Disability Affects Three Out of Every 10 U.S. Adults

By Kristina Fiore

HYATTSVILLE, Md., July 25 -- Nearly 30% of the noninstitutionalized adult U.S. population -- about 62 million people -- have some disability that affects daily activity.
More than 20% of the population reported difficulties walking, bending, reaching overhead, or using their fingers to grasp something, Barbara M. Altman, Ph.D., formerly of the CDC, and colleagues wrote in a National Center for Health Statistics report this week.
"What we have is a large segment of the population who have problems, and they're not all being taken care of," Dr. Altman said.
About two-thirds of these disabled Americans are younger than 65, Dr. Altman said.
"You see so much about the aging population, but you don't see as many numbers about the population from ages 18 to 64," she said. "However there's a larger number of people with disabilities under 65."
Dr. Altman said disability among those younger than 65 was likely related to problems associated with obesity -- such as diabetes and arthritis -- and heart disease, which may also be associated with obesity.
"It's what we see after age 65, but it's the beginning of it and we don't pay as much attention when people are younger," she said. "But that's the point in time to take preventive measures."
The findings emerged from an analysis of data collected by the National Health Interview Survey (NHIS), which canvassed 157,976 adults from 2001-2005 via the Sample Adult Core Questionnaire.
Other significant disabilities involved vision and hearing, with more than 13% of those surveyed reporting difficulties. Emotional or cognitive difficulties were less prevalent, with only 3% of the population reporting each difficulty.
Problems with more complex activities like working, participating in social activities, or being able to manage self-care were reported by 14% of the population.
Work complications were the biggest problem, reported by 12% of those surveyed; just 4% reported difficulties with self-care.
Other survey findings included:
Over half of noninstitutionalized adults with self-care limitations were ages 65 and older; about half of adults with emotional difficulties were under 45 years old.
Adults without disabilities were more than twice as likely to have a college degree as adults who had trouble with complex activities and 70% more likely to have a college degree than those with basic actions difficulty.
Almost one-third of adults with complex activity limitation and 30% of those with basic actions difficulty were obese, compared with 19% of adults with no reported disability.
About 40% of adults ages 18 to 44 with either complex or basic activity limitation reported being smokers, compared with 22% of nondisabled adults in the same age group.
Dr. Altman said the rate of smoking in the 18- to 44-year-old age group with disabilities was particularly concerning because it "furthers their risk for other health problems."
Primary source: National Center for Health StatisticsSource reference:Altman B, et al "Disability and health in the United States, 2001 -- 2005" National Center for Health Statistics 2008.

Fructose Converts Quickly to Lipids Triggering Hyperlipidemia

By Charles Bankhead
DALLAS, 26 july 2008-- Lipogenesis increased significantly when glucose was replaced with fructose on a gram-for-gram basis in energy drinks consumed by six healthy volunteers, researchers here found.
Conversion of fructose to lipid occurred quickly, usually within four hours after ingestion, Elizabeth Parks, Ph.D., of the University of Texas Southwestern Medical Center, and colleagues reported in the June issue of the Journal of Nutrition.
Moreover, consumption of a high-fructose drink for breakfast increased liver-mediated fat storage after lunch, the researchers said.
"Our study shows for the first time the surprising speed with which humans make body fat from fructose," said Dr. Park. "Once you start the process of fat synthesis from fructose, it's hard to slow it down."
The findings provide strong support for clinical guidelines that recommend limiting processed carbohydrates, which often contain high-fructose corn syrup, she added.
Studies involving controlled feeding have shown that fructose could increase serum triacylglycerol levels and maintain the increase throughout the day in healthy individuals and in patients with diabetes. Chronic elevation of triacylglycerol levels could lead to accumulation of atherogenic lipoprotein remnants, the authors said.
Replacement of glucose with fructose in a fat-containing breakfast drink has been shown to increase the four-hour appearance of the meal's fatty acids in VLDL, suggesting increased reesterification of breakfast fat in the liver, they continued.
So the authors hypothesized that a fructose-induced rise in lipogenesis in the morning would further increase triacylglycerol concentrations following lunch. They also sought to determine the lipogenic effects of two different doses of fructose in healthy, relatively lean individuals.
Four men and two women volunteered for the study. Their mean age was 28 and they had a mean body mass index of 24.3 and mean serum triacylglycerol level of 1.03 mmol/L.
On separate days, the volunteers consumed breakfast energy drinks sweetened with 100% glucose, a 50-50 mix of glucose and fructose, and a 25-75 mix of glucose and fructose. The volunteers ate a standardized lunch four hours after consuming the drink.
Lipogenesis was assessed by serial testing for four hours after breakfast, and postprandial lipemia was measured following the lunch meal.
The drink containing only glucose led to a peak fractional lipogenesis of 7.8%. In contrast, the 50-50 mix and the 25-75 mix more than doubled peak fractional lipogenesis (15.98% and 16.9%, respectively, P<0.02).
Fructose consumption at breakfast induced a dramatic rise in postprandial lipemia after the lunch meal. Consumption of the fructose-containing drinks was associated with an increase in postprandial serum triacylglyerols of 11% to 29% compared with the glucose-only drink.
Concentrations of triacylglycerol-rich lipoproteins increased by 76% to 200% with the 50-50 and 25-75 mix of glucose and fructose.
"The message from this study is powerful because body fat synthesis was measured immediately after the sweet drinks were consumed," Dr. Parks said. "The carbohydrates came into the body as sugars, they liver took the molecules apart . . . and put them back together to build fats. All this happened within four hours after the fructose drink. As a result, when the next meal was eaten, the lunch fat was more likely to be stored than burned."
The message should not be misconstrued by people who are trying to lose weight, she continued. Specifically, they should not eliminate dietary fruits, which have high fructose concentrations.
Overeating and excess caloric consumption remain the principal drivers of weight gain and obesity, she concluded.
The biggest limitation of the study, the researchers acknowledged, is it's small sample size. However, they said, the repeated measures design supports the notion that the differences were real and would be reproducible.
Another limitation is the fact that the drinks were consumed first thing in the morning when participants were in the fasting state. That could lead to an underestimation of lipogenesis.
The study was supported by the National Institutes of Health, the Cargill Higher Education Fund, and the Sugar Association.
The authors reported no conflicts of interest.
Primary source: Journal of NutritionSource reference:Parks EJ, et al "Dietary sugars stimulate fatty acid synthesis in adults" J Nutr 2008; 138: 1039-1046.

Anti-HIV therapy boosts life expectancy more than 13 years
Improvements due to modern antiretroviral cocktails

BIRMINGHAM, Ala., 26 july 2008 – The life expectancy for patients with human immunodeficiency virus (HIV) has increased by more than 13 years since the late 1990s thanks to advancements in antiretroviral therapy, according to researchers at the University of Alabama at Birmingham (UAB) and Simon Fraser University in Vancouver, British Columbia.
Improved survival has led to a nearly 40 percent drop in AIDS deaths among 43,355 HIV-positive study participants in Europe and North America, bolstering the call for improved anti-HIV efforts worldwide, the study authors said.
The study is published in the British medical journal The Lancet. It was compiled by The Antiretroviral Therapy Cohort Collaboration, which includes UAB, Simon Fraser University and more than a dozen other research sites around the world.
The authors looked at changes in life expectancy and mortality among the 43,355 HIV patients taking a cocktail of drugs called combination antiretroviral therapy (cART). Data was compiled from a total of 14 studies in Europe and North America.
"Since their introduction in 1996 cART regimens have become more effective, better tolerated and easier to follow," said Michael Mugavero, M.D., an assistant professor in UAB's Division of Infectious Diseases and a co-author on the study.
"We are now seeing the benefits of years of research, hard work and efforts to make these medications widely available. This has led to dramatic improvements in life expectancy, but patients who start cART with more advanced HIV infection do not have the same level of benefit," Mugavero said.
The new Lancet study found cART yielded a 13.8-year life-expectancy increase – from 36.1 years in study participants who began therapy during the 1996-1999 period, to 49.9 years in participants who began therapy during the 2003-2005 period.
Despite the good results, the study found life expectancy for HIV patients is far lower on average than the general population, which includes all those with other chronic illnesses. For example, an HIV-positive patient starting cART at age 20 will live to 63, about 20 years shorter than the average life span of non-infected adults.
With nearly half of all patients diagnosed with advanced HIV infection, the life expectancy benefits of cART are not fully realized, said Mugavero and lead study author Robert Hogg, Ph.D., of Simon Fraser University. Improved AIDS testing and increased access to care is needed.

