FRIDAY - April 25, 2008------------------------------------------------------News Archive/Return to Today's News Alerts

Preemies Bounce Back From Pain With Cuddling

Research published in the open access journal BMC Pediatrics suggests that very preterm babies, born between 28 and 31 weeks, could benefit from skin-to-skin cuddling with their mother before and during painful procedures such as a heel lance.

Celeste Johnston of McGill University, Montreal, Canada and colleagues have already shown that skin-to-skin contact, known as kangaroo mother care (KMC) helps babies born at 32 to 36 weeks to recover from pain. They hoped to determine whether KMC could reduce pain and aid recovery in even younger preterm babies born at 28 to 31 weeks. It was previously thought that such young babies were not developed enough to benefit from comfort strategies.

They carried out a randomized crossover trial to see whether such babies could bounce back from pain following a heel lance blood test, which involves pricking the baby’s heel to obtain a blood sample. The team asked mothers to hold their babies for 15 minutes prior to and throughout a heel lance procedure. On another occasion the same babies in the trial were treated as normal and simply swaddled in the prone position in the incubator before and after the procedure.

The team was able to assess the babies' pain based on the Premature Infant Pain Profile (PIPP), which takes into account facial expressions, heart rate, and blood oxygen levels. They measured the PIPP just before the heel lance and at 30-second intervals during and after the procedure.

They found that PIPP scores at 90 seconds after the lance procedure were much lower in the KMC babies than in those without skin-to-skin contact. The facial expression of pain was shown less than half the time in the babies treated with KMC.

Babies receiving KMC also recovered from the pain within a couple of minutes, whereas the incubator babies were still suffering at more than three minutes. This delay could make all the difference to the health of a very preterm baby - born before 32 weeks - who needs almost constant incubator care.

"The pain response in very preterm neonates appears to be reduced by skin-to-skin maternal contact," says Johnston, "This response is not as powerful as it is in older preterm babies, but the shorter recovery time using KMC is important in helping maintain the baby's health." Johnston also points out that the approach could also have benefits for the mother whose parental role diminishes while her baby is in intensive care.

Published April 24, 2008, in the online journal BioMed Central: Pediatrics
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How Neurons Generate Movement

When the eye tracks a bird’s flight across the sky, the visual experience is normally smooth, without interruption. But underlying this behavior is a complex coordination of neurons that has remained mysterious to scientists. Now, UCSF researchers have broken ground in understanding how the brain generates this tracking motion, a finding that offers a window, they say, into how neurons orchestrate all of the body’s movements.

The study reveals that individual neurons do not fire independently across the entire duration of a motor function as traditionally thought. Rather, they coordinate their activity with other neurons, each firing at a particular moment in time.

“Scientists have known that neurons that connect to muscles initiate movement in a coordinated fashion. But they have not known how the neurons we are studying – which coordinate these front-line neurons -- commit the brain to move the eyes,”says co-lead author David Schoppik, PhD, who conducted the study while a doctoral candidate in the laboratory of senior author Stephen Lisberger, PhD, at the University of California, San Francisco.

“For decades, scientists have been asking, ‘Do the signals involve a handful of neurons or thousands? What is the nature of the commands?’ The classical understanding has been that one class of neuron is responsible for one movement, such as generating eye movement to the left, and that it remains active across the entire duration of a behavior,” he says.

"The new findings suggest a totally different way of looking at how movement is controlled across time,” says Lisberger, a Howard Hughes Medical Institute Investigator at UCSF, where he is professor of physiology, director of the W.M. Keck Foundation Center for Integrative Neuroscience, and co-director of the Sloan Center for Theoretical Neurobiology.

The findings, the researchers say, could inform efforts to develop neural prosthetics to treat paralysis and motor dysfunctions, such as those resulting from stroke. “The brain’s messages don’t reach the muscles in these conditions,” says Schoppik, “so it’s critical that the drive to these prosthetics reflect what the brain is trying to do to move muscles. Understanding how multiple neurons work together could influence the type of software created to drive these devices.”

The investigation of how neurons give rise to motor behaviorshas been stymied until now, says Schoppik, by the difficulties inherent in studying more than one neuron in action at a time during the course of a behavior. In the current study, the scientists overcame this obstacle in a study of macaque monkeys that had been trained to track a moving object with their eyes.

Basing their approach on two key pieces of information - first, that when a neuron responds to a stimulus there is always a slight variation in its performance, a phenomenon that neuroscientists traditionally refer to as “noise,” and, second, that each attempt of the eye to pursue a moving target is also unique – they proposed that some aspects of neural variation may reflect behavioral variation.

They used this inherent variability as a probe. Using a formula from financial securities market analysis that looks at how individual stocks behave at a given time within the context of fluctuations in the larger financial market, they explored how individual neurons would behave relative to their neighbors.

They compared the deviations from the average spiking activity of single neurons and simultaneous deviations from the mean eye velocity. They also measured the degree to which variation shared across two pairs of concurrently active neurons. The data demonstrated that individual neurons encode different aspects of behavior, controlling eye velocity fluctuations at particular moments during the course of eye movement, while the population of neurons collectively tiles the entire duration of the movement.

The analysis also revