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Week Ending FRIDAY January 7, 2011---------News Archive

Happiness and Health

The biology of emotion may teach us how to help people live longer.

A vast scientific literature has detailed how negative emotions harm the body. Serious, sustained stress or fear can alter biological systems in a way that, over time, adds up to “wear and tear” and, eventually, illnesses such as heart disease, stroke, and diabetes. Chronic anger and anxiety can disrupt cardiac function by changing the heart’s electrical stability, hastening atherosclerosis, and increasing systemic inflammation.

Jack P. Shonkoff, Julius B. Richmond FAMRI Professor of Child Health and Development at HSPH and at the Harvard Graduate School of Education, and Professor of Pediatrics at Harvard Medical School, explains that early childhood “toxic stress” - the sustained activation of the body’s stress response system resulting from such early life experiences as chronic neglect, exposure to violence, or living alone with a parent suffering severe mental illness - has harmful effects on the brain and other organ systems. Among these effects is a hair-trigger physiological response to stress, which can lead to a faster heart rate, higher blood pressure, and a jump in stress hormones.

“But negative emotions are only one-half of the equation,” says Laura Kubzansky, HSPH associate professor of society, human development, and health. “It looks like there is a benefit of positive mental health that goes beyond the fact that you’re not depressed. What that is is still a mystery. But when we understand the set of processes involved, we will have much more insight into how health works.”

Kubzansky is at the forefront of such research. In a 2007 study that followed more than 6,000 men and women aged 25 to 74 for 20 years, for example, she found that emotional vitality—a sense of enthusiasm, of hopefulness, of engagement in life, and the ability to face life’s stresses with emotional balance—appears to reduce the risk of coronary heart disease. The protective effect was distinct and measurable, even when taking into account such wholesome behaviors as not smoking and regular exercise.

Research suggests that certain personal attributes—whether inborn or shaped by positive life circumstances—help some people avoid or healthfully manage diseases such as heart attacks, strokes, diabetes, and depression. These include:

Emotional vitality: a sense of enthusiasm, hopefulness, engagement

Optimism: the perspective that good things will happen, and that one’s actions account for the good things that occur in life

Being good at “self-regulation,” i.e. bouncing back from stressful challenges and knowing that things will eventually look up again; choosing healthy behaviors such as physical activity and eating well; and avoiding risky behaviors such as unsafe sex, drinking alcohol to excess, and regular overeating

Among dozens of published papers, Kubzansky has shown that children who are able to stay focused on a task and have a more positive outlook at age 7 report better general health and fewer illnesses 30 years later. She has found that optimism cuts the risk of coronary heart disease by half.

Kubzansky’s methods illustrate the creativity needed to do research at the novel intersection of experimental psychology and public health. In the emotional vitality study, for example, she used information that had originally been collected in the massive National Health and Nutrition Examination Survey, or NHANES, an ongoing program that assesses the health and nutritional status of adults and children in the United States. Starting with the NHANES measure known as the “General Well-Being Schedule,” Kubzansky crafted an adaptation that instead reflected emotional vitality, and then scientifically validated her new measure. Her research has also drawn on preexisting data from the Veterans Administration Normative Aging Study, the National Collaborative Perinatal Project, and other decades-long prospective studies.

In essence, Kubzansky is leveraging gold-standard epidemiological methods to ask new public health questions. “I’m being opportunistic,” she says. “I don’t want to wait 30 years for an answer.”

Some public health professionals contend that the apparent beneficial effects of positive emotions do not stem from anything intrinsically protective in upbeat mind states, but rather from the fact that positive emotions mark the absence of negative moods and self-destructive habits. Kubzansky and others disagree. They believe that there is more to the phenomenon - and that scientists are only beginning to glean the possible biological, behavioral, and cognitive mechanisms.

Previous work supports this contention. In 1979, Lisa Berkman, director of the Harvard Center for Population and Development Studies, co-authored a seminal study of nearly 7,000 adults in Alameda County, California. Participants who reported fewer social ties at the beginning of the survey were more than twice as likely to die over the nine-year follow-up period, an effect unrelated to behaviors such as smoking, drinking, and physical activity. Social ties included marriage, contact with friends and relatives, organizational and church membership.

If scientists proved unequivocally that positive moods improve health, would policymakers act? Some observe that, in the U.S., we define “happiness” in economic terms - the pursuit of material goods. They contend that even an avalanche of research showing that emotional well-being protected health would have no traction in the policy world. Many Americans believe, after all, that people are responsible for their own lives.

But others see direct policy implications. “In public health, it’s important to understand how we can translate guidelines into behavior,” notes Eric Rimm, HSPH associate professor in the Departments of Epidemiology and Nutrition and director of the program in cardiovascular epidemiology. “Seventy to 80 percent of heart attacks in this country occur not because of genetics nor through some mysterious causative factors. It’s through lifestyle choices people make: diet, smoking, exercise. Why are people choosing to do these things? Does mood come into play?”

