecular Foundry, a DOE nanoscience research center, led a study in which the first structural images of CETP interacting with HDLs and LDLs were recorded. The images and structural analyses support the hypothesis that cholesterol is transferred from HDLs to LDLs via a tunnel running through the center of the CETP molecule.

“Our images show that CETP is a small (53 kilodaltons) banana-shaped asymmetric molecule with a tapered N-terminal domain and a globular C-terminal domain,” Ren says. “We discovered that the CETP’s N-terminal penetrates HDL and its C-terminal interacts with LDL forming a ternary complex. Structure analyses lead us to hypothesize that the interaction may generate molecular forces that twist the terminals, creating pores at both ends of the CETP. These pores connect with central cavities in the CETP to form a tunnel that serves as a conduit for the movement of cholesterol from the HDL.”

Ren reports the results of this study in a paper in the journal Nature Chemical Biology titled “Structure basis of transfer between lipoproteins by cholesteryl ester transfer protein.” Co-authoring this paper were Lei Zhang, Feng Yan, Shengli Zhang, Dongsheng Lei, M. Arthur Charles, Giorgio Cavigiolio, Michael Oda, Ronald Krauss, Karl Weisgraber, Kerry-Anne Rye, Henry Powna and Xiayang Qiu.

Cardiovascular or heart disease, mainly atherosclerosis, remains the leading cause of death in the United States and throughout the world. Elevated levels of LDL cholesterol and/or reduced levels of HDL cholesterol in human plasma are major risk factors for heart disease. Since CETP activity can reduce HDL-cholesterol concentrations and CETP deficiency is associated with elevated HDL-cholesterol levels, CETP inhibitors have become a highly sought-after pharmacological target for the treatment of heart disease. However, despite this intense clinical interest in CETP, little is known concerning the molecular mechanisms of CETP-mediated cholesterol transfers among lipoproteins, or even how CETP interacts with and binds to lipoproteins.

“It has been very difficult to investigate CETP mechanisms using conventional structural imaging methods because interaction with CETP can alter the size, shape and composition of lipoproteins, especially HDL,” Ren says. “We were successful because we used our optimized negative-staining electron microscopy protocol that allows us to flash-fix the structure and efficiently screen more than 300 samples prepared under different conditions.”

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Combining recommended therapies improved survival odds by up to 90 percent over two years.

Gregg Fonarow, UCLA

A UCLA-led study has found that a combination of several key guideline-recommended therapies for heart failure treatment resulted in an improvement of up to 90 percent in the odds of survival over two years.

The research is published today (Feb. 21) in the online Journal of the American Heart Association.

Heart failure, a chronic, progressive disease, affects millions of individuals and results in morbidity, the use of significant health care resources, and substantial costs.

While certain therapies are recommended for heart failure patients in the national guidelines of the American College of Cardiology and the American Heart Association, this study is the first to examine the specific incremental contribution of each of these therapies in improving survival when combined together progressively in a real-world clinical practice, the researchers said.

“We found incremental and cumulative improvement in the odds of two-year survival rates as each of these guideline-recommended therapies was implemented with patients,” said the study’s first author, Dr. Gregg Fonarow, UCLA’s Eliot Corday Professor of Cardiovascular Medicine and Science and director of the Ahmanson–UCLA Cardiomyopathy Center at the David Geffen School of Medicine at UCLA.

Fonarow noted that the findings also provide further rationale for employing performance-improvement systems and disease-management programs to ensure the implementation of recommended therapies in eligible heart failure patients.

For the study, researchers utilized the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF), a database of patients at 167 cardiology-practice clinics across the country.

The team reviewed medical chart data from 1,376 patients who died at 24 months, compared with 2,752 controls who survived to 24 months. Researchers specifically targeted patients who had weakening function in the heart’s left venticle, a symptom of chronic heart failure, which occurs when the when the entricle can no longer pump enough blood to the body’s other organs.

The seven key guideline-recommended therapies evaluated were:

• Three types of heart failure medications: beta blockers, aldosterone antagonists, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
• Cardiac resynchronization therapy, which helps coordinate heart contractions.
• Anti-coagulant therapy for atrial fibrillation, to prevent clot formation in patients with an irregular heart beat.
• Implantable cardioverter-defibrillator devices, to deliver electrical shocks if potentially fatal heart-rhythm abnormalities occur.
• Heart-failure patient education.

Researchers found that as each therapy was added, the overall survival rate increased incrementally — starting with a 39 percent improved odds of two-year survival when just beta blockers were prescribed, and up to 81 percent to 90 percent when several other therapies were added — compared to no treatment at all.

However, the team found that the survival benefit appeared to plateau once a patient sequentially received four to five therapies, demonstrating an 83 percent reduction in the odds of 24-month mortality.

“Together the cumulative 24-month survival benefits of these therapies are impressive,” said Fonarow, co-chief of clinical cardiology in the UCLA Division of Cardiology. “High-quality, patient-centered outcomes research is a national priority and can better inform clinical decision-making. This study provides patients, clinicians, purchasers and policymakers with compelling evidence of the incremental improvements in clinical outcomes for patients with heart failure that can be achieved with guideline-recommended therapies.”

