Study: Cognitive Training Shows Staying Power

   (NIH) - 1/16/2014 - Training to improve cognitive abilities in older people lasted to some degree 10 years after the training program was completed, according to results of a randomized clinical trial supported by the National Institutes of Health.
   The findings showed training gains for aspects of cognition involved in the ability to think and learn, but researchers said memory training did not have an effect after 10 years.
   The report, from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study, appears in the January 2014 issue of the Journal of the American Geriatrics Society. The project was funded by the National Institute on Aging (NIA) and the National Institute of Nursing Research (NINR), components of the NIH.
   “Previous data from this clinical trial demonstrated that the effects of the training lasted for five years,” said NIA Director Richard J. Hodes, M.D. “Now, these longer term results indicate that particular types of cognitive training can provide a lasting benefit a decade later. They suggest that we should continue to pursue cognitive training as an intervention that might help maintain the mental abilities of older people so that they may remain independent and in the community.”
   “ACTIVE is an important example of intervention research aimed at enabling older people to maintain their cognitive abilities as they age,” NINR Director Patricia Grady said. “The average age of the individuals who have been followed over the last 10 years is now 82. Given our nation’s aging population, this type of research is an increasingly high priority.”
   The original 2,832 volunteers for the ACTIVE study were divided into three training groups — memory, reasoning and speed-of-processing — and a control group. The training groups participated in 10 60- to 70-minute sessions over five to six weeks, with some randomly selected for later booster sessions. The study measured effects for each specific cognitive ability trained immediately following the sessions and at one, two, three, five and 10 years after the training.
   The investigators were also interested in whether the training had an effect on the participants’ abilities to undertake some everyday and complex tasks of daily living. They assessed these using standardized measures of time and efficiency in performing daily activities, as well as asking the participants to report on their ability to carry out everyday tasks ranging from preparing meals, housework, finances, health care, using the telephone, shopping, travel and needing assistance in dressing, personal hygiene and bathing.
   At the end of the trial, all groups showed declines from their baseline tests in memory, reasoning and speed of processing. However, the participants who had training in reasoning and speed of processing experienced less decline than those in the memory and control groups. Results of the cognitive tests after 10 years show that 73.6 percent of reasoning-trained participants were still performing reasoning tasks above their pre-trial baseline level compared to 61.7 percent of control participants, who received no training and were only benefiting from practice on the test. This same pattern was seen in speed training: 70.7 percent of speed-trained participants were performing at or above their baseline level compared to 48.8 percent of controls. There was no difference in memory performance between the memory group and the control group after 10 years.
   Participants in all training groups said they had less difficulty performing the everyday tasks compared with those in the control group. However, standard tests of function conducted by the researchers showed no difference in functional abilities among the groups.
   “The speed-of-processing results are very encouraging,” said Jonathan W. King, Ph.D., program director for cognitive aging in the Division of Behavioral and Social Research at NIA and co-author. “The self-reported improvements in daily function are interesting, but we do not yet know whether they would truly allow older people to live independently longer; if they did, even a small effect would be important, not only for the older adults, but also for family members and others providing care.”
   The ACTIVE study followed healthy, community-dwelling older adults from six cities — Baltimore; Birmingham, Ala.; Boston; Detroit; State College, Pa.; and Indianapolis. The participants averaged 74 years of age at the beginning of the study and 14 years of education, 76 percent were female, 74 percent were white and 26 percent were African-American. The 10-year follow-up was conducted with 44 percent of the original sample between April 1998 and October 2010.
   The ACTIVE study was conducted by the following investigators:

• George W. Rebok, Ph.D., Johns Hopkins University, Baltimore
• Karlene Ball, Ph.D., University of Alabama at Birmingham
• Michael Marsiske, Ph.D., University of Florida, Gainesville
• John N. Morris, Ph.D., and Richard N. Jones, Sc.D., Hebrew Senior Life, Boston
• Sharon L. Tennstedt, Ph.D., New England Research Institutes, Watertown, Mass.
• Frederick W. Unverzagt, Ph.D., Indiana University School of Medicine, Indianapolis
• Sherry L. Willis, Ph.D., University of Washington, Seattle

   The National Institute of Nursing Research (NINR) supports basic and clinical research that develops the knowledge to build the scientific foundation for clinical practice, prevent disease and disability, manage and eliminate symptoms caused by illness, and enhance end-of-life and palliative care. See: http://www.ninr.nih.gov. For more information on research, aging, and health, go to http://www.nia.nih.gov.