NIDDK publishes a strategic plan for research into benign prostate disease

26 july 2008--For the first time, a strategic plan for research into benign prostate disease, based on the latest scientific knowledge, has been published by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health (NIH). The NIDDK Prostate Research Strategic Plan is the culmination of discussions and meetings among experts over the past two years in an effort to outline a strategic vision for research into these elusive and multi-faceted diseases.
"The NIDDK Prostate Research Strategic Plan reflects NIH's commitment to advancing translational research by facilitating planning efforts among basic scientists, clinicians, advocacy groups, and patients," said NIDDK Director Griffin P. Rodgers, M.D. "The educational summaries in each section of the plan provide clear explanations of the scientific data and the reasoning behind each of the recommended research priorities."
The research area of benign prostate disease includes two of the most significant non-cancerous disorders affecting males — benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). BPH, an enlargement of the prostate gland, is often associated with lower urinary tract symptoms (LUTS). LUTS, which can include symptoms such as overactive bladder, restricted or excessive urination, and sensations of urgency, affects men of all races and ethnic groups and can become severe over time. An estimated 50 percent of men in their 50s have BPH and 26 to 46 percent of men between the ages of 40 and 79 have moderate to severe symptoms. CP/CPPS is generally described as inflammation of the prostate gland. There is no detectable bacterial basis, but CP/CPPS sometimes is associated with urinary symptoms, pain, and sexual dysfunction. The source of the pain in this syndrome is unknown and there are no generally effective methods for preventing or treating the condition.
The NIDDK Prostate Research Strategic Plan addresses the four major research areas judged critical for advancing the field. These include basic science, epidemiology and population-based studies, translational research, and clinical sciences. Recommendations from the plan include:
Promote interdisciplinary research that focuses on how benign prostate diseases are influenced by other organ-specific diseases and systemic conditions, such as obesity, high blood pressure, high cholesterol, cardiovascular disease, diabetes, and erectile dysfunction. For example, the possible influence of high blood pressure on BPH/LUTS is a previously unexplored area of research.
Study the primary prevention of benign prostate diseases, including possible benefits of lifestyle changes such as avoidance of alcohol and caffeine, frequency of sexual practice, pelvic massage therapy, stress reduction, and diet modulation for relief of CP/CPPS.
Develop data and human tissue resources from patients of various ages to derive information useful in investigating risk factors, underlying causes and natural history of disease progression, quality of life, quality of care, and decision making regarding treatment of benign prostate disease. Develop imaging approaches and other biomarker studies to assess severity and risk of progression based on physical and cellular findings.
Develop targeted medical therapies based on new insights into disease-relevant cellular pathways and physiological events.
Develop standardized, clinically significant benign prostate disease syndrome definitions and classifications based on measurable phenotypic features.
Train and mentor epidemiologists, health services researchers, clinical investigators, and students interested in the study of benign prostate disease.
"The long-standing, unanswered questions about the causes of these disorders prompted the NIDDK to examine the state of the science and to develop a new vision for future research," explained Chris Mullins, Ph.D., NIDDK's director of basic cell biology programs in urologic and kidney disease. "As part of this process we convened the Prostate Research Planning Committee, composed of clinical and basic scientists and epidemiologists from around the country, to review and evaluate past and current research and to make individual recommendations for new research priorities. The NIDDK Prostate Research Strategic Plan is the result of that collaborative effort."
The plan is designed to be read by a broad audience of researchers, clinicians, advocacy groups, representatives of funding organizations, and patients. Each major section includes a mission statement, a lay summary, an overview of current knowledge, and high-priority recommendations for future research. The plan is online at http://www2.niddk.nih.gov/NR/rdonlyres/318606D2-A9D1-4CAD-B9BF-8EB3009C83BE/0/NIDDKProstateStrategicPlan.pdf and can be purchased online in print or compact disc format at http://catalog.niddk.nih.gov/PubType.cfm?Type=182&CH=NKUDIC.
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NIDDK conducts and supports research in diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic, and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe, and disabling conditions affecting Americans. For more information about NIDDK and its programs, see www.niddk.nih.gov.
The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

Plasma DNA level is a reliable marker of recurrent esophageal cancer, study finds

Elevated plasma DNA levels occur prior to clinical evidence of recurrence in majority of patients
CHICAGO , 26 july2008– New research published in the July issue of the Journal of the American College of Surgeons shows elevated plasma DNA is a reliable marker of recurrent esophageal cancer. The study also suggests that plasma DNA levels rise before clinical evidence of cancer recurrence in the majority of patients.
Esophageal cancer, one of the leading causes of cancer death worldwide, is usually diagnosed at a late stage. An accurate marker for detecting esophageal cancer that has spread (metastasized) beyond the esophagus may allow for better selection of patients for adjuvant therapy, prediction of response to therapy and early intervention when the disease does recur. Although carcinoembryonic antigen (CEA) and plasma DNA are known to be elevated in patients with esophageal cancer and are higher in patients with metastatic disease, the sensitivity and specificity of these markers in the diagnosis of recurrent cancer has not been compared.
"The diagnosis of metastatic esophageal cancer prior to surgery and recurrent disease after surgery remains challenging, as the clinical staging of esophageal cancer is difficult and current scanning technologies are limited," said Farzaneh Banki, MD, assistant professor of surgery, Department of Surgery, Keck School of Medicine at the University of California, Los Angeles. "The results of our study suggest that measuring DNA levels could improve the diagnosis of and prediction of recurrence of this disease."
The study analyzed the sensitivity and specificity of plasma DNA as a preoperative marker of metastasized disease and a postoperative marker in residual or recurrent esophageal cancer. Plasma DNA was measured in 45 patients with esophageal cancer and 44 healthy volunteers; serum CEA was measured in 31 patients.
Plasma DNA was found to be more sensitive than CEA for detecting cancer that cannot be removed through a surgical procedure (100 percent versus 40 percent) and was also more sensitive than CEA in detecting recurrent esophageal cancer (100 percent versus 33 percent). All patients with recurrent disease had elevated plasma DNA, and no patient with normal plasma DNA had recurrent disease (i.e., there were no false positives or false negatives for plasma DNA). Plasma DNA rose before there was clinical evidence of recurrence in 67 percent of patients, versus 17 percent of patients measured for CEA).
The researchers suggest the role of plasma DNA is of more value after surgical intervention in identifying patients with recurrent disease. In contrast, a normal CEA level should be interpreted cautiously, as it does not exclude recurrent disease. The researchers assert that greater numbers of patients and longer follow-up are necessary to confirm these findings.