The toll of toxic stress goes far beyond poorer health for individuals - population-wide, the cost of chronic diseases related to these conditions is enormous. “Imagine if we could enact a policy that would reduce heart disease by just 1 percent,” suggests Shonkoff. “How many billions of dollars and how many lives would that save? Now what if we could also reduce diabetes - which is growing in epidemic proportions - and even stroke?” The point, Shonkoff says, is that society pays a considerable cost for treating chronic diseases in adulthood, and reducing toxic stress early in life may actually get out in front of these diseases to prevent them.

In Laura Kubzansky’s Society and Health Psychophysiology Lab - modest and neutral as the blandest therapy office - volunteers responding to a Craigslist ad for a research study are in for a surprise. First, they are rigged up to a tangle of electrodes, which continuously monitor heart rate, cardiac output, and other measures. A cuff measures blood pressure. Test tube spittoons collect saliva to be tested for stress-related hormones such as cortisol and DHEA.

Then comes the fun. The volunteers must give a five-minute improvised speech on a knotty topic, such as the gasoline tax or welfare reform. Next, they are asked to perform a complicated math exercise, such as counting backward from 2,027 by 13 - swiftly, and with a loud buzzer signaling a faulty calculation, after which they must start over. Two lab assistants occasionally toss off challenging remarks. And the nerve-wracking performance is videotaped.

The experiment gauges the potentially beneficial effects on heart health of oxytocin, a natural hormone that acts as a neurotransmitter and is thought to be both a cause and effect of positive social relationships. Kubzansky manipulates three variables: oxytocin levels, stress, and social support. She administers oxytocin - a prescription drug that cannot be purchased in a conventional drug store - through a nasal spray. She induces stress by asking the volunteers to publicly perform. And she creates social support by having some participants bring an encouraging friend with them, while others are instructed to show up alone.

The experiment is designed to answer several questions: How do the stress-reduction benefits of oxytocin compare to those of social support? Does oxytocin offer the same protective effects in women as in men? Most important, does oxytocin tamp down the damage from toxic stress hormones that course through the body under duress, causing corrosive effects over time?

Kubzansky concedes that psychological states such as anxiety or depression - or happiness and optimism - are forged by both nature and nurture. “They are 40–50 percent heritable, which means you may be born with the genetic predisposition. But this also suggests there is a lot of room to maneuver.” Her “dream prevention”: instill emotional and social competence in children - with the help of parents, teachers, pediatricians, sports coaches, school counselors, mental health professionals, and policy makers - that would help confer not only good mental health but also physical resilience for a lifetime.

Even in adulthood, it’s not too late to cultivate these qualities, she says. While psychotherapy or meditation may work for one person, someone else may prefer faith-based activities, sports, or simply spending time with friends. “My guess is that many of the people who are chronically distressed never figured out how to come back from a bad experience, focus on something different, or change their perspective.”

Drawing on recently compiled data from a nationally representative study of older adults, Kubzansky is beginning to map what she calls “the social distribution of well-being.” She is working with information collected on participants’ sense of meaning and purpose, life satisfaction, and positive mood. By tracking how these measures and health fall out across traditional demographic categories such as race and ethnicity, education, income, gender, and other categories, she hopes to understand in a fine-grained way what it is about certain social environments that confers better frame of mind and better physical health.

The last thing she wants, Kubzansky says, is for her research to be used to blame people for not simply being happier—and therefore healthier. Referring to one of her first major studies, which found a link between worry and heart disease, she said: “My biggest fear was that journalists would pick it up and the headlines would be, ‘Don’t worry, be happy.’ That’s useless. Not everyone lives in an environment where you can turn off worry. When you take this research out of the social context, it has the potential to be a slippery slope for victim blaming.”

Kubzansky, who is married and has two young children, says her work has made her think a lot more about finding balance in her own life. To that end, she says, she recently signed up for a yoga class. She also plays classical piano - both chamber music with friends and solo hours at the keyboard for her own enjoyment.

“When I’m playing piano,” she explains, “I’m in the moment. I’m not worrying or thinking or trying to work out a problem. I’m just doing this thing that takes all my attention.”

That insight is also at the center of her research. “Everyone needs to find a way to be in the moment,” she says, “to find a restorative state that allows them to put down their burdens.”

Sara Rimer is a Boston-based journalist and author. Madeline Drexler is editor of the Review.

IVF Breakthrough Improves Embryo Implantation

A University of Adelaide reproductive biologist has achieved a major breakthrough in IVF technology that is expected to help millions of women around the world who have suffered previous miscarriages after IVF treatment.

Professor Sarah Robertson, an NHMRC Principal Research Fellow and member of the University'sRobinson Institute, has partnered with a Danish company to develop a product which improves IVF embryo implantation rates for some women by up to 40%.

In the world's largest clinical trial on IVF media, Professor Robertson and ORIGIO a/s - a European company specialising in assisted reproductive technologies - have shown for the first time that growth factor molecules are critical to ensuring optimal embryo development.