Weight Loss, Type 2 Diabetes Risk Questioned

   (NIH) - 10/21/2012 - An intensive diet and exercise program resulting in weight loss does not reduce cardiovascular events such as heart attack and stroke in people with longstanding type 2 diabetes, according to a study supported by the National Institutes of Health.
   The Look AHEAD (Action for Health in Diabetes) study tested whether a lifestyle intervention resulting in weight loss would reduce rates of heart disease, stroke, and cardiovascular-related deaths in overweight and obese people with type 2 diabetes, a group at increased risk for these events.
   Researchers at 16 centers across the United States worked with 5,145 people, with half randomly assigned to receive an intensive lifestyle intervention and the other half to a general program of diabetes support and education. Both groups received routine medical care from their own health care providers.
   Although the intervention did not reduce cardiovascular events, Look AHEAD has shown other important health benefits of the lifestyle intervention, including decreasing sleep apnea, reducing the need for diabetes medications, helping to maintain physical mobility, and improving quality of life. Previous Look AHEAD findings are available at www.lookaheadtrial.org.
   "Look AHEAD found that people who are obese and have type 2 diabetes can lose weight and maintain their weight loss with a lifestyle intervention," said Dr. Rena Wing, chair of the Look AHEAD study and professor of psychiatry and human behavior at Brown University. "Although the study found weight loss had many positive health benefits for people with type 2 diabetes, the weight loss did not reduce the number of cardiovascular events."
   Data are currently being analyzed to fully understand the cardiovascular disease results. Investigators are preparing a report of the findings for a peer-reviewed publication.
   Few, if any, studies of this size and duration have had comparable success in achieving and maintaining weight loss. Participants in the intervention group lost an average of more than 8 percent of their initial body weight after one year of intervention. They maintained an average weight loss of nearly 5 percent at four years, an amount of weight loss that experts recommend to improve health. Participants in the diabetes support and education group lost about 1 percent of their initial weight after one and four years.
   In September, the NIH stopped the intervention arm, acting on the recommendation of the study’s data and safety monitoring board. The independent advisory board, charged with monitoring the study data and safety of participants, found that the intensive lifestyle did no harm but did not decrease occurrence of cardiovascular events, the primary study goal. At the time, participants had been in the intervention for up to 11 years.
   Because there was little chance of finding a difference in cardiovascular events between the groups with further intervention, the board recommended stopping the intensive lifestyle intervention, but encouraged the study to continue following all Look AHEAD participants to identify longer-term effects of the intervention.
  "The intervention group did not have fewer cardiovascular events than the group receiving general diabetes support and education, but one positive factor we saw was that both groups had a low number of cardiovascular events compared to previous studies of people with diabetes," said Dr. Mary Evans, director of Special Projects in Nutrition, Obesity, and Digestive Diseases within the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the study's primary sponsor.
   Type 2 diabetes — affecting nearly 24 million people in the United States alone — has increased in prevalence along with the country's epidemic of overweight and obesity. Cardiovascular diseases are the most common cause of death among people with type 2 diabetes. Look AHEAD is the first study to examine the long-term effects of a lifestyle intervention on major cardiovascular disease events and death in adults with type 2 diabetes.
   "Look AHEAD provides important, definitive information about the long-term health effects of weight loss in people with type 2 diabetes," NIDDK Director Dr. Griffin Rodgers said. "Beyond cardiovascular disease, this study and others have shown many other health benefits of weight loss through improved diet and increased physical activity. For example, for overweight and obese adults at high risk for diabetes, modest weight loss has been shown to prevent or delay developing type 2 diabetes."
   Participants were 45 to 76 years old when they enrolled in the study. Sixty percent of enrollees were women. More than 37 percent were from racial and ethnic minority groups. Researchers are now analyzing data to measure effects of the lifestyle intervention on subgroups, including racial and ethnic groups and people with a history of cardiovascular disease.
  Find more information about the Look AHEAD trial (NCT00017953), including a list of current publications, at www.lookaheadtrial.org. For a list of centers enrolling patients for diabetes or obesity trials, search for keywords "diabetes" or "obesity" at www.clinicaltrials.gov.

   Source: National Institutes of Health release.

Study: Coffee Drinkers Have Lower Risk of Death

   (NIH) - 5/23/2012 - Older adults who drank coffee — caffeinated or decaffeinated — had a lower risk of death overall than others who did not drink coffee, according a study by researchers from the National Cancer Institute (NCI), part of the National Institutes of Health, and AARP.
   Coffee drinkers were less likely to die from heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections, although the association was not seen for cancer. These results from a large study of older adults were observed after adjustment for the effects of other risk factors on mortality, such as smoking and alcohol consumption. Researchers caution, however, that they can't be sure whether these associations mean that drinking coffee actually makes people live longer. The results of the study were published in the May 17, 2012 edition of the New England Journal of Medicine.
   Neal Freedman, Ph.D., Division of Cancer Epidemiology and Genetics, NCI, and his colleagues examined the association between coffee drinking and risk of death in 400,000 U.S. men and women ages 50 to 71 who participated in the NIH-AARP Diet and Health Study. Information about coffee intake was collected once by questionnaire at study entry in 1995-1996. The participants were followed until the date they died or Dec. 31, 2008, whichever came first.
   The researchers found that the association between coffee and reduction in risk of death increased with the amount of coffee consumed. Relative to men and women who did not drink coffee, those who consumed three or more cups of coffee per day had approximately a 10 percent lower risk of death. Coffee drinking was not associated with cancer mortality among women, but there was a slight and only marginally statistically significant association of heavier coffee intake with increased risk of cancer death among men.
   "Coffee is one of the most widely consumed beverages in America, but the association between coffee consumption and risk of death has been unclear. We found coffee consumption to be associated with lower risk of death overall, and of death from a number of different causes," said Freedman. "Although we cannot infer a causal relationship between coffee drinking and lower risk of death, we believe these results do provide some reassurance that coffee drinking does not adversely affect health."
   The investigators caution that coffee intake was assessed by self-report at a single time point and therefore might not reflect long-term patterns of intake. Also, information was not available on how the coffee was prepared (espresso, boiled, filtered, etc.); the researchers consider it possible that preparation methods may affect the levels of any protective components in coffee.
   "The mechanism by which coffee protects against risk of death — if indeed the finding reflects a causal relationship — is not clear, because coffee contains more than 1,000 compounds that might potentially affect health," said Freedman. "The most studied compound is caffeine, although our findings were similar in those who reported the majority of their coffee intake to be caffeinated or decaffeinated."