Researchers unravel key mechanism of cellular damage in aging and disease

25 july 2008--Damage can be measured by newly captured events in cell's powerhouse
Researchers have taken a first snapshot of how a class of highly reactive molecules inflicts cellular damage as part of aging, heart disease, stroke, cancer, diabetes, kidney disease and Alzheimer's disease to name a few. According to a study published today in the journal Cell, researchers have discovered a tool that can monitor related damage and determine the degree to which antioxidant drugs effectively combat disease.
Reactive oxygen species (ROS), which include free radicals, are highly reactive molecules that force change upon many molecules they encounter. The body uses ROS to signal for wound healing and to destroy invaders. Excess amounts, however, damage sensitive cell components, including proteins and DNA, in a process called oxidative stress. ROS are kept in check by the body's natural antioxidants, but when uncontrolled can lead to disease.
These highly reactive molecules are created as a side effect when structures within all human cells, the mitochondria, use oxygen to convert food into energy for life. Researchers once thought that altered mitochondrial function was important only in rare genetic diseases, but recent studies have revealed that oxidative stress plays a role in conditions that afflict many millions of patients. As a result, mitochondrial medicine is gaining momentum as groups like the Mitochondria Interest Group at the National Institutes of Health, professional societies and drug companies push basic science toward drug discovery.
"Our study provides a better glimpse of why a cell under assault by disease makes 10 times as many reactive oxygen species as the same cell when healthy," said Shey-Shing Sheu, Ph.D., professor of Pharmacology and Physiology at the University of Rochester Medical Center, and a study author. "We have discovered a chemical tool for investigating how diseases cause damage, mitochondrion by mitochondrion, which should represent a tremendous advance as both a disease biomarker and for drug discovery."
Meltdown at the Powerhouse
The primary role of mitochondria is to convert food into chemical energy in the form of adenosine triphosphate (ATP), the molecule used by all human cells to store energy. To drive ATP production, electrons are passed along a series of enzymes, but a few "leak" during the process. Leaked electrons react with available oxygen to form the reactive oxygen species, termed superoxide. The emerging theory is that excess superoxide production causes the mitochondria to swell and rupture, resulting in a "cellular energy crisis" that ultimately leads to cell death in the many diseases of oxidative injury.
In the Cell study, researchers used a newly patented, protein-based probe to discover, and make visible, for the first time, fleeting bursts of superoxide production in mitochondria termed "superoxide flashes." The superoxide bursts oxidize cysteine residues in the probe, causing it to emit fluorescent light, which can then be detected and analyzed for patterns. Experiments not only identified superoxide flashes for the first time, but also confirmed that they exhibit a similar size and duration, regardless of the cell type they occur in. This uniform pattern of low-level superoxide production in the mitochondria of healthy cells is normal, perhaps keeping the ROS signaling system ready to fire, researchers said. The one quality of superoxide flashes found to vary was frequency, which dramatically increased during disease.
The research team looked at one kind of oxidative stress in particular: that caused when the oxygen supply to the heart is initially cut off (e.g. during a heart attack or stroke) and then re-established. When heart muscle cells were exposed to a non-oxygen solution for six hours, superoxide flash frequency decreased four-fold, to one event per 100 seconds. Upon re-introduction of oxygen, superoxide production increased eight-fold, confirming past work that re-oxygenation after a heart attack comes with a burst of destructive and uncontrolled superoxide production and oxidative stress.
Existing methods for measuring superoxide production involve chemical indicators or older protein probes, but these previous methods are not specific for superoxide, are damaged by light and provide a limited signal above background noise. The new probe is more sensitive, specific to superoxide, provides a stronger signal than other probes, and is the first to permit reversible measurements of superoxide levels on a millisecond timescale. The research team also created a genetically engineered mouse that expresses the probe within the mitochondria of all of its cells. These "superoxide mice" will enable researchers in the future to quantify the impact of uncontrolled mitochondrial superoxide production across many diseases.
Efforts to develop antioxidant drugs (e.g. vitamin E) to treat diseases of increased oxidative stress have met with limited success to date because they tried to eliminate ROS, rather than maintain the right amount, Sheu said. He established the Mitochondrial Research & Innovation Group (MRIG) at the Medical Center in 2002 with the goal of designing therapies to deliver precise amounts of antioxidants to the mitochondria of diseased cells only. MRIG teams are, for example, screening through compounds to confirm that oxidative stress can be reversed by mitochondria-specific drugs. The new superoxide flash probe will provide a powerful tool for determining the effectiveness of new classes of antioxidant drugs in reducing superoxide production at the right place and time.
The "birthday" for superoxide flashes came in June of 2003 in the lab of Robert Dirksen, Ph.D., associate professor of Pharmacology and Physiology at the Medical Center, when Linda Groom observed spontaneous bursts of fluorescent light using the newly developed protein-based superoxide indicator. The current paper's lead author was Wang Wang, Ph.D. formerly a postdoctoral fellow at the National Institute on Aging at the National Institutes of Health. Aiwu Cheng, Jinhu Yin, Weidong Wang, Edward Lakatta and Mark Mattson also contributed from the NIH, as did Joseph Kao from the University of Maryland. Also contributing from Peking University in Beijing were Huaqiang Fang, Wanrui Zhang, Jie Liu, Xianhua Wang, Kaitao Li, Peidong Han, Ming Zheng, and Heping Cheng, the corresponding author.
"One co-author on the current paper, Dr. Cheng of Peking University, 15 years ago published a seminal study regarding local calcium release events, or calcium sparks," Dirksen said. "This study has been cited more than 900 times and has provided a major contribution to our understanding how the heart beats and why it fails. We believe that our serendipitous discovery of local mitochondrial superoxide flash events could be even more important because superoxide flash frequency may provide an accurate, real-time picture of how uncontrolled oxidative stress contributes to the progression of several, debilitating cardiovascular and neurological diseases."

Older people may need less sleep, study finds

25 july 2008--Along with all the other changes that come with age, healthy older people also lose some capacity for sleep, according to a new report published online on July 24th in Current Biology, a Cell Press publication. When asked to stay in bed for 16 hours in the dark each day for several days, younger people get an average of 9 hours of shuteye compared to 7.5 for older people, the researchers report.
" The most parsimonious explanation for our results is that older people need less sleep," said Elizabeth Klerman of Brigham and Women's Hospital & Harvard Medical School. "It's also possible that they sleep less even when given the opportunity for more sleep because of age-related changes in the ability to fall asleep and remain asleep," she added, noting that the new results apply only to healthy individuals taking no medication and having no medical conditions or sleep disorders.
The study also found that most healthy people, and young people in particular, don't get as much sleep as they need.
The idea that sleep changes markedly across the life span isn't new. In fact, insomnia is a common complaint among older people. But whether age-related changes in sleep were due to changes in social factors, circadian rhythms, or shifts in an internal "set point" for sleep need or the ability to sleep had remained unresolved.
In the new study, Klerman and her colleague Derk-Jan Dijk, of the University of Surrey in the UK, set out to compare the capacity for sleep in young people (between the ages of 18 and 32) compared to older people (age 60 to 72) under conditions that controlled for circadian rhythms by allowing the chance to sleep during both the night and the day and by controlling individual choices in sleep opportunities.
" While humans can sometimes override the homeostatic set point and not sleep when tired, there is no evidence that they can sleep when they are not tired," Klerman explained.
Given the same amount of time in bed, older people take longer to fall asleep and sleep for less time than younger people do, they found. When required to remain in bed for 16 hours a day, older people slept 1.5 hours less on average than younger people, they showed. That age-related decline in sleep included an even split between rapid eye movement (REM) sleep, which is associated with dreaming, and non-REM sleep, they found.
Most younger subjects slept for many more hours during the study than their usual self-selected sleep times. Given the evidence that insufficient sleep is associated with increased risk of accidents, errors, and metabolic changes similar to diabetes, Klerman emphasized that younger people should sleep more.
The findings may also influence treatment for insomnia in older people, Klerman said.
" If older people believe that they need more sleep than they can achieve even when they spend extra time in bed, then they may complain of insomnia: being awake when wanting to be asleep. They may start using medications needlessly. If they are tired during the day, they should consider evaluation for a sleep disorder that may be interfering with their ability to obtain good sleep at night."
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The researchers include Elizabeth B. Klerman, Division of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Derk-Jan Dijk, Surrey Sleep Research Centre, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.