The resulting product, EmbryoGen, to be released in 2011, contains a signalling molecule called GM-CSF found naturally in the mother's tissues which protects the embryo from stress, making it stronger and more robust in the early implantation period.

The clinical trial, involving 1319 IVF patients exposed to either EmbryoGen or standard IVF embryo media, resulted in an average 20% improvement in embryo implantation rates at 12 weeks for all IVF women whose embryos developed in EmbryoGen. The effect is primarily due to benefits for women who had previously miscarried, who showed an impressive 40% increase in implantation success.

"This is a wonderful advance for couples undertaking IVF, particularly those who have previously lost babies in the first trimester," Professor Robertson says.

It is also the culmination of more than two decades' work for Professor Robertson, who based her PhD on the role of growth factors in healthy pregnancies and then worked with Swedish colleagues to explore applications in IVF embryos.

"This breakthrough has been 20 years in the making," Professor Robertson says. "It's enormously rewarding to see one's basic research translate into practical outcomes that will benefit so many families."

"From day one we went right back to the fundamental biology to see what makes an embryo healthy in its normal environment in the reproductive tract. We discovered that embryo is exposed to growth factor signals from the mother's tissues, which is critical to its optimal development.

"This is a major paradigm shift for reproductive medicine. All of the other ART companies around the world, along with biologists and clinicians in this area, have thought that embryos don't need growth factors.

"We have demonstrated through extensive animal and human clinical trials that the reality is just the opposite. EmbryoGen is not only completely safe and natural - it contains signalling molecules that the embryo expects to find in the mother's body - but our data from animal studies shows that it may also result in IVF babies that are larger and healthier at birth."

Professor Robertson says IVF children are often smaller at birth, sometimes leading to long term effects in later life.

"By adding back this growth factor and protecting the embryo from stress, the result should be babies that are of a similar size to those naturally conceived." The data on the perinatal outcomes will be available later this year.

EmbryoGen will be launched in Europe and the Middle East by mid 2011 and in the USA in late 2012.


THURSDAY January 6, 2011---------News Archive

Predicting Drug Likelihood for Causing Birth Defects

Researchers in the Children's Hospital Boston Informatics Program (CHIP) have created a preclinical model for predicting a drug's teratogenicity (tendency to cause fetal malformations) based on characterizing the genes that it targets.

When pregnant women need medications, there is often concern about possible effects on the fetus. Although some drugs are clearly recognized to cause birth defects (thalidomide being a notorious example), and others are generally recognized as safe, surprisingly little is known about most drugs' level of risk.

A new model for determining drug safety, described in the March 2011 issue of Reproductive Toxicology (published online November, 2010), uses bioinformatics and public databases to profile 619 drugs already assigned to a pregnancy risk class, and whose target genes or proteins are known.

For each of the 7,426 genes targeted, CHIP investigators Asher Schachter, MD, MMSc, MS, and Isaac Kohane, MD, PhD, crunched databases to identify genes involved in biological processes related to fetal development, looking for telltale search terms like "genesis," "develop," "differentiate" or "growth."

The researchers found that drugs targeting a large proportion of genes associated with fetal development tended to be in the higher risk classes. Based on the developmental gene profile, they created a model that showed 79 percent accuracy in predicting whether a drug would be in Class A (safest) or Class X (known teratogen).

For example, the cholesterol-lowering drugs cerivastatin, lovastatin, pravastatin and fluvastatin are all in Class X. All of these drugs also targeted very high proportions of high-risk genes (98 to 100 percent). The anti-coagulant warfarin, also in Class X, had a proportion of 88 percent.

When Schachter and Kohane applied the model to drugs across all risk classes, the proportion of developmental genes targeted roughly matched the degree of known risk (see graph). However, the model needs further validation before Schachter is willing to share actual predictions for specific drugs.

"We don't want to risk misleading pregnant women from taking necessary medicines," he says.

One difficulty in validating the model is that the "known" teratogenicity it's being tested against often isn't known.

Between Class A and Class X are Classes B, C and D, with increasing amounts of risk, but the boundaries between them are based on minimal data. Teratogenic effects may be difficult to spot, since most drugs are taken relatively rarely in pregnancy, some may be taken along with other drugs, and any effects tend to be rare or too subtle to be noted in medical records. Moreover, data from animal testing doesn't necessarily apply to humans.

"A lot of drugs in the middle of the spectrum, and maybe even some in Class A, may cause subtle defects that we haven't detected," says Schachter. "We can't provide a yes/no answer, but we found a pattern that can predict which are riskier."

Given the degree of uncertainty, Schachter and Kohane believe their model may be of interest to drug developers and prescribing physicians, and might provide useful information to incorporate in drug labeling.

"We can now say to patients, 'This drug targets a ton of genes that are involved in developmental processes,'" says Schachter.