   Source: U.S. National Institutes of Health

Institute to Focus on Exploring Genome Function

   (NIH) - 4/25/2012 - The National Human Genome Research Institute (NHGRI), part of the National Institutes of Health, has awarded 10 grants, totaling $10.5 million, to develop revolutionary technologies that will help researchers identify millions of genomic elements that play a role in determining what genes are expressed and at what levels in different cells. These multi-year grants are part of the Encyclopedia of DNA Elements (ENCODE) project, whose aim is to provide the scientific community with a comprehensive catalog of functional genomic elements that will ultimately help explain the role that the genome plays in health and disease.
   "The ENCODE project is providing a Rosetta Stone to understand how the sequence of the human genome forms the words that tell our bodies how to work at the molecular level," said Eric D. Green, M.D., Ph.D., director of NHGRI, which directs and funds the ENCODE project. "By developing more revolutionary technologies for probing genome function, we expect to accelerate these efforts."
   Sequencing the human genome and identifying the small fraction of its bases that directly code for proteins were among the first steps in understanding how the genome functions. But the remaining larger fraction of functional genomic elements continues to be a mystery. In response, NHGRI launched the ENCODE project to identify all the functional elements in the human genome, along with the modENCODE project to identify the functional elements in the fly and worm genomes and a smaller effort examining the mouse genome. These projects have been rapidly releasing data to the research community.
   These ENCODE efforts have collected large amounts of data with a wide variety of cell types, in many cases identifying key functional landmarks. By studying these landmarks, researchers can establish the locations of DNA sequences that perform a variety of essential functions.
   "In an exciting development, researchers are beginning to use the ENCODE catalogs to understand how variation in the DNA sequence might influence diseases such as cancer and autoimmune disorders," said Mike Pazin, Ph.D., a program director for ENCODE in NHGRI's Division of Extramural Research.
   Each person has one genome sequence that is basically the same in all cell types. In contrast, many genomic elements function in only some cell types. As a result, researchers must test many cell types using many different experimental approaches to develop a detailed inventory of the functional elements in the genome. Revolutionary technological improvements are required to discover and test the millions of functional elements and to learn more precisely what they do. Significant advances are also needed to establish whether information about these functional elements can be used in the diagnosis and treatment of disease.
   "The current ENCODE efforts owe a good part of their success to technology development that has occurred over the last decade," said Elise A. Feingold, Ph.D., a program director for ENCODE in NHGRI's Division of Extramural Research. "In addition to the technologies developed through this program, ENCODE has benefitted enormously from advances fostered by NHGRI’s DNA sequencing technology initiative, the $1000 Genome Program."
   The new technology development grants are focused on these areas:
Discovery of functional genomic elements will be addressed by funding projects for a new assay to identify RNA splicing elements, new assays to identify promoters and enhancers, as well as a project to improve assays for identifying functional elements by allowing these assays to work reliably using smaller samples. Splicing is the process that joins RNA copies of gene segments together to form mRNA, the blueprint for the production of proteins.

   Errors in splicing sometimes lead to human disease. Promoters specify the sites in the genome where genes begin and much gene regulation occurs. Enhancers are genomic elements that can turn on expression of nearby and distant genes. Mutations in promoters and enhancers can cause human disease.
   Validation of biological elements will be addressed by funding projects for new methods with improved throughput, and a smaller project to improve accuracy by testing elements in their natural genomic context.
Computational analysis will be addressed by funding projects to predict regulatory protein binding and gene expression based on sequence alone, and to predict chromosomal interactions and link functional elements to their target genes.
   Recipients of the technology development awards are:
  1.  Discovery of Functional Elements

   Christopher Burge, Ph.D.; Massachusetts Institute of Technology, Cambridge, Mass.; $800,000 (over three years); Researchers will develop a new technology to catalog all of the RNA branch points that form in mRNA during splicing.
   Mats Ljungman, Ph.D.; University of Michigan, Ann Arbor; $1,200,000 (over three years); Using bromouridine labeling of RNA, these researchers will develop new assays (BruChase-Seq and BrUV-Seq) to identity promoters and enhancers and to measure mRNA degradation and splicing kinetics.
  Raymond David Hawkins, Ph.D.; University of Washington School of Medicine, Seattle; $460,000 (over two years); These researchers will improve the power of ChIP-seq assays to identify functional elements. ChIP-seq is one of the fundamental assays used in ENCODE to identify the locations in the genome that are attached to a particular protein.
   2. Validating the Biological Role of Functional Elements

   Barak Cohen, Ph.D.; Washington University in St. Louis; $1.1 million (over three years); These investigators will develop a method to test tens of thousands of promoters in primary cells.
  Peggy Farnham, Ph.D.; University of California Davis; $540,000 (over two years); These investigators will test the function of genomic regions that bind large numbers of regulatory proteins. They will precisely remove parts of the genome, and ask how neighboring genes are affected.
   Jason Lieb, Ph.D.; University of North Carolina at Chapel Hill; $1.3 million (over three years); Researchers will develop a method to test tens of thousands of regions of open chromatin for enhancer, promoter, insulator and silencer activity. In cells, the DNA of the genome is associated with proteins to form chromatin. Active regulatory elements in the genome are thought to reside in open chromatin, where the DNA is more exposed.
  Tarjei Sigurd Mikkelsen, Ph.D.; The Broad Institute of MIT and Harvard, Cambridge, Mass.; $1.1 million (over three years); Researchers will test tens of thousands of elements in integrated reporters, for enhancer activity, insulator function and RNA processing regulation. Insulators are elements that form boundaries in the genome, dividing the genome into functionally separated neighborhoods.
  Jay Shendure, M.D., Ph.D.; University of Washington, Seattle; $1.9 million(over three years); These investigators will develop methods to capture or synthesize tens of thousands of regulatory elements, and test them in cell lines and mice. Capture is a technique used to purify particular DNA sequences from a complex mix.
3. Computational Analysis
   Christina Leslie, Ph.D.; Memorial Sloan-Kettering Cancer Center, New York City; $1.6 million (over three years); Investigators will develop new computational approaches to understand cell-specific gene expression programs, modeling cell-specific transcription as a function of chromatin state and transcription factor binding. Though the genome is essentially the same in all cell types, different genes are active in different cell types because different cell types have different regulatory proteins.
   Guo-cheng Yuan, Ph.D.; Dana-Farber Cancer Institute, Boston; $530,000 (over two years); Researchers will develop novel computational methods to characterize chromatin states and predict chromatin interactions from these states. Functional elements that work together are thought to physically interact with each other by looping out parts of the genome that are in between.
   For more information about the ENCODE and modENCODE projects, please visit http://www.genome.gov/10005107.