Yale study shows why cigarette smoke makes flu, other viral infections worse

25 july 2008--A new study by researchers at Yale School of Medicine could explain why the cold and flu virus symptoms that are often mild and transient in non-smokers can seriously sicken smokers. Published in the Journal of Clinical Investigation, the study also identified the mechanism by which viruses and cigarette smoke interact to increase lung inflammation and damage.
Until recently, scientists haven't been able to explain why smokers have more exaggerated responses to viral infections. Smokers have been more likely than non-smokers to die during previous influenza epidemics and are more prone to chronic obstructive pulmonary disease (COPD). Furthermore, children who are exposed to second-hand smoke have more severe responses when infected with respiratory synctial virus.
The prevailing view has been that cigarette smoke decreases anti-viral responses. But the Yale researchers—lead author Jack A. Elias, M.D., the Waldermar Von Zedtwitz Professor of Medicine and chair of internal medicine at Yale School of Medicine, and first author Min-Jong Kang, M.D., associate research scientist—found the opposite to be true.
Their experiments showed that the immune systems of mice exposed to cigarette smoke from as little as two cigarettes a day for two weeks overreacted when they were also exposed to a mimic of the flu virus. The mice's immune systems cleared the virus normally but the exaggerated inflammation caused increased levels of tissue damage.
"The anti-viral responses in the cigarette smoke exposed mice were not only not defective, but were hyperactive," said Elias. "These findings suggest that smokers do not get in trouble because they can't clear or fight off the virus; they get in trouble because they overreact to it."
"It's like smokers are using the equivalent of a sledge hammer, rather than a fly swatter, to get rid of a fly," said Elias.
The team found that mice with viral infections that had been exposed to cigarette smoke had accelerated emphysema and airway scarring. Elias and his team also defined the signaling pathway that mediates this exaggerated innate immune response.
"If the exaggerated responses are verified in human studies, it will be the first explanation for why viral infections are more serious in smokers," said Elias. "Once verified, we can find ways to prevent the destruction of lung tissue and the higher illness and death among smokers."
"These studies have identified molecular pathways that can explain how cigarette smoke exposure and viral infections interact to make breathing problems worse in diseases like COPD," said James P. Kiley, director, Division of Lung Diseases of the National Heart, Lung, and Blood Institute. "With further research, these findings may even lead to more effective drug treatments for COPD."
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Other authors on the study included Chun Geun Lee, Jae-Young Lee, Charles S. Dela Cruz, Zhijian J. Chen and Richard Enelow.
Citation: The Journal of Clinical Investigation, Vol. 118, No. 8 (August 2008)

Endocrinologists Issue Consensus Statement on Pre-Diabetes

By Todd Neale
JACKSONVILLE, Fla., 25 july 2008-- The treatment of pre-diabetes requires intensive lifestyle modification and the use of drugs for high-risk patients, declared a consensus statement issued here by an American College of Endocrinology task force.
The statement was meant to fill the void in recommendations for treating pre-diabetes by defining specific goals and targets for glucose levels, weight, blood pressure, and lipids, according to Alan Garber, M.D., Ph.D., of Baylor College of Medicine in Houston, who chaired the 17-member task force.
The CDC estimates that about 57 million U.S. adults have pre-diabetes, defined as impaired fasting glucose of 100 to 125 mg/dL, impaired glucose tolerance of 140 to 199 mg/dL, or both. (See: Number of Patients with Diabetes Climbs to 24 Million)
About 6% to 10% of patients with impaired glucose tolerance will develop diabetes each year, and among patients with both impaired fasting glucose and glucose tolerance, about 60% will have diabetes in six years.
Also, half of all patients with impaired glucose tolerance meet the criteria for metabolic syndrome, according to the task force report.
"The preferred treatment approach for all the abnormalities of persons in this group is intensive lifestyle management, given its safety and the strong evidence of efficacy of this approach in improving glycemia and reducing cardiovascular risk factors," the report said.
The task force recommended that patients with pre-diabetes lose 5% to 10% of their body weight assisted by self-monitoring, the setting of realistic goals, stimulus control, cognitive strategies, social support, and appropriate reinforcement.
Pre-diabetics should get at least 150 minutes of moderate-intensity exercise - such as walking or biking -- per week, the task force said, and should limit total and saturated fat and transfatty acids.
For patients at a particularly high risk -- for example, those with worsening glycemia, cardiovascular disease, or nonalcoholic fatty liver disease -- complementing lifestyle modification with medication should be considered, the task force said.
"Although lifestyle can clearly modify the progression of patients towards overt diabetes, it may not be sufficient," Dr. Garber said.
The task force recommended metformin and acarbose for controlling glycemia on the basis of their efficacy in reducing the transition from pre-diabetes to diabetes and their safety.
The authors cited safety concerns with thiazolidinediones as well as insufficient evidence to recommend new agents such as glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and meglitinides.
In addition, pre-diabetics should meet the same lipid and blood pressure targets as diabetics using statins, ACE inhibitors, and angiotensin Ireceptor blockers as first-line treatments, according to the report.
The authors made similar recommendations for lifestyle modification and medication use for children and adolescents with pre-diabetes.
However, they said, the "emphasis must be placed on lifestyle change which can be beneficial in improving glycemic and cardiovascular risk parameters."
In addition to the treatment recommendations, the task force outlined measures for monitoring patients with pre-diabetes for a worsening of the condition.
These included an annual glucose tolerance test and testing for microalbuminuria and twice-yearly evaluation of fasting plasma glucose, hemoglobin A1c, and lipids.
The authors said that "the costs of diabetes prevention can be balanced against cost savings realized from fewer patient-years of the disease, a reduction in complications, and decreased need for hospitalization."
They also stressed that health insurance should start providing better coverage for lifestyle intervention programs.
"Healthcare systems that emphasize acute care to the exclusion of disease prevention or chronic disease management will fail patients with diabetes and patients at high risk of diabetes," they said.
Primary source: American College of EndocrinologySource reference:American College of Endocrinology Task Force on Pre-Diabetes "Consensus statement on the diagnosis and management of pre-diabetes in the continuum of hyperglycemia -- when do the risks of diabetes begin?" 2008.

Biologics and Combinations Top Arthritis Recommendations

By Charles Bankhead
ATLANTA, 25 july 2008 -- Early, aggressive treatment of rheumatoid arthritis with biologic agents and potent drug combinations has moved front and center in the newly updated American College of Rheumatology practice guidelines.
Patients with high disease activity and poor-prognosis features warrant consideration for first-line treatment with a biologic response modifier or a combination of nonbiologic disease-modifying antirheumatic drugs (DMARDs), according to the guidelines published in the June 15 issue of Arthritis & Rheumatism.
Even patients with low disease activity at diagnosis might be candidates for biologic DMARDs and combination therapy if they have high-risk or poor-prognosis features.
The guidelines reflect recognition that early aggressive intervention offers patients the best opportunity to minimize or avoid joint damage and disability, Kenneth G. Saag, M.D., of the University of Alabama at Birmingham, who was lead author of the guidelines. However, the guidelines leave ample room for clinical judgment in treating an individual patient.
"The recommendations developed are not intended to be used in a cookbook or prescriptive manner, or to limit a physician's clinical judgment," said Dr. Saag. "They provide guidance based on clinical evidence and expert-panel input."
The update, the first by the ACR since 2002, gave formal recognition and a systematic approach to treatment strategies that have been employed widely for several years: early use of nonbiologic DMARDs and biologic agents.
For example, the panel recommended triple-DMARD therapy "for all patients with poor prognostic features and moderate or high levels of disease activity, regardless of disease duration." The authors noted that the majority of patients with a confirmed diagnosis of rheumatoid arthritis (RA) already are treated with nonbiologic DMARDs or biologics.
The authors addressed only the use of traditional DMARDs and biologics. Steroids, anti-inflammatories, and other therapies used in RA were beyond the scope of the guidelines.
The 2008 guideline also is the first from the ACR to be developed by a formal group process. Prior iterations had evolved primarily from informal consensus, the authors said.
The guidelines panel recommended leflunomide (Arava) or methotrexate monotherapy as initial treatment for virtually all patients, regardless of disease duration, disease activity, or poor-prognosis features. However, clinical flow charts that accompany the recommendations waste little time in arriving at aggressive therapy, particularly in patients with unfavorable clinical characteristics.
Other key recommendations in the guideline include:
Use of tumor necrosis factor inhibitors in patients with new or early RA and severe, worsening symptoms.
Delay the start or resumption of treatment with methotrexate, leflunamide, or a biologic agent in patients who have active bacterial infections, herpes zoster infection, hepatitis B or C, or active or latent or suspected tuberculosis.
Prohibition on anti-TNF agents in patients who have a history of heart failure, lymphoma, or multiple sclerosis.
Dr. Saag and many of the co-authors acknowledged multiple relationships with medical and healthcare industries.
Primary source: Arthritis & RheumatismSource reference:Saag KG, et al "American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis" Arthritis Rheum 2008; 59: 762-784.