Each individual therapy, with a single exception, was also associated with a survival benefit. Beta blockers and cardiac resynchronization therapy imparted the greatest individual benefits by providing lowered odds of mortality of 42 percent and 44 percent, respectively.

Fonarow also noted that being able to independently value these heart failure therapies may provide a basis for choosing between treatments when a choice needs to be made on a clinical level, based on cost, tolerance or adherence issues.

The one therapy that was not associated with improved mortality benefit was the use of aldosterone antagonists. Fonarow said that while multiple randomized clinical trials have demonstrated the benefits of aldosterone antagonist therapy in heart failure patients, more study in an outpatient setting needs to be done to evaluate the real-world clinical effectiveness of these agents.

Medtronic Inc., a manufacturer of cardiac resynchronization therapy and implantable defibrillator devices, provided financial and material support for the IMPROVE HF registry. The company had no role or input in the selection of end-points or quality measures used in the study.

Fonarow has received honoraria and consultant fees from Medtronic. Additional author financial disclosures are listed in the study manuscript.

Other authors include Dr. Nancy M. Albert of the Heart Vascular Institute at the Cleveland Clinic Foundation; Dr. Anne B. Curtis of the department of medicine at the University at Buffalo; Dr. Mihai Gheorghiade of the Center for Cardiovascular Innovation at Northwestern University’s Feinberg School of Medicine; J. Yang Liu of the department of statistics, CRDM, Medtronic Inc.; Mandeep R. Mehra of the  division of cardiology at the University of Maryland School of Medicine; Dr. Christopher M. O’Connor of the division of cardiology at Duke University Medical Center; Dr. Dwight Reynolds of the division of cardiology at the University of Oklahoma Health Sciences Center; Dr. Mary Norine Walsh of the Care Group at St. Vincent Heart Center of Indiana; and Dr. Clyde W. Yancy of the division of cardiology at Northwestern University’s Feinberg School of Medicine.

Delivered through catheter, gel promotes cell repopulation in tissue damaged by heart attack.

Tissue spins in a beaker at the end of the cleansing process that removes all of the cells.

University of California, San Diego, researchers have developed a new injectable hydrogel that could be an effective and safe treatment for tissue damage caused by heart attacks.

The study by Karen Christman and colleagues appears in today’s (Feb. 21) issue of the Journal of the American College of Cardiology. Christman is a professor in the Department of Bioengineering at the UC San Diego Jacobs School of Engineering and has co-founded a company, Ventrix Inc., to bring the gel to clinical trials within the next year.

Therapies like the hydrogel would be a welcome development, Christman explained, since there are an estimated 785,000 new heart attack cases in the United States each year, with no established treatment for repairing the resulting damage to cardiac tissue.

The hydrogel is made from cardiac connective tissue that is stripped of heart muscle cells through a cleansing process, freeze-dried and milled into powder form, and then liquefied into a fluid that can be easily injected into the heart. Once it hits body temperature, the liquid turns into a semi-solid, porous gel that encourages cells to repopulate areas of damaged cardiac tissue and to preserve heart function, according to Christman. The hydrogel forms a scaffold to repair the tissue and possibly provides biochemical signals that prevent further deterioration in the surrounding tissues.

“It helps to promote a positive remodeling-type response, not a pro-inflammatory one in the damaged heart,” Christman said.

What’s more, the researchers’ experiments show that the gel also can be injected through a catheter, a method that is minimally invasive and does not require surgery or general anesthesia.

New, unpublished work by her research team suggests that the gel can improve heart function in pigs with cardiac damage, which brings this potential therapy one step closer to humans, said Christman.

There are few injectable cardiac therapies in development designed to be used in large animals such as pigs, which have a heart that is similar in size and anatomy to the human heart, Christman explained. “Most of the materials that people have looked at have been tested in rats or mice, and they are injectable via a needle and syringe. However, almost all of them are not compatible with catheter delivery and would gel too quickly, clogging the catheter during the procedure.”

In experiments with rats, the gel was not rejected by the body and did not trigger arrhythmic heart beating, providing some assurance that the gel will be similarly safe for humans, the researchers note.

Christman has an equity interest in Ventrix Inc., a company that may potentially benefit from the research results, and also serves on the company’s Scientific Advisory Board. The terms of this arrangement have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies.

The study’s co-authors include Jennifer Singelyn, Priya Sundaramurthy, Todd Johnson, Pamela Schup-Magoffin, Diane Hu, Denver Faulk, Jean Wang and Kristine M. Mayle in the Department of Bioengineering; Kendra Bartels, Anthony N. DeMaria, and Nabil Dib of the UC San Diego School of Medicine; and Michael Salvatore and Adam M. Kinsey of Ventrix, Inc. The research was funded in part by the National Institutes of Health Director’s New Innovator Award Program (part of the NIH Roadmap for Medical Research), the Wallace H. Coulter Foundation and the National Science Foundation.