   Source: National Institutes of Health

NIH Study: Arsenic Turns Stem Cells Cancerous

   (NIH) - 4/7/2011 - Researchers at the National Institutes of Health have discovered how exposure to arsenic can turn normal stem cells into cancer stem cells and spur tumor growth. Inorganic arsenic, which affects the drinking water of millions of people worldwide, has been previously shown to be a human carcinogen. A growing body of evidence suggests that cancer is a stem-cell based disease. Normal stem cells are essential to normal tissue regeneration, and to the stability of organisms and processes. But cancer stem cells are thought to be the driving force for the formation, growth, and spread of tumors.
   Michael Waalkes, Ph.D., and his team at the National Toxicology Program Laboratory, National Institute of Environmental Health Sciences, part of NIH, had shown previously that normal cells become cancerous when they are treated with inorganic arsenic. This new study shows that when these cancer cells are placed near, but not in contact with normal stem cells, the normal stem cells very rapidly acquire the characteristics of cancer stem cells. It demonstrates that malignant cells are able to send molecular signals through a semi-permeable membrane, where cells can't normally pass, and turn the normal stem cells into cancer stem cells.
   “This paper shows a different and unique way that cancers can expand by recruiting nearby normal stem cells and creating an overabundance of cancer stem cells,” Waalkes said. “The recruitment of normal stem cells into cancer stem cells could have broad implications for the carcinogenic process in general, including tumor growth and metastases.”
   This reveals a potentially important aspect of arsenic carcinogenesis and may help explain observances by researchers working with arsenic that arsenic often causes multiple tumors of many types to form on the skin or inside the body. The paper is online in Environmental Health Perspectives.Waalkes' lab started working with stem cells about five years ago. The researchers used a prostate stem cell line, not embryonic stem cells.
   “Using stem cells to answer questions about disease is an important new growing area of research. Stem cells help to explain a lot about carcinogenesis, and it is highly likely that stem cells are contributing factors to other chronic diseases,” Waalkes said.
   Stem cells are unique in the body. They stay around for a long time and are capable of dividing and renewing themselves. “Most cancers take 30 or 40 years to develop,” said Linda Birnbaum, Ph.D., director of NIEHS and NTP. “It makes sense that stem cells may play a role in the developmental basis of adult disease. We know that exposures to toxicants during development and growth can lead to diseases later in life.”
   Next, the laboratory team will look to see if this finding is unique to arsenic or if it is applicable to other organic and inorganic carcinogens.
   Source:  http://www.nih.gov/

Gene Regulator in Brain's Executive Hub Tracked

   (NIH) - 2/5/2012 - For the first time, scientists have tracked the activity, across the lifespan, of an environmentally responsive regulatory mechanism that turns genes on and off in the brain's executive hub. Among key findings of the study by National Institutes of Health scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain's prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth.
   Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make –what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan.
   “Developmental brain disorders may be traceable to altered methylation of genes early in life,” said Barbara Lipska, a scientist in the NIH’s National Institute of Mental Health (NIMH) and lead author of the study. “For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability. Regulation of these genes may be particularly sensitive to environmental influences during this critical early life period.”
   Lipska and colleagues report on the ebb and flow of the human prefrontal cortex's (PFC) epigenome across the lifespan, February 2, 2012, online in the American Journal of Human Genetics.
   “This new study reminds us that genetic sequence is only part of the story of development. Epigenetics links nurture and nature, showing us when and where the environment can influence how the genetic sequence is read,” NIMH Director Thomas R. Insel said.

   In a companion study published last October, the NIMH researchers traced expression of gene products in the PFC across the lifespan. The current study instead examined methylation at 27,000 sites within PFC genes that regulate such expression. Both studies examined post-mortem brains of non-psychiatrically impaired individuals ranging in age from two weeks after conception to 80 years old.
   In most cases, when chemicals called methyl groups attach to regulatory regions of genes, they silence them. Usually, the more methylation, the less gene expression.Lipska's team found that the overall level of PFC methylation is low prenatally when gene expression is highest and then switches direction at birth, increasing as gene expression plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study found that methylation is strongly influenced by gender, age and genetic variation.
   For example, methylation levels differed between males and females in 85 percent of X chromosome sites examined, which may help to explain sex differences in disorders like autism and schizophrenia.
   Different genes — and subsets of genes — methylate at different ages. Some of the suspect genes found to peak in methylation around birth code for enzymes, called methytransferases, that are over-expressed in people with schizophrenia and bipolar disorder. This process is influenced, in turn, by methylation in other genes, as well as by genetic variation. So genes associated with risk for such psychiatric disorders may influence gene expression through methylation in addition to inherited DNA.
   Scientists worldwide can now mine a newly created online database of PFC lifespan DNA methylation from the study. The data are accessible to qualified researchers at:
http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000417.v2.p1. BrainCloud, a web browser application developed by NIMH to interrogate the study data, can be downloaded at http://BrainCloud.jhmi.edu.