Making patients move requires the right exercise advice

COLUMBIA, Mo. 24 july 2008-- knowledge that regular exercise supports physical and mental well-being. Despite this and recommendations from health care providers, the majority of patients with chronic illnesses remain inactive. In a new study, University of Missouri researchers found that adults with chronic illness who received interventions focused on behavior-changing strategies significantly increased their physical activity levels. In contrast, interventions based on cognitive approaches, which attempt to change knowledge, beliefs and attitudes, and are most commonly used by health care providers, did not improve physical activity.
"The information that physicians are giving patients isn't working. Patients are not motivated when they hear 'exercise is good; it will improve your health.' What works is providing patients with simple, action-orientated strategies to increase their activity levels," said Vicki Conn, professor and associate dean of research in the MU Sinclair School of Nursing.
Behavior strategies include feedback, goal setting, self-monitoring, and stimulus or cues. Self-monitoring, any method where participants record and track their activity over time, significantly increased awareness and provided motivation for improvement, Conn said.
"It is important for care providers to set very specific, manageable goals with patients," Conn said. "For example, ask them to exercise for 20 minutes, three times a week and track their progress by writing it down. Have them schedule exercise on their calendars, or prompt them by setting their walking shoes by their doors. Ask how they can reward themselves if they accomplish the goal. This will help incorporate activity into their daily routines and provide them with a sense of accomplishment."
Conn completed a meta-analysis incorporating data from 22,527 participants in 163 research reports. No previous analysis has examined physical activity levels following interventions among adults with diverse chronic illnesses. Conn found that interventions were similarly effective regardless of gender, age, ethnicity and socioeconomic status.
"Behavior interventions increased participants' activity by an average of 48 minutes per week, which is enough to provide them with health benefits," Conn said. "People may feel overwhelmed by the thought of exercise, or think they have to work out 60 minutes, five days a week, but doing just 12 minutes per day may get them started toward better health."
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The study "Meta-Analysis of Patient Education Interventions to Increase Physical Activity Among Chronically Ill Adults," was published in Patient and Education Counseling. Conn's research is funded by a more than $1 million grant from the National Institutes of Health.

NIST membrane model may unlock secrets of early-stage Alzheimer's

24 july 2008-- Researchers at the National Institute of Standards and Technology (NIST) and three collaborating institutions are using a new laboratory model of the membrane surrounding neurons in the brain to study how a protein long suspected of a role in early-stage Alzheimer’s disease actually impairs a neuron’s structure and function. The team’s findings are reported in a new paper in the Biophysical Journal.*
The brain’s neurons transmit nerve impulses down a long stem that is surrounded by a two-layer membrane. In the neuron’s normal, “rest” state, this membrane actively sorts sodium ions to the outside of the cell and potassium ions to the inside. To transmit a nerve impulse, an electrochemical change ripples down the membrane in advance of the impulse, making it temporarily more permeable and allowing the ions to swap places. That in turn changes the electrical potential across the membrane, allowing the impulse to pass. Afterwards, the membrane returns to rest and begins sorting the ions again.
Medical experts have hypothesized for years that small polypeptides called amyloid beta peptides somehow create a “leaky” membrane that disrupts this balanced back-and-forth switching of the electrical potential and, in turn, normal impulse transmission. Alzheimer’s disease—the progressive brain disorder that is the nation’s sixth leading cause of death—is believed to start with such breakdowns. As the disease progresses, amyloid beta peptides clump together to form plaques that further destroy nerve function.
Studying the beginnings of Alzheimer’s is nearly impossible in humans because by the time the disease is diagnosed, most patients have moved into its later stages. Researchers at NIST have developed a laboratory model that recreates a simplified version of the nerve cell membrane, allowing the study of Alzheimer’s disease mechanisms at the molecular level. A clever piece of molecular-level design, the system is built by first covering a silica surface with gold. Sulfur atoms, which bond well to gold, are then added to act as anchors to hold the bilayer membrane. The result is a stable, tethered membrane with an aqueous environment on both sides that accurately models the behavior of the nerve cell membrane.
A collaborative team of researchers from NIST, Carnegie Mellon University, the University of California-Irvine and the Biochemistry Institute (BCHI) in Vilnius, Lithuania, exposed the membrane model to different concentrations of a specific form of amyloid beta peptides comprised of soluble, tiny (5-6 nanometers, approximately twice the diameter of a DNA helix) chains. The researchers found increased cation movement across the normally strong barrier at the higher concentrations of the peptides. The data support the hypothesis that membrane “leakiness” is not due to a permanent hole being formed but rather to an aggregation of amyloid beta peptides in the membrane that allows cations to be passed from peptide to peptide across the bilayer, like a baton handed off by relay runners.
The researchers are continuing to use their model system to better understand the role amyloid beta peptides play in early-stage Alzheimer’s disease. Future plans include investigating how amyloid beta peptide aggregates arrange themselves in the membrane, how the peptide aggregates affect or influence calcium channels (portals for calcium ion movement) in the membrane, and how the peptides interact with membranes constructed with other types of lipids.
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* G. Valincius, F. Heinrich, R. Budvytyte, D.J. Vanderah, D.J. McGillvray, Y. Sokolov, J.E. Hall and M. Losche. Soluble amyloid ß oligomers affect dielectric membrane properties by bilayer insertion and domain formation: Implications for cell toxicity. Biophysical Journal (published online June 13, 2008).

No justification for denying obese patients knee replacements

24 july 2008--Long term outcome following total knee arthoplasty: A controlled longitudinal study.There is no justification for denying obese patients knee replacement surgery: They benefit almost as much as anyone else from the procedure, concludes a small study published ahead of print in the Annals of the Rheumatic Diseases.
Around 55,000 knee replacements are performed every year in England to relieve the pain and disability of knee osteoarthritis.
But in some parts of the country the surgery is offered only to patients who are not clinically obese (body mass index (BMI) below 30 kg/m2), on the grounds that obesity is itself a risk factor for knee osteoarthritis.
The research team monitored the progress of 325 people over the age of 45 for around six years after they had had knee replacement surgery.
Their progress was compared with that of 363 general practice patients, matched for age and sex, who had not had knee replacements.
At the start and end of the study, all participants completed a validated questionnaire designed to assess their mobility, mental health and wellbeing (vitality).
To begin with, the patients said they had significantly worse mobility than those in the comparison group, scoring an average of 20 compared with 89.
By the end of the study, mobility in the patients had increased by an average of 6 points, while that in the comparison group had fallen by 14.
Mental health scores, which were similar at the outset, improved in both groups, but while wellbeing fell among both groups, the fall was greater among the patients who had had surgery.
When the researchers restricted their analysis to participants who were obese, the improvements persisted, and BMI did not appear to be a significant factor in this.
But there was a stark contrast in mobility among those who had and had not had the surgery.
Mobility score rose three points among those who had had surgery, but fell 36 points among those who had not had a knee replacement. And among those over the age of 75 who had not had the surgery, mobility score fell 40 points.
"The long term improvement in physical function that we observed in patients who have undergone TKA [knee replacement surgery] is striking when set against the decline that occurred in [the comparison group]," say the authors.
"These benefits extend to patients [who are obese] and, provided appropriate selection criteria are applied with regard to fitness for surgery, there seems no justification for withholding [knee replacement surgery] from patients who are obese," they conclude.