Or, conversely, if a young pregnant woman has a heart condition and needs to be treated, physicians may be reassured by a cardiac drug's profile, he adds. "Instead of saying, 'we don't know,' we can now say that the drug is more likely to be safe in pregnancy."

"We have here a prismatic example of the utility of a big-picture, macrobiological approach," says Kohane, director of CHIP. "By combining a comprehensive database of protein targets of drugs and a database of birth defects associated with drugs, we find a promising predictive model of drug risk for birth defects."

The study was funded by a grant from the National Institute of General Medical Sciences.

Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including nine members of the National Academy of Sciences, 12 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 392-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children's visit: Vector Blog.

ADHD Kids' Faulty On-Switch for Concentration

Brain scans of children with attention-deficit/hyperactivity disorder (ADHD) have shown for the first time why people affected by the condition sometimes have such difficulty in concentrating.

The study, funded by the Wellcome Trust, may explain why parents often say that their child can maintain concentration when they are doing something that interests them, but struggles with boring tasks.

Using a 'Whac-a-Mole' style game, researchers from the Motivation, Inhibition and Development in ADHD Study (MIDAS) group at the University of Nottingham found evidence that children with ADHD require either much greater incentives – or their usual stimulant medication – to focus on a task. When the incentive was low, the children with ADHD failed to "switch off" brain regions involved in mind-wandering. When the incentive was high, however, or they were taking their medication, their brain activity was indistinguishable from a typically-developing non-ADHD child.

ADHD is the most common mental health disorder in childhood, affecting around one in 50 children in the UK. Children with ADHD are excessively restless, impulsive and distractible, and experience difficulties at home and in school. Although no cure exists for the condition, symptoms can be reduced by medication and/or behavioural therapy. The drug methylphenidate (more often known by the brand name Ritalin) is commonly used to treat the condition.

Previous studies have shown that children with ADHD have difficulty in 'switching-off' the default mode network (DMN) in their brains. This network is usually active when we are doing nothing, giving rise to spontaneous thoughts or 'daydreams', but is suppressed when we are focused on the task before us. In children with ADHD, however, it is thought that the DMN may be insufficiently suppressed on 'boring' tasks that require focused attention.

The MIDAS group researchers compared brain scans of eighteen children with ADHD, aged between nine and fifteen years old, against scans of a similar group of children without the condition as both groups took part in a task designed to test how well they were able to control their behaviour. The children with ADHD were tested when they were taking their methylphenidate and when they were off their medication. The findings are published in the Journal of Child Psychology and Psychiatry.

While lying in a magnetic resonance imaging (MRI) scanner, which can be used to measure activity in the brain, the children played a computer game in which green aliens were randomly interspersed with less frequent black aliens, each appearing for a short interval. Their task was to 'catch' as many green aliens as possible, while avoiding catching black aliens. For each slow or missed response, they would lose one point; they would gain one point for each timely response.

To study the effect of incentives, the reward for avoiding catching the black alien was then increased to five points, with a five-point penalty incurred for catching the wrong alien.

By studying the brain scans, the researchers were able to show that typically developing children switched off their DMN network whenever they saw an item requiring their attention. However, unless the incentive was high, or they had taken their medication, the children with ADHD would fail to switch off the DMN and would perform poorly. This effect of incentives was not seen in children without ADHD – activity in their DMN was switched off by items requiring their attention regardless of the incentive on offer.

Professor Chris Hollis, who led the study, says: "The results are exciting because for the first time we are beginning to understand how in children with ADHD incentives and stimulant medication work in a similar way to alter patterns of brain activity and enable them to concentrate and focus better. It also explains why in children with ADHD their performance is often so variable and inconsistent, depending as it does on their interest in a particular task."

Dr Martin Batty, co-author of the study, adds: "Using brain imaging, we have been able to see inside the children's heads and observe what it is about ADHD that is stopping them concentrating. Most people are able to control their 'daydreaming' state and focus on the task at hand. This is not the case with children with ADHD. If a task is not sufficiently interesting, they cannot switch off their background brain activity and they are easily distracted. Making a task more interesting – or providing methylphenidate – turns down the volume and allows them to concentrate."

Dr Elizabeth Liddle, first author of the study, says that these findings help explain one of the interesting characteristics of ADHD – that children with the condition appear able to control themselves much better when motivated to do so.

"The common complaint about children with ADHD is that 'he can concentrate and control himself fine when he wants to', so some people just think the child is being naughty when he misbehaves," says Dr Liddle. "We have shown that this may be a very real difficulty for them. The off-switch for their 'internal world' seems to need a greater incentive to function properly and allow them to attend to their task."


WEDNESDAY January 5, 2011---------News Archive

Enzyme May Explain Symptoms of Preeclampsia

Virginia Commonwealth University School of Medicine (VCU) researchers have found a significant increase of the MMP-1 enzyme in the blood vessels of pregnant women with preeclampsia. This may explain some of its symptoms, including hypertension, swelling and protein in the urine.