   Source: U.S. Department of Health and Human Services.

NIH Study: Caffeine Linked To Estrogen Changes

   (NIH) - 1/29/2012 - Asian women who consumed an average of 200 milligrams or more of caffeine a day — the equivalent of roughly two cups of coffee — had elevated estrogen levels when compared to women who consumed less, according to a study of reproductive age women by researchers at the National Institutes of Health and other institutions.
   However, white women who consumed 200 milligrams or more of caffeine a day had slightly lower estrogen levels than women who consumed less. Black women who consumed 200 milligrams or more of caffeine a day were found to have elevated estrogen levels, but this result was not statistically significant.
   Total caffeine intake was calculated from any of the following sources: coffee, black tea, green tea, and caffeinated soda.
   Findings differed slightly when the source of caffeine was considered singly. Consuming 200 milligrams or more of caffeine from coffee mirrored the findings for overall caffeine consumption, with Asians having elevated estrogen levels, whites having lower estrogen levels, and the results for blacks not statistically significant. However, consumption of more than one cup each day of caffeinated soda or green tea was associated with a higher estrogen level in Asians, whites, and blacks.
   The changes in estrogen levels among the women who took part in the study did not appear to affect ovulation. Studies conducted in animals had suggested that caffeine might interfere with ovulation.
   The study was published online in the American Journal of Clinical Nutrition.
   "The results indicate that caffeine consumption among women of child-bearing age influences estrogen levels," said Enrique Schisterman, Ph.D., of the Division of Epidemiology, Statistics and Prevention Research at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute where some of the research was conducted. "Short term, these variations in estrogen levels among different groups do not appear to have any pronounced effects. We know that variations in estrogen level are associated with such disorders as endometriosis, osteoporosis, and endometrial, breast, and ovarian cancers. Because long term caffeine consumption has the potential to influence estrogen levels over a long period of time, it makes sense to take caffeine consumption into account when designing studies to understand these disorders."
   The study authors noted that 89 percent of U.S. women from 18-34 years of age consume the caffeine equivalent of 1.5 to two cups of coffee a day.
   The study's first author was Karen C. Schliep, Ph. D., M.S.P.H., from the University of Utah, Salt Lake City, who conducted the study during a research appointment at NICHD. Dr. Schliep undertook the research with Dr. Schisterman and colleagues at the University of Utah, the NICHD and the State University of New York at Buffalo.
   More than 250 women from 18 to 44 years old participated in the study between 2005 and 2007. On average, they consumed 90 milligrams of caffeine a day, approximately equivalent to one cup of caffeinated coffee.
   Most of the participants in the study reported to the study clinic one to three times a week for two menstrual cycles. Their visits were scheduled to correspond with specific stages of the menstrual cycle. At the visits, the women reported what they had eaten in the last 24 hours and answered questions about their exercise, sleep, smoking and other aspects of their lifestyle and reproductive hormone levels were measured in blood. The study authors noted that collection of these details during multiple time points across two menstrual cycles produced more precise information about the link between caffeine and hormones than was possible in earlier studies. The researchers also noted that the study participants were more racially diverse than those who took part in previous studies.
   Source: National Institutes of Health news release of  1/26/2012

New Robotic System to Screen 10,000 Chemicals

   (NIH) - 12/13/2011 - A high-speed robotic screening system, aimed at protecting human health by improving how chemicals are tested in the United States, begins today to test 10,000 compounds for potential toxicity. The compounds cover a wide variety of classifications, and include consumer products, food additives, chemicals found in industrial processes, and human and veterinary drugs. A complete list of the compounds is publicly available at www.epa.gov/ncct/dsstox
   Testing this 10,000 compound library begins a new phase of an ongoing collaboration between the National Institutes of Health, the U.S. Environmental Protection Agency, and the U.S. Food and Drug Administration, referred to as Tox21. NIH partners include the National Toxicology Program (NTP), administered by the National Institute of Environmental Health Sciences (NIEHS), and the NIH Chemical Genomics Center (NCGC), part of the NIH Center for Translational Therapeutics (NCTT), housed at the National Human Genome Research Institute (NHGRI).
   “There has never been a compound library like this before,” NIEHS/NTP Director Linda Birnbaum said.
   Birnbaum is especially excited that some of the compounds the NTP has brought forward for testing are mixtures of chemicals. “All of us are exposed to many different chemicals at the same time, not just one chemical at a time,” she said. “These new technologies allow us to more rapidly advance our understanding of not only individual chemicals, but mixtures of chemicals as well.”
   A subset of the NTP portion of the 10,000 compound library will focus on pilot testing several formulations or mixtures of compounds, a priority area for NIEHS/NTP. The library constituents were selected after a thorough analysis of existing scientific studies, more than 200 public chemical databases, and chemical nominations received from internal and external partners. Each test compound will undergo a thorough chemical analysis to verify its identity and determine its purity, concentration, and stability.
   The goal of the testing is to provide results that will be useful for evaluating if these chemicals have the potential to disrupt processes in the human body to an extent that leads to adverse health effects.
   The compounds will be tested in the Tox21 robotic screening system at the NCGC in Rockville, Md. The Tox21 robot, unveiled earlier this year, was purchased with funds provided by the NTP as part of its contribution to the Tox21 partnership.
   “The robot has undergone rigorous testing since it was installed and unveiled earlier this year. It’s ready to start testing this large compound library,” NHGRI Director Eric Green said. “This is a milestone for Tox21, because it will allow us to test chemicals at a rate previously impossible for anyone to do by hand.”
   The development of methods for evaluating chemical toxicity has the potential to revolutionize the assessment of new environmental chemicals and the development of new drugs for therapeutic use.
   “We are happy to contribute NCGC’s pharmaceutical collection of approximately 3,500 compounds of approved and investigational drugs as part of the Tox21 program,” NCTT Scientific Director Christopher Austin said. “Drug toxicity is one of the primary reasons that the development of new drugs fails and approved drugs are removed from the market, and the ability to better predict toxicity would improve the efficiency of drug development enormously.”
   The EPA seeks to understand the molecular basis of such chemicals to better protect human health and that of the environment.
   “The Tox21 partnership integrates revolutionary advances in molecular biology, chemistry, and computer science, to quickly and cost-effectively screen the thousands of chemicals in use today,” said Paul Anastas, assistant administrator of the EPA Office of Research and Development. “The innovative robotics screening technology will generate chemical toxicity data that EPA has never had before.”
   The FDA, also a partner in Tox21, emphasizes the value of this effort for the public. “The Tox21 rapid assessment of drug toxicity can become a powerful safety tool for protecting the American public. It also has the potential to help bring innovative drugs to market by allowing drug developers to identify unsafe candidate drugs early,” said Janet Woodcock, M.D., director of the FDA Center for Drug Evaluation and Research.
  All testing results will be available to the public through NIH and EPA chemical toxicity databases. In addition, NCTT has created a Tox21 chemical inventory browser freely available at http://tripod.nih.gov/tox21chem to provide researchers with additional about the chemicals. For more information about Tox21, visithttp://www.niehs.nih.gov/health/assets/docs_p_z/ntp-tox21.pdf
   The NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit www.niehs.nih.gov. Subscribe to one or more of the NIEHS news lists to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.
   The NTP is an interagency program established in 1978. The program was created as a cooperative effort to coordinate toxicology testing programs within the federal government, strengthen the science base in toxicology, develop and validate improved testing methods, and provide information about potentially toxic chemicals to health, regulatory, and research agencies, scientific and medical communities, and the public.  