New study finds advanced liver cancer patients live longer by taking anti-cancer drug sorafenib

24 july 2008--Researchers at Mount Sinai School of Medicine in New York have found that sorafenib (Nexavar) helps patients with advanced liver cancer live about 44 percent longer compared with patients who did not receive the anti-cancer drug. The findings, published in the July 23rd, 2008 issue of the New England Journal of Medicine, is a significant advance in the management of liver cancer, which is the third cause of cancer death globally, often resulting in death within a year of diagnosis.
"This is the first time that we've had an effective systemic treatment for liver cancer," said Josep Llovet, MD, Director of Research in Liver Cancer at Mount Sinai School of Medicine in New York, and a Professor at the Barcelona Clinic Liver Cancer (BCLC) Group in Barcelona, Spain and lead author of the study. "Our findings demonstrated survival advantages that are both statistically significant and clinically meaningful."
Sorafenib, a tablet that is taken orally, is approved in the United States for treating a form of advanced kidney cancer, and is currently being evaluated in patients with other cancers. Some 40 percent of liver cancers (and up to 80 percent in Asia and sub-Saharan Africa) are diagnosed at an advanced stage. Therapy for advanced liver cancer may include surgery (if possible), radiation therapy and/or regional chemotherapy (delivered directly into the liver). However, no systemic treatment—anti-cancer medication that enters the bloodstream, either as an oral or intravenous medicine—has proven effective to date for advanced liver cancer.
Dr. Llovet and his associates examined overall survival and the time it took for cancer to grow among patients with previously untreated liver cancer who were randomly assigned to receive either 400 mg of sorafenib twice daily (299 patients) or a placebo (303 patients).
Patients who received sorafenib lived a median of 10.7 months compared with 7.9 months for those who received a placebo. Time to cancer progression was also significantly longer in the treatment group: 5.5 vs. 2.8 months. Due to the positive findings, the study was terminated early.
The incidence of adverse side effects was similar between the two groups (52 percent in the sorafenib group and 54 percent for placebo). The most common moderate to serious side effects were diarrhea (11 percent vs. 2 percent), skin reactions in the hands and feet (8 percent vs. 1 percent), fatigue (10 percent vs. 15 percent) and bleeding (6 percent vs. 9 percent).

Heart Disease Linked to Impaired Cognition and Later Dementia

By Judith Groch

LONDON, 23 july 2008-- Coronary heart disease in midlife is associated with poorer results on cognitive tests, such as reasoning, vocabulary, and verbal fluency, with the effect particularly marked in men, a study found.
This "lifelong" view of developing dementia, which stresses the importance of risk factors in midlife, also found that the earlier in life heart disease was diagnosed, the worse the person's later cognitive performance, Archana Singh-Manoux, Ph.D., of University College London and INSERM in Villejuif Cedex, France, and colleagues reported in the European Heart Journal.
There is an increasing consensus that events in earlier life can have an impact on whether dementia develops in older age, Dr. Singh-Manoux said.
Until now, research on the association between coronary heart disease and dementia has focused more on cerebrovascular disease than on coronary heart disease, with emphasis on the elderly, the researchers said.
So the researchers examined the effect of the history and duration of coronary heart disease (including nonfatal myocardial infarction and definite angina) on cognition in a population with a mean age of 61.
Data come from the long-running Whitehall II study, begun in 1985, of 10,308 civil servants working in Whitehall London (33% women), ages 35 to 55 at baseline (1985-88).
Coronary heart disease events were assessed up to the 2002 to 2004 phase of the study when 5,837 participants (28.4% women) took six cognitive tests: verbal and mathematical reasoning, vocabulary, phonemic and semantic fluency, memory, and the mini-mental-state-examination (MMSE).
Results were standardized to T-scores (mean=50, standard deviation=10).
Analysis of covariance was used first to model the association between coronary heart disease history and cognition and then to examine the effect of time since a first heart event (in the preceding five years, five to 10 years previous, and more than 10 years previous).
Among men, compared with those with no history of coronary heart disease, analyses adjusted for age, education, marital status, and cardiovascular medication, having a history of coronary heart disease was associated with lower T-scores on reasoning (21.16, 95% confidence interval 22.07 to 20.25), vocabulary (22.11, 95% CI 23.01 to 21.21), and the MMSE (21.45, 95% CI 22.42 to 20.49).
In women, these effects were also evident for phonemic and semantic fluency (-2.85 and -1.75, respectively).
Among men, the trend within coronary heart disease cases suggested progressively lower scores on reasoning, vocabulary
and semantic fluency among those with a longer duration of heart disease.
Men whose first coronary event occurred more than 10 years before had lower scores on reasoning (22.94, 95% CI 24.35 to 21.52), vocabulary (23.58, 95% CI 25.00 to 22.16), semantic fluency (22.10, 95% CI 23.54 to 20.64), and the MMSE (21.84, 95% CI 23.35 to 20.32).
The test for trend and an examination of the effect for each five-year period among men suggests a trend for lower cognitive scores for verbal and mathematical reasoning and semantic fluency with increase in the time since a first cardiac event.
Among women, the association between time since the first event diagnosed 10 years earlier and cognitive performance showed a trend toward lower scores for semantic fluency. However, for this analysis, the numbers were small.
The prevalence of dementia rises with age, doubling every four to five years after the age of 60 so that over a third of those older than 80 are likely to have dementia, the researchers said.
Thus, although heart disease manifests itself in midlife, dementia occurs later in life. Increasingly, it is recognized that there is a long preclinical phase characterized by progressive neuropathological changes.
This suggests an association between coronary heart disease history and cognitive performance in middle-aged adults that is eventually recognized as cognitive deficit or dementia, the researchers said.
At this point the researchers said they cannot explain the pathophysiological pathway for their findings.
It is possible, they said, that shared risk factors drive this association or that impaired cognition or incipient dementia may in itself lead to coronary heart disease through poor health self-care.
Thus, they said, examining these associations in midlife or early older age offers some advantage over studying the elderly when other age-related conditions can obscure or confound the results.
Study limitations included the fact that all participants had stable white-collar jobs and were not representative of the general population. Despite the size of the study, it was underpowered especially for women, so that gender comparisons could not be made.
Also, the researchers said, missing data were likely to bias the results, leading to underestimation of the association between heart disease and cognition.
Finally, they said, the lack of baseline cognitive data prevented making causal inferences on the direction of the association.
It is important to emphasize, the researchers said, that major risk factors for coronary heart disease, such as smoking, diabetes, hypertension, hyperlipidemia, and lack of exercise are modifiable.
These findings of evolving risk show the importance of preventive strategies in highlighting these risk factors not only for coronary heart disease but also for cognitive outcome, the researchers concluded.

Primary source: European Heart JournalSource reference:Singh-Manoux A, et al "History of coronary heart disease and cognitive performance in midlife: the Whitehall II study" European Heart Journal 2008; DOI: 10.1093/eurheartj/ehn298.

Nursing Homes Unprepared for Pandemic Flu Fallout


23 july 2008-- If an influenza pandemic swept through the United States, nursing homes might not be prepared to deal with patient overflow from hospitals, say researchers who looked at more than 400 nursing homes in Michigan and Nebraska to come to this conclusion.
Of those nursing homes, only 23 percent had a specific pandemic influenza plan, 23 percent had a pandemic response incorporated into an overall disaster response plan, and 52 percent had no pandemic plan.
The researchers also found that less than half of the nursing homes had provided pandemic education to staff members, and just 6 percent had conducted pandemic influenza outbreak exercises. Half of the nursing homes had stockpiled commonly used items such as gloves and hand products.
Among the positive findings -- 77 percent of the nursing homes had a person or staff position designated as being responsible for pandemic preparedness, and access to laboratory facilities for the detection of influenza was available at 84 percent of nursing homes.
The findings were published in the July 23 issue of the Journal of the American Medical Association.
"If nursing homes are called upon to serve as alternative care centers for patients who can't be treated in overcrowded hospitals, the impact on the nursing homes could be vast. Nursing homes serve a vulnerable population prone to dire consequences from an emergency," study author Dr. Philip W. Smith, chief of the section of infectious diseases at the University of Nebraska Medical Center, said in a university news release. "While most facilities felt that nursing homes were being counted on to take hospital overflow patients in a pandemic, in reality, few homes would be able to do so."
"Nursing homes may not be equipped to handle an influx of influenza as well as non-influenza patients. They may also be unwilling to accept overflow patients, if it means displacing their current residents," added senior author Dr. Lona Mody, an assistant professor of internal medicine at the University of Michigan Health System. "Nursing homes run a high occupancy rate, making it logistically difficult to accept a lot of patients if there is a time crunch."
Specific areas that need improvement "include communication with nearby health departments and hospitals at planning stage and exercising formulated plans. Planning for staff shortages is also critical," Mody said.
More information
The U.S. Department of Health & Human Services has more about pandemic flu.