The findings could lead to a treatment for pregnant women with preeclampsia, one of the most significant health problems in pregnancy and a leading cause worldwide of both premature births as well as sickness and death of the mother and baby.

Preeclampsia occurs in one out of 20 pregnancies, and is diagnosed when a mother develops high blood pressure and starts spilling protein into her urine after about 20 weeks of pregnancy. Research has shown that the blood vessels of women with preeclampsia are dysfunctional, but the cause of preeclampsia is not known, and the only treatment is delivery of the baby.

In a study published in the January issue of The American Journal of Pathology, the VCU team reported a significant increase in an enzyme called MMP-1 - which is produced in inflammed tissues and acts to break down collagen - in the blood vessels of women with preeclampsia.

"The increase in MMP-1 that we found would compromise the integrity of the mother's blood vessels, which could explain two of the clinical symptoms of preeclampsia – edema and proteinuria," said corresponding author Scott Walsh, Ph.D., professor in the VCU Department of Obstetrics and Gynecology.

The swelling experienced by pregnant women with preeclampsia is due to edema, or leakage of protein out of the blood vessels into surrounding tissues. Proteinuria is a leakage of protein through the blood vessels of the kidney and into the urine.

The team also found that MMP-1 causes blood vessel contraction by activating a receptor known as PAR1, which could explain the hypertension - high blood pressure - of women with preeclampsia.

"This finding may be especially important for preeclampsia because we found increased amounts of PAR1 in blood vessels of preeclamptic women as compared to normal pregnant women. MMP-1 activation of PAR1 is a totally new mechanism to explain hypertension," Walsh said.

PAR1 is best known for its role in the coagulation of blood, but it is not known for a role in hypertension, said Walsh.

The team showed that neutrophils - white blood cells - and neutrophil products increase MMP-1 and PAR1. According to Walsh, neutrophil infiltration may increase the amount of in MMP-1 and PAR1 in blood vessels leading to vessel dysfunction and clinical symptoms of preeclampsia.

"Activation of the PAR1 receptor by MMP-1 causes changes in the endothelial cells of blood vessels that we speculated could result in contraction of blood vessels. This new information provides a rationale for the use of PAR1 inhibitors to treat preeclampsia," said Walsh.

This work was supported by grants from the National Heart, Lung and Blood Institute, the National Center on Minority Health and Health Disparities, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and Fogarty International.

Walsh collaborated with said Jerome F. Strauss, III, M.D., Ph.D., dean of the VCU School of Medicine; Guadalupe Estrada-Guitierrez, Ph.D., Fogarty Scholar with the VCU Department of Obstetrics and Gynecology, and the Instituto Nacional de Perinatologia in Mexico City, Mexico; Renato Cappello, Ph.D., with the VCU Department of Obstetrics and Gynecology; Nikita Mishra Ph.D., with the VCU Department of Obstetrics and Gynecology and Physiology and Biophysics; Roberto Romero, Ph.D., Chief Perinatology Research Branch, NICHD/NIH, and Department of Obstetrics and Gynecology, Wayne State University/Hutzel Hospital, Detroit.

About VCU and the VCU Medical Center: Virginia Commonwealth University is a major, urban public research university with national and international rankings in sponsored research. Located on two downtown campuses in Richmond, VCU enrolls more than 32,000 students in 211 certificate and degree programs in the arts, sciences and humanities. Sixty-nine of the programs are unique in Virginia, many of them crossing the disciplines of VCU's 13 schools and one college. MCV Hospitals and the health sciences schools of Virginia Commonwealth University compose the VCU Medical Center, one of the nation's leading academic medical centers. For more, see www.vcu.edu.

Pregnant, Constipated? Fruit Fly Gives A Clue

Clues about how the human gut helps regulate our appetite have come from a most unusual source – fruit fly faeces.

Nerve cells in the gut of the Fruit Fly may help us understand intestinal discomfort.Scientists at the University of Cambridge are using the fruit fly to help understand aspects of human metabolism, including why pregnant women suffer from bloating and constipation, and even the link between a low calorie diet and longevity.

Although scientists have known for some time that there are as many as 500 million nerve cells in our gut, the sheer complexity that this presents means that little is known about the different types of nerve cell and their functions.

Now, researchers led by Dr Irene Miguel-Aliaga, with funding from the Wellcome Trust and the Biotechnology and Biological Sciences Research Council, have used the fruit fly, Drosophila melanogaster, to investigate the function of these intestinal neurons. The fly has simpler versions of our nervous and digestive systems, which lend it to genetic manipulation. Their findings are published in the journal Cell Metabolism.

"We reasoned that what comes out of the gut may be able to tell us about what is going on inside," explains Dr Miguel-Aliaga. "So, we devised a method to extract information about several metabolic features from the flies' faecal deposits – which are actually rather pretty and don't smell bad. Then we turned specific neurons on and off and examined what came out."

Dr Miguel-Aliaga and colleagues found that these intestinal neurons have very important and specialised functions, such as regulating appetite or adjusting intestinal water balance during reproduction.