   The NTP is headquartered at the NIEHS. For more information about the NTP, visit http://ntp.niehs.nih.gov.

   Source: National Institutes of Health release of December 7, 2011.

Autism Research Data Source Called Largest

   (NIH) - 12/13/2011 - A data partnership between the National Database for Autism Research (NDAR), and the Autism Genetic Resource Exchange (AGRE) positions NDAR as possibly the largest repository to date of genetic, phenotypic, clinical, and medical imaging data related to research on autism spectrum disorders (ASD), according to a recent news release from the National Institutes of Health.

   "The collaboration between AGRE and NDAR exemplifies the efforts of government and stakeholders to work together for a common cause," said Thomas R. Insel, M.D., director of the National Institute of Mental Health, part of NIH. "NDAR continues to be a leader in the effort to standardize and share ASD data with the research community, and serves as a model to all research communities." 

   NDAR is supported by the National Institutes of Health; AGRE is an Autism Speaks program.  NDAR's mission is to facilitate data sharing and scientific collaboration on a broad scale, providing a shared common platform for autism researchers to accelerate scientific discovery. Built around the concept of federated repositories, NDAR integrates and standardizes data, tools, and computational techniques across multiple public and private autism databases. 

   Through NDAR, researchers can access results from these different sources at the same time, using the rich data set to conduct independent analyses, supplement their own research data, or evaluate the data supporting published journal articles, among many other uses. Databases previously federated with NDAR include Autism Speaks' Autism Tissue Program, the Kennedy Krieger Institute's Interactive Autism Network (IAN), and the NIH Pediatric MRI Data Repository. 

   AGRE currently houses a clinical dataset with detailed medical, developmental, morphological, demographic, and behavioral information from people with ASD and their families. Approved NDAR users will have access to data from the 25,000 research participants represented in NDAR, as well as 2,500 AGRE families and more than 7,500 participants who reported their own information to IAN. NDAR is supported by NIMH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, the National Institute of Environmental Health Sciences, and the NIH Center for Information Technology. 

   According to the NIMH, it's mission is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure.