Hoping Two Drugs Carry a Side Effect: Longer Life

By NICHOLAS WADE
BOSTON, Mass., 23 july 2008 — One day last month, clad in white plastic garments from head to toe, Dr. David Sinclair showed a visitor around his germ-free mouse room here at Harvard Medical School.
The mice, subjects in studies of health and longevity, are kept in wire baskets under intensive nursing care. A mouse gym holds a miniature exercise machine that tests the rodents’ ability to balance on a rotating bar. In a nearby water maze, mice must recall visual cues to swim to safety on a hidden platform, a test of their powers of memory. Those that forget their lessons are rescued as they start to submerge and humanely dried out under a heat lamp, Dr. Sinclair assured his visitor.
Dr. Sinclair is a co-founder of Sirtris, a company that itself has been swimming in uncharted waters as it works to develop drugs that may extend the human life span. But it seemed to have found a safe platform last month when it was bought last month by the pharmaceutical giant GlaxoSmithKline for $720 million.
Sirtris has two drugs in clinical trials. One is being tested against Type 2 diabetes, one of the many diseases of aging that the company’s scientists hope the drugs will avert. With success against just one such disease, the impact on health “could be possibly transformational,” said Dr. Patrick Vallance, head of drug discovery at GlaxoSmithKline.
The new drugs are called sirtuin activators, meaning that they activate an enzyme called sirtuin. The basic theory is that all or most species have an ancient strategy for riding out famines: switch resources from reproduction to tissue maintenance. A healthy diet but with 30 percent fewer calories than usual triggers this reaction in mice and is the one intervention that reliably increases their life span. The mice seem to live longer because they are somehow protected from the usual diseases that kill them.
But most people cannot keep to a diet with a 30 percent cut in calories, so a drug that could activate the famine reflex might be highly desirable. Dr. Leonard Guarente, an M.I.T. biologist who founded the field of sirtuin biology, thinks the famine reflex is mediated through the sirtuin enzymes. Dr. Sinclair, his former student, discovered that sirtuins could be activated by drugs. The most potent activator that emerged from his screens was resveratrol, a natural substance found in red wine, though in amounts probably too low to be significant for health.
The Sirtris drug being tested in diabetic patients is a special formulation of resveratrol that delivers a bloodstream dose five times as high as the chemical alone. This drug, called SRT501, has passed safety tests and, at least in small-scale trials, has reduced the patients’ glucose levels.
The other drug is a small synthetic chemical that is a thousand times as potent as resveratrol in activating sirtuin and can be given at a much smaller dose. Safety tests in people have just started, with no adverse effects so far.
The hope is that activating sirtuins in people would, like a calorically restricted diet in mice, avert degenerative diseases of aging like diabetes, heart disease, cancer and Alzheimer’s. There is no Food and Drug Administration category for longevity drugs, so if the company is to submit a drug for approval, it needs to be for a specific disease.
Nonetheless, longevity is what has motivated the researchers and what makes the drugs potentially so appealing.
Dr. Christoph Westphal, the chief executive of Sirtris, said of the potential of the drugs, “I think that if we are right, this could extend life span by 5 or 10 percent.” He added that his goal was to develop drugs against specific diseases, with the extension of life being “almost a side effect of our medicine.”
Sirtris was founded in 2004 after Dr. Westphal, then working at a Boston venture capital firm, approached Dr. Sinclair. Because of widespread interest in the sirtuin activation idea, Dr. Westphal had little difficulty raising money and recruiting distinguished scientists to Sirtris’s advisory board.
He later decided to sell the company to GlaxoSmithKline, he said, because it was getting harder to raise money and clinical trials could proceed faster with the larger company’s resources. Sirtris was acquired at an 84 percent premium, better than the 50 percent at which most companies are bought, Dr. Westphal said.
The impact of Sirtris’s drugs, if successful, could extend beyond the drug industry. Dr. Guarente believes that many people might start taking them in middle age, though after having started a family because they may suppress fertility.
Mice on the drugs generally remain healthy right until the end of their lives and then just drop dead.“If they work in people that way, one would look to an extension of health span, with an extension of life as a possible side effect,” Dr. Guarente said. “It would necessitate changing ideas about when people retire and when they stop paying into the system.”
GlaxoSmithKline could put SRT501, its resveratrol formulation, on the market right away, selling it as a natural compound and nutritional pharmaceutical that does not require approval by the F.D.A. “We haven’t made any decisions, but that clearly is an option,” Dr. Vallance said.
If GlaxoSmithKline decides instead to seek F.D.A. approval, it will need to prove that resveratrol is safe in the large doses required for efficacy. Resveratrol seems to exert many influences on the body, some of which are not exerted through sirtuin. “None of us should be naïve enough to think resveratrol won’t have multiple effects, including some you don’t want,” Dr. Vallance said.
GlaxoSmithKline’s purchase of Sirtris has pushed the optimism of sirtuin researchers and others to new heights. “We are all holding our breath,” said Dr. Huber Warner, editor of the Journals of Gerontology. But the success of the drugs is far from assured.
Most potential drugs fail to make it past clinical trials, and the same may prove true for Sirtris’s candidates. The sirtuin-activating chemicals the company has designed could turn out to be toxic. Another uncertainty is that the underlying science is still in flux and debate rages among academic researchers over many details of how caloric restriction works.
Some biologists think that sirtuin is not the only mediator of the famine reflex, and that resveratrol may not work through sirtuin at all in exerting its beneficial effects on mice. “There are data both for and against that hypothesis, though that doesn’t dissuade one from pursuing it as a potential benefit,” said Dr. Thomas Rando, who studies aging in stem cells at Stanford University.
In initial tests in mice, resveratrol has doubled muscular endurance, lowered the bad form of cholesterol, protected against various bad effects of a high-fat diet and suppressed colon cancer. New reports are confirming some of these benefits, but others are ambiguous or puzzling.
According to a study published on July 3 in the journal Cell Metabolism by Dr. Sinclair and Dr. Rafael de Cabo of the National Institute on Aging, resveratrol given to aging mice reduced their cataracts, strengthened their bones, improved coordination and enhanced their health in several other ways. Yet despite their better health, the mice lived no longer than usual.
“Minimally this calls into question one pillar of the GSK investment,” said Dr. Ronald Evans, a leading expert on hormonal responses at the Salk Institute. Dr. Evans said that sirtuin research was promising but unproved, and that he did not agree that sirtuin was the probable mediator of the famine reflex, a concern that “calls into question the second pillar of the GSK investment.”
The frontiers of science are often turbulent, and it can take years for clarity to emerge from confusion. Dr. Westphal said the decision to ignore the academic debate about exactly how resveratrol may work was one of two principal reasons for Sirtris’s quick success. The other was to focus the company’s limited resources on developing just two drugs.
The researchers at Sirtris are no strangers to skepticism. Dr. Guarente and Dr. Sinclair were ridiculed when they first started looking for longevity genes more than 15 years ago, because aging was then considered to be an intractable problem. His colleagues, Dr. Guarente said, “thought I was nuts.”
Dr. Sinclair, when he first arrived as a young postdoctoral student in Dr. Guarente’s lab to work on longevity, was downcast to learn of the other students’ severe doubts. “The view even in Lenny’s lab was that this problem was going nowhere, it was a house of cards that would fall down any month now.” He called his parents in Australia to tell them he may have made a big mistake. But the research led eventually to the discovery of the sirtuinlike proteins and their role in extending the life span of yeast, worms and flies.
He and Dr. Guarente developed the sirtuin field with the hope of increasing longevity. But because of Sirtris’s focus on developing drugs that have the F.D.A.’s approval for specific diseases, both are being less explicit about their hopes of reversing aging. “There’s a much greater chance of a drug that can treat disease than of extending life span,” Dr. Sinclair said.
“I’m becoming more boring in my old age,” he added apologetically.
GlaxoSmithKline’s press releases refer to the sirtuins as “enzymes that the company believes control the aging process.” But Dr. Vallance is more guarded, saying aging is too hard to measure. The goal is not the extension of human life span; rather, “The prolongation of health is the aim,” Dr. Vallance said.