Female flies in their reproductive stage get constipated – their gut emptying rate is reduced even though they are eating more food; at the same time, they retain more water and the contents of their intestines become more concentrated. The researchers showed that these intestinal changes are triggered by the sex peptide, a hormone that males inject into the female during copulation, which activates of a small group of gut neurons. This shares the same function as the sex hormones found in humans, such as progesterone, oxytocin and oestrogen.

"Humans and fruit flies reproduce in very different ways, yet the associated symptoms of constipation and bloating and their cause – a reproductive hormone – are the same," explains Dr Miguel-Aliaga. "This suggests that this mechanism has been conserved through evolution. These intestinal changes may provide a benefit at a time of high nutritional demand by maximizing nutrient absorption."

The research also provides tantalising clues about the link between calorie intake and longevity. Intestinal changes which help maximize nutrient absorption would likely be active all the time, as they would provide a selective advantage when food is scarce. However, in flies – and possibly in humans – this may come at a cost: a shorter lifespan.

It has been known for some time that when female flies mate and receive the sex peptide, their lifespan shortens. However, this is not caused entirely by the two most obvious effects of this sex peptide, their increased food intake or their laying of many eggs. The explanation, argue the researchers, may lie in the intestinal changes triggered by the sex peptide that lead to constipation and water retention.

"A mechanism that maximises nutrient absorption by slowing the passage of food through the intestine is fine when food is scarce or during reproduction," says Dr Miguel-Aliaga, "but when we are eating a normal diet, constipation may lead to the build up of waste products produced during internal metabolism. Similarly, it could lead to changes in the composition of the gut bacteria, which are essential to regulating metabolism.

"Our research suggests that in addition to paying attention to what we eat, which has been the focus of longevity research, we may also have to consider what our body does with the food and what goes on in our guts."


TUESDAY January 4, 2011---------News Archive

Gene Structure Linked to Developmental Diseases

A team of researchers from Whitehead Institute at the Massachusetts Institute of Technology (MIT), University of Colorado, and University of Massachusetts have discovered the mechanism that controls how genes turn each cell into a specific type.

The protein complexes that generate this genome structure play a pivotal role in regulating gene reading (transcription) and cell fate, and are recognized as involved in multiple developmental diseases.

“I think we have a fundamental new insight into the underlying causes of several neurological and developmental diseases, including Opitz-Kaveggia syndrome, Lujan syndrome and Cornelia de Lange syndrome,” says Whitehead Institute Member Richard Young. “And it comes with a surprising new understanding of the control of genes.”

According to the Young lab’s paper, published online in Nature (August 10, 2010), a DNA loop forms at the beginning of each gene which will enable activation of cell-specific behavior.

This DNA loop will dictate what each cell type, such as skin, nerve, or embryonic stem cells, will do to maintain a specific cell state of being. In order for each gene to be activated, regulatory and gene expression machinery bound to parts of the DNA called the promoter and the enhancer, must come into contact with each other.

This contact is facilitated and maintained by protein complexes called Mediator and Cohesin, and forms a set of DNA loops that is specific to each cell type.

“That’s such a surprise,” says Young, whose lab is deciphering the overall cellular circuitry required to regulate gene expression and cell state. “We thought that a loop of DNA probably formed at the beginning of some genes—it’s an old model—but we didn’t expect that loops are formed by these complexes at active cell-type-specific genes.”

Problems with this DNA loop structure can interfere with the activation of cell-type-specific genes, which can cause the cell to lose its normal state of being. Infact, mutations in the protein complexes Mediator and Cohesin, can cause various developmental syndromes and diseases.

Finding this DNA loop structure in the genome was not the original goal for Michael Kagey, Jamie Newman, and Steve Bilodeau, who are postdoctoral researchers in the Young lab and co-first authors of the Nature paper. While looking for the genes required for embryonic stem cells to maintain their cell state, the trio found that Mediator and Cohesin were located uniquely at active, cell-type-specific genes. Mediator was already known to play some role in gene activation and Cohesin was known to hold chromosomes together.

“We had no idea,” says Newman, “that Mediator and Cohesin form a novel complex that generates stable DNA loops at active cell-type specific genes.”

When the researchers turned off (or "knocked down") Mediator or Cohesin in embryonic stem cells, the cells lost their defined embryonic stem cell state and started turning into other cell types.

“If you lose Mediator or Cohesin function in embryonic stem cells, you can’t maintain proper cell state and inappropriate differentiation occurs” says Bilodeau. “We think this is the underlying problem in patients with Mediator or Cohesin mutations—you have a broad spectrum of developmental defects.”

Cornelia de Lange patients, many of whom have defects in the Cohesin apparatus, have broad developmental defects, including severe intellectual disability, skeletal abnormalities, small stature, and gastrointestinal dysfunction. Patients with mutations in the Mediator apparatus have various neurological deficiencies.