  Source: National Institutes of Health

NIH Grantees Rebut Flu Strain/Tropics Theory

   (NIH) - 11/16/2011 - Influenza researchers have found that flu strains migrate back and forth between different regions of the world, evolving along the way. This is contrary to the common belief that flu strains from the tropics are the source of global seasonal epidemics.
   The research appeared online on Nov. 14 in the Proceedings of the National Academy of Sciences. It was supported in part by the Centers of Excellence for Influenza Research and Surveillance and the Influenza Genome Sequencing Project, funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
   "This study helps us to better understand why the persistence, movement and evolution of flu viruses are complex and largely unpredictable," said NIAID Director Anthony S. Fauci, M.D. "These findings also remind us of the importance of maintaining vigilance in our global influenza surveillance efforts."
   Previous studies had shown that in general, influenza viruses in tropical regions tend to be more varied and circulate year-round rather than seasonally, like flu viruses found in temperate regions with more moderate climates. The prevailing theory had been that tropical areas of the world may be the source of flu viruses from which new seasonal flu strains originate.
   To test this theory, researchers led by Justin Bahl, Ph.D., and Gavin J.D. Smith, Ph.D., of the Duke-National University Graduate Medical School in Singapore, genetically analyzed strains of H3N2 influenza virus, a common cause of seasonal influenza among humans, collected between 2003 and 2006. They sequenced the full genome of 105 flu virus samples from Hong Kong and compared these with H3N2 virus sequences obtained from seven geographic areas with varying climates, including five temperate regions (Australia, Europe, Japan, the United States, and New Zealand) and two tropical regions (Hong Kong and Southeast Asia). The strains were arranged into a phylogenetic, or family, tree, showing the relationships between the strains and how they evolved over time.
   "Earlier genetic studies had looked at H3N2 in a global context and concluded that new strains came from the tropics," said Dr. Bahl. "However, in those studies, a lot of key genetic data from the tropics was missing." This made it difficult to draw a firm conclusion about the origin of new flu strains, he said.
   The researchers found that in temperate regions where flu seasons are relatively short, many new H3N2 virus strains arise every year, but they rarely persist from one season to the next. However, in Hong Kong and Southeast Asia, where flu seasons occur for longer periods of time, strains do persist between seasons.
   Keeping these patterns in mind, the investigators traced the geographical movement of the strains to determine whether new flu strains actually originate in tropical regions. Instead, they found that influenza strains frequently migrate back and forth between tropical and temperate regions, and that the tropical regions were not necessarily the source of new strains.
   In fact, none of the seven temperate and tropical regions they examined was the source of all new H3N2 flu strains in a given year. The migration pattern was more complex. Virus strains moved from one region to several others each year, and flu outbreaks were traced back to more than one source. And although the virus that migrated between Southeast Asia and Hong Kong persisted over time, its persistence was caused by the introduction of virus from the temperate regions. Therefore, the tropical regions did not maintain a source for the annual H3N2 influenza epidemics. Further, in contrast to annual flu epidemics in temperate climates, relatively low levels of genetic diversity among flu strains, and no seasonal fluctuations were found in the tropical regions.
   "We found that the H3N2 influenza virus population is constantly moving between regions, and every region is a potential source for new epidemics," Bahl said. "Regions with more connections to others, such as travel centers, may contribute more to the global diversity of circulating viruses."
   The complexity of the global virus circulation found in the study suggests that efforts to control flu should include region-specific strategies, according to the researchers. In future studies, the researchers intend to examine whether the virus behaves differently in temperate and tropical areas, including regions not included in this analysis, and in places that are more or less connected to the rest of the world.
   The new findings build on earlier influenza virus evolution research funded in part by NIAID
   Source: National Institutes of Health.

Compound Improves Lifespan of Obese Mice

   (NIH) - 8/20/2011 - Researchers have reported that obese male mice treated with a synthetic compound called SRT1720 were healthier and lived longer compared to non-treated obese mice. The experimental compound was found to improve the function of the liver, pancreas and heart in mice.
   The National Institute on Aging (NIA) supported the study, in collaboration with Sirtris, a GlaxoSmithKline company. The study was primarily conducted by the NIA, part of the National Institutes of Health, and is published online in the Thursday, August 18, 2011, issue of Scientific Reports.
   "This study has interesting implications for research on the biology of aging. It demonstrates that years of healthy life can be extended in an animal model of diet-induced obesity by a synthetic compound that modulates a gene pathway associated with aging," said NIA Director Richard J. Hodes, M.D. More research is needed to assess the relevance of these findings in people, Hodes and the researchers noted.
  SRT1720, a patented molecule, has been shown to activate the SIRT1enzyme, part of a class of enzymes called sirtuins. Sirtuins have been previously implicated in aging processes and are thought to contribute to the positive effects of dietary restriction (also known as calorie restriction) in higher organisms, including nonhuman primates.
   In this study, scientists compared the health of 1-year-old, or middle-aged, male mice fed a high-fat diet with a high dose of SRT1720, a low dose of SRT1720 or no SRT1720. Additionally, these mice were compared to a control group of 1-year-old male mice fed a standard diet.
   "As we hypothesized, SRT1720 mimics dietary restriction, moderating many of the harmful effects of the high-fat diet and obesity. Furthermore, we found that the higher dose of the compound had a stronger effect and there were no signs of toxicity from SRT1720 even after 80 weeks of treatment," said study leader and senior author Rafael de Cabo, Ph.D., of the Laboratory of Experimental Gerontology at the NIA.
   Scientists reported changes caused by SRT1720 in the following areas:

•    Lifespan. While all mice on the high-fat diet gained weight, mice treated with SRT1720 had an increased average and maximum lifespan compared to mice on the high-fat diet without SRT1720. From birth, the mice on the higher dose lived an average of 18 percent longer, and the mice on the lower dose lived an average of 4 percent longer than the mice on the high-fat diet without SRT1720. From 56 weeks of age, mean lifespan in low-dose mice increased by 11 percent and in high-dose mice by 44 percent.

•    Liver. Mice treated with SRT1720 had less fat accumulation on their livers compared to non-treated, high-fat-diet mice. Scientists also tested liver function using two measurements. In both tests, mice treated with SRT1720 demonstrated better liver function than non-treated mice on a high-fat diet, but only one test showed the liver of treated mice to have equal function as mice on standard diet. Livers of treated mice were smaller than those from untreated mice on a high-fat diet, although they were still larger than livers of mice on a standard diet. In addition, SRT1720 suppressed liver inflammation and protected mice against cell death in the liver.

•    Pancreas. SRT1720 protected high-fat-diet mice from resistance to insulin, which is often associated with obesity and can precede diabetes. Glucose (blood sugar) measurements were approximately equal for all groups of mice, including mice on a standard diet. Insulin levels were approximately double in mice on the high-fat diet without SRT1720 compared to mice on the standard diet and on a high-fat diet with SRT1720.

•    Heart. High-density lipoprotein (HDL), associated with good cardiovascular health, was highest in mice on a high-fat diet with a high dose of SRT1720, even compared to mice on a standard diet. SRT1720 protected mice against cell death in the heart and suppressed inflammation. All groups of mice on a high-fat diet experienced the same increase in cholesterol, compared to mice on a standard diet.