Gray and Green together: Older adults can play role in creating healthier environment

23 july 2008--Volunteering for environmental protection activities can be physically and mentally sustaining for older people, according to the latest issue of Public Policy & Aging Report (PPAR). In fact, this demographic group is in a unique position to have a noticeable impact on its surroundings.
For those looking to fill meaningful roles in the community after retirement, volunteerism provides opportunities for social integration. The programs of environmental organizations routinely bring together people of different generations. Many of these involve healthy physical activity, such as the testing of rivers or clean up of natural areas, for example.
"Citizen involvement on a large scale is needed to address pressing issues of environmental conservation and sustainability," state authors Karl Pillemer, PhD, and Linda P. Wagenet, PhD, of Cornell University. In one of this PPAR's four articles, they examine the prospects and promise for what the two call "environmental volunteerism and civic engagement" (EVCE) among older persons and point to some directions for encouraging this movement.
The ongoing increase in the number of older U.S. citizens, coupled with a senior population seeking meaningful participation in society, can greatly serve environmental protection efforts.
Even the U.S. government has begun to tap this resource. For over five years, the Environmental Protection Agency's Aging Initiative has provided opportunities for older adults to become environmental stewards in their own communities.
Additionally, older people are beginning to develop a more complex relationship with their surroundings. Public health research suggests there are a number of environmental problems that disproportionately compromise the health of the older population. This group is particularly vulnerable to the adverse effects of air pollution, temperature extremes, and major weather events. America's elder citizens are also beginning to have a greater effect on the environment - through greater recreational travel, an increase in pharmaceutical waste, and the growth of independent and assisted living facilities.
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This issue of PPAR, published by The National Academy on an Aging Society, is titled "Gray and Green Together" and can be purchased at http://www.agingsociety.org.
The National Academy on an Aging Society is the policy institute of The Gerontological Society of America, the nation's oldest and largest multidisciplinary organization devoted to research, education, and practice in the field of aging. The principal mission of the Society — and its 5,000+ members — is to advance the study of gerontology and disseminate information among scientists, decision makers, and the general public.

Tuberculosis presents major challenges to HIV treatment in developing countries

23 july 2008--Human immunodeficiency virus (HIV) care and treatment programs in resource-limited settings must aggressively address tuberculosis (TB) and the emerging multidrug-resistant TB epidemic to save patient lives and to curb the global TB burden, a major cause of death for persons with HIV, according to an article in the July 23/30 issue of JAMA.
Tuberculosis is a threat throughout the course of HIV disease. "As HIV care expands further, there is both an opportunity and necessity for incorporation of TB control activities into these programs. Tuberculosis programs simply do not have the capacity to provide ongoing TB screening, prevention, and treatment for millions of individuals receiving HIV care," the authors write.
Diane V. Havlir, M.D., of the University of California, San Francisco, and colleagues examined interactions between HIV and TB for HIV care programs and the framework for HIV programs to incorporate TB activities, and global progress in implementation.
The authors write that TB poses numerous challenges, including drug-resistance; difficulty in diagnosis and treatment in HIV-infected persons; and complications from drug interactions. "Finding and treating TB cases, administering antiretroviral therapy (ART) and isoniazid preventive therapy [IPT; an antibacterial drug], and infection control are critical activities to incorporate into HIV care programs, the first chronic care models to emerge in many developing countries. Because patients with HIV are at risk for TB throughout life, activities should be ongoing in pediatric and adult ART clinics, pre-ART clinics (keeping relatively healthy patients engaged in care), and maternal health programs."
The authors propose several strategic approaches to reduce TB burden for HIV care and treatment programs. They include:
TB Intensified Case Finding - Finding and treating TB promptly is the most effective TB control measure. Intensified case finding includes both active identification of TB among patients with HIV in care and screening their household members for active TB.
Treating Individuals With Active TB – The authors propose expansion of a care model whereby TB is treated by HIV programs. HIV care staff are trained to diagnose and treat a wide array of infections associated with HIV disease. "Tuberculosis should be no exception."
Isoniazid Preventive Therapy - HIV programs may need to work with country policymakers to permit IPT administration, which in some countries is either against national policy or impossible because of the stringent requirements for the exclusion of TB before IPT initiation.
Antiretroviral Therapy - ART is one of the most powerful weapons against TB. From the perspective of TB prevention, the earlier that ART is initiated, the less the risk for TB.
TB Infection Control - One of the most challenging areas in TB infection control is the implementation of measures in both outpatient and inpatient health care facilities that will reduce the risk of TB transmission and protect health care workers. Tuberculosis infection control guidelines exist but are rarely implemented.
TB Recording and Reporting - It is essential that HIV care programs adhere to TB reporting requirements. Standardized recording and reporting formats in accordance with national TB and AIDS control guidelines should be used.
Joint HIV/TB Planning - The successful implementation of TB interventions in HIV services requires effective communication, coordination, and collaboration with TB control programs.
"HIV care programs must take a bold approach to TB prevention, diagnosis, and treatment to successfully address the catastrophic and intersecting epidemics of HIV and TB. HIV programs need to take advantage of new earmarked funds for HIV/TB activities from agencies such as PEPFAR and the Global Fund to Fight HIV, TB, and Malaria. They must push for access for rapid TB diagnostic tests, conduct operational research, and launch educational efforts in partnership with the community to reduce TB transmission. Shortages in the health care workforce and laboratory capabilities clearly represent the greatest obstacles. However, the possibility for progress has never been greater with the global commitment to health care infrastructure strengthening geared toward consolidating the momentum through disease-specific efforts such as HIV and TB," the authors conclude.
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(JAMA. 2008;300[4]:423-430. Available pre-embargo to the media at www.jamamedia.org)

Viagra helps depressed women: study

CHICAGO , 22 july 2008-- The erectile dysfunction drug Viagra has proven effective at combating sexual dysfunction in depressed women, according to a study published Tuesday.
Sexual dysfunction is a common side effect of antidepressants and a major reason why people stop taking medication for their depression.
This is particularly problematic given that twice as many women as men are prescribed antidepressants but the most effective drugs used to combat sexual dysfunction in men are not approved for use in women, the authors wrote.
Researchers tested Viagra on 98 women whose depression was in remission but were still experiencing sexual dysfunction such as lack of arousal or pain during sex.
The women were told to take a pill one to two hours before sex for eight weeks. Half were given placebos pills which had no pharmacological effects.
Some 73 percent of the women given placebos reported no improvement with treatment while only 28 percent of the women taking Viagra said they did not notice an improvement, the study published in the Journal of the American Medical Association found.
Some of the women experienced headaches, flushing and indigestion but none of them withdrew from the trial because of side effects.
"By treating this bothersome treatment-associated adverse effect in patients who have been effectively treated for depression, but need to continue on their medication to avoid relapse or recurrence, patients can remain antidepressant-adherent, reduce the current high rates of premature medication discontinuation, and improve depression disease management outcomes," wrote lead author George Nurnberg of the University of New Mexico School of Medicine.