“We hope these new insights into the control of cell-type-specific gene regulation will facilitate development of new therapeutics for patients with Mediator and Cohesin mutations,” says Bilodeau.

This research was supported by the National Institutes of Health (NIH), the Canadian Institutes of Health Research (CIHR), the American Cancer Society, the W. M. Keck Foundation, and Landon and Lavinia Clay.

Richard Young’s primary affiliation is with Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a professor of biology at Massachusetts Institute of Technology.

Full Citation: “Mediator and cohesin connect gene expression and chromatin architecture” Nature, August 19, 2010.

Female Chimps Treat Sticks Like Dolls

The must-have gift for young female chimpanzees this past holiday season might be part of the Christmas tree, not under it.

“We have seen juveniles occasionally carrying sticks for many years, and because they sometimes treated them rather like dolls, we wanted to know if in general this behavior tended to represent something like playing with dolls,” said Professor Richard W. Wrangham.
That’s the finding of scientists at Harvard University and Bates College, who say female chimpanzees appear to treat sticks as dolls, carrying them around until they have offspring of their own. Young males engage in such behavior much less frequently.

The new work by Sonya M. Kahlenberg and Richard W. Wrangham, described in the journal Current Biology and released Monday (Dec. 20), provides the first suggestive evidence of a wild nonhuman species playing with rudimentary dolls, as well as the first known sex difference in a wild animal’s choice of playthings.

The two researchers say their work adds to a growing body of evidence that human children are probably born with their own ideas of how they want to behave, rather than simply mirroring other girls who play with dolls or boys who play with trucks. Doll play among humans could have its origins in object-carrying by earlier apes, the researchers say, suggesting that toy selection is probably not due entirely to socialization.

“In humans, there are robust sex differences in children’s toy play, and these are remarkably similar across cultures,” said Kahlenberg, a lecturer in biology at Bates who conducted the research as a postdoctoral researcher in Wrangham’s group at Harvard. “While socialization by elders and peers has been the primary explanation, our work suggests that biology may also have an important role to play in activity preferences.”

In 14 years of data on chimpanzee behavior at the Kibale National Park in Uganda, Kahlenberg and Wrangham counted more than 100 examples of stick carrying. In many cases, young females weren’t using the sticks for foraging or fighting, as adults sometimes do, or for any other discernible purpose.

Some young chimpanzees carried sticks into their nests to sleep with them, and on one occasion built a separate nest for the stick. The researchers even witnessed the animals playing a version of the “airplane game,” lying on their backs with their “offspring” balanced across their upraised hands.

“We have seen juveniles occasionally carrying sticks for many years, and because they sometimes treated them rather like dolls, we wanted to know if in general this behavior tended to represent something like playing with dolls,” said Wrangham, the Ruth Moore Professor of Biological Anthropology at Harvard. “If the doll hypothesis was right, we thought that females should carry sticks more than males do, and that the chimpanzees should stop carrying sticks when they had their first offspring. We have now watched enough young chimpanzees to test both points.”

Kahlenberg and Wrangham’s observations included a few adult females that carried sticks, but only before they became mothers. Their finding links juvenile play to adult behavior, since female chimpanzees, not males, carry infants more than 99 percent of the time.

“Obviously, in humans there is a huge role for peers, parents, and others to influence a child’s preferences for different kinds of toys, and the same may well be true of chimpanzees,” Wrangham said. “One of the things that makes our finding fascinating is that there is little evidence of anything comparable in other chimpanzee communities, which raises the possibility that the chimpanzees are copying a local behavioral tradition. So this may be a lovely case of biological and social influences being intertwined.”

Kahlenberg and Wrangham’s research was supported by the National Science Foundation, The Leakey Foundation, the National Geographic Society, the Getty Foundation, and the Wenner-Gren Foundation.


MONDAY January 3, 2011---------News Archive

Predicting Chronic Granulomatous Disease Survival

National Institutes of Health (NIH) study could improve care for chronic granulomatous disease.

Investigators at NIH have observed that the survival rate for people with chronic granulomatous disease (CGD), a rare immune deficiency disease, is greatly improved when even very low levels of it's microbe-killing molecules are detected early.

Jaden Dhaliwal was diagnosed with CGD at 23 months of age.
CGD molecules are produced by an enzyme called NADPH oxidase, and can be detected from genetic analysis. Patients who produce the highest levels of superoxide had the highest survival rates, whereas those who produced the lowest levels of superoxide had the lowest survival rates. Without treatment children often die in the first decade of life.

"Advances in treatment of CGD have made it possible for people with this once-fatal disease of early childhood to survive into adulthood; however, the disease remains difficult to manage," says NIAID Director Anthony S. Fauci, M.D. "Having a marker to help predict disease prognosis will enable physicians to recommend treatment options that are more tailored to the needs of individual patients."

The study is available online in the New England Journal of Medicine.