•    Exercise and oxygen metabolism. Mice on a high-fat diet had higher levels of oxygen consumption during periods typically characterized by less activity. SRT1720 reversed this trend; treated mice had lower resting levels of oxygen. High-fat-diet mice with no or a low dose of SRT1720 were less active than mice on a high dose of SRT1720 or on a standard diet.

•    Genes. SRT1720 suppresses genes typically expressed in mice on a high-fat diet. For example, SRT1720 suppressed genes that are associated with aging in the liver and previously identified as associated with aging in the kidney and brain.

   To verify that the positive health effects caused by SRT1720 were, at least in part, dependent on the Sirt1 pathway, scientists conducted a series of experiments using cell cultures. The researchers also assessed changes to mitochondrial respiration in adult Sirt1-specific knockout mice. The tests showed that SRT1720 did not have an effect in mice or cultures lacking the Sirt1 gene although it did have an effect in mice and cultures with Sirt1.
   While the findings are promising, scientists emphasize the limitations of their research.
   "In mice, SRT1720 reversed many of the health problems associated with a high-fat diet and did not have toxic side effects, but it is too early to know whether these findings could be replicated in other animal models, much less humans," said de Cabo. "The bottom line is that we need much more research before considering     
   SRT1720 or related compounds as a possible treatment for diseases of aging."
   The study was a collaborative effort between the laboratories of de Cabo; James L. Ellis of Sirtris, and David A. Sinclair, Ph.D., co-director of the Glenn Laboratories for Molecular Biology of Aging at Harvard Medical School, Boston and consultant to Sirtris. Researchers from the following institutions also collaborated in the study: University of Pennsylvania School of Medicine, Philadelphia; University of Oklahoma Health Sciences Center, Oklahoma City; Ècole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland; University of Michigan, Ann Arbor; and University of Kentucky, Lexington.
   This research was performed under a Cooperative Research and Development Agreement between the NIA and Sirtris, a GSK company.
   Source: National Institutes of Health

NIH Autism Study Points to Molecular Differences

   (NIH) - 6/9/2011 - Autism blurs the molecular differences that normally distinguish different brain regions, a new study suggests. Among more than 500 genes that are normally expressed at significantly different levels in the front versus the lower middle part of the brain’s outer mantle, or cortex, only eight showed such differences in brains of people with autism, say researchers funded in part by the National Institutes of Health.
   "Such blurring of normally differentiated brain tissue suggests strikingly less specialization across these brain areas in people with autism," explained Daniel Geschwind, M.D., Ph.D., of the University of California, Los Angeles, a grantee of the NIH’s National Institute of Mental Health. "It likely reflects a defect in the pattern of early brain development."  .
   He and his colleagues published their study online May 26, 2011 in the journal Nature. The research was based on postmortem comparisons of brains of people with the disorder and healthy controls.
   In fetal development, different mixes of genes turn on in different parts of the brain to create distinct tissues that perform specialized functions. The new study suggests that the pattern regulating this gene expression goes awry in the cortex in autism, impairing key brain functions.
   "This study provides the first evidence of a common signature for the seemingly disparate molecular abnormalities seen in autism," said NIMH director Thomas R. Insel, M.D. "It also points to a pathway-based framework for understanding causes of other brain disorders stemming from similar molecular roots, such as schizophrenia and ADHD."
   In an earlier study, the researchers showed that genes that turn on and off together at the same time hold clues to the brain’s molecular instructions. These modules of co-expressed genes can reveal genetic co-conspirators in human illness, through what Geschwind and colleagues call "guilt by association." A gene is suspect if its expression waxes and wanes in sync with others in an illness-linked module.
   Using this strategy, the researchers first looked for gene expression abnormalities in brain areas implicated in autism – genes expressed at levels different than in brains of healthy people. They found 444 such differently expressed genes in the cortexes of postmortem brains of people with autism.
   Most of the same genes turned out to be abnormally expressed in the frontal cortex as in the temporal cortex (lower middle) of autistic brains. Of these, genes involved in synapses, the connections between neurons, tended to be under-expressed when compared with healthy brains. Genes involved in immune and inflammatory responses tended to be over-expressed. Significantly, the same pattern held in a separate sample of autistic and control brains examined as part of the study.
   Autistic and healthy control brains were similarly organized -- modules of co-expressed genes correlated with specific cell types and biological functions.
   Yet normal differences in gene expression levels between the frontal and temporal cortex were missing in the modules of autistic brains. This suggests that the normal molecular distinctions — the tissue differences — between these regions are nearly erased in autism, likely affecting how the brain works. Strikingly, among 174 genes expressed at different levels between the two regions in two healthy control brains, none were expressed at different levels in brains of people with autism. An analysis of gene networks revealed two key modules of co-expressed genes highly correlated with autism.
   One module was made up of genes in a brain pathway involved in neuron and synapse development, which were under-expressed in autism. Many of these genes were also implicated in autism in previous, genome-wide studies. So, several different lines of evidence now converge, pointing to genes in this M12 module (see picture below) as genetic causes of autism.
   A second module of co-expressed genes, involved in development of other types of brain cells, was over-expressed in autism. These were determined not to be genetic causes of the illness, but likely gene expression changes related to secondary inflammatory, immune, or possible environmental factors involved in autism.
   This newfound ability to see genes in the context of their positions in these modules, or pathways, provides hints about how they might work to produce illness, according to Geschwind and colleagues. For example, from its prominent position in the M12 module, the researchers traced a potential role in creating defective synapses to a gene previously implicated in autism.
   Follow-up studies should explore whether the observed abnormalities in the patterning of gene expression might also extend to other parts of the brain in autism, say the researchers. The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.
   Source: National Institutes of Health release of June 2, 2011.