People with CGD have increased susceptibility to infections caused by bacteria such as Staphylococcus aureus, and fungi such as Aspergillus. They can have abscesses in the lungs, liver, spleen, bones or skin. Severe cases can also have tissue masses, called granulomas, obstructing their bowel or urinary tract. CGD affects an estimated 1,200 people in the United States and approximately 25,000 people worldwide.

The disease is caused by inherited mutations in any one of five different genes required by immune cells to make NADPH oxidase. NADPH oxidase in turn makes superoxide, an oxygen-derived molecule that immune cells use to destroy harmful bacteria and fungi.

All CGD patients have impaired superoxide production. Some make a little superoxide, while others make none. The research team found that the level of superoxide production is linked to a mutation in the NADPH oxidase gene. The more superoxide a patient with CGD can make, the less severe the disease and the greater the life expectancy.

Until now, the severity of CGD has been linked only to how people inherit the NADPH oxidase gene mutation.

If people inherit the mutation from each parent, autosomal recessive trait, the disease is generally less severe than in those who inherit the mutation as an X-linked trait on the female sex chromosome. The majority of people with CGD inherit the mutation as an X-linked trait.

For their study, the NIH team tested the level of superoxide production by immune cells isolated from blood samples taken from 287 people with CGD, aged 1 to 64 years old, compared with superoxide production in healthy people. Some tests dated back to 1993, though patients and families affected by CGD have come to the NIH Clinical Center for treatment since the 1970s.

"By precisely measuring superoxide production, we observed that even tiny residual amounts, at levels below what doctors paid attention to in the past, had a significant impact on patient survival," says John Gallin, M.D., director of the NIH Clinical Center, chief of the Clinical Pathophysiology Section of the NIAID Laboratory of Host Defenses, and senior author on the paper.

Treatment of CGD consists of lifelong antibiotics and antifungal medications. Some people also receive injections with interferon-gamma, a protein that can stimulate the immune cells to fight infections.

For people with the most severe forms of CGD, bone marrow transplantation is a treatment option. Hematopoietic stem cell transplantation from a matched donor is curative although not without significant risk.

"We have worked for over three decades with patients with CGD, which at one time was almost entirely fatal, and have seen vast improvements in care and treatment. This work now gives us another tool to help individuals fight this disease" comments Dr. Gallin.

The study was conducted at the NIH Clinical Center and led by researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, and their associated contract labs at SAIC-Frederick Inc.

Additional support for this research was provided by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute, also components of NIH, and SAIC-Frederick Inc.

Gene Variation That Can Lead to Violent Behavior

A multinational research team has found a genetic variant in a brain molecule that contributes to violent behavior with drinking alcohol.

The findings, which include human genetic analyses and gene knockout studies in animals, appear in the Dec. 23 issue of Nature.

"Impulsivity, or action without foresight, is a factor in many pathological behaviors including suicide, aggression, and addiction," explains senior author David Goldman, M.D., chief of the Laboratory of Neurogenetics at the NIH's National Institute on Alcohol Abuse and Alcoholism (NIAAA). "But it is also a trait that can be of value if a quick decision must be made or in situations where risk-taking is favored."

In collaboration with researchers in Finland and France, Dr. Goldman and colleagues studied a sample of violent criminal offenders in Finland. The hallmark of the violent crimes committed by individuals in the study sample was that they were spontaneous and purposeless.

"We conducted this study in Finland because of its unique population history and medical genetics," says Dr. Goldman. "Modern Finns are descended from a relatively small number of original settlers, which has reduced the genetic complexity of diseases in that country. Studying the genetics of violent criminal offenders within Finland increased our chances of finding genes that influence impulsive behavior."

The researchers sequenced DNA of the impulsive subjects and compared those sequences with DNA from an equal number of non-impulsive Finnish control subjects. They found that a single DNA change that blocks a gene known as HTR2B was predictive of highly impulsive behavior. HTR2B encodes one type of serotonin receptor in the brain. Serotonin is a neurotransmitter known to influence many behaviors, including impulsivity.

"Interestingly, we found that the genetic variant alone was insufficient to cause people to act in such ways," notes Dr. Goldman. "Carriers of the HTR2B variant who had committed impulsive crimes were male, and all had become violent only while drunk from alcohol, which itself leads to behavioral disinhibition."

"Discovery of a genetic variant which predicts impulsive behavior under certain conditions in one human population may have much wider implications," says NIAAA Acting Director Kenneth R. Warren, Ph.D. "The interaction with alcohol intoxication is interesting, as is the apparent involvement of a neurotransmitter pathway that has been regarded as important in addictions and other behavior."

The researchers then conducted studies in mice and found that when the equivalent HTR2B gene is knocked out or turned off, mice also become more impulsive. Studies of any alcohol interaction in the knockout mice are ongoing.

Taken together, the findings could lead to a better understanding of some aspects of impulsivity and ultimately may lead to strategies for diagnosing and treating some clinically important manifestations of impulsive behavior. The researchers caution, however, that impulsivity is a complex trait with multiple genetic and environmental causes.

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at www.niaaa.nih.gov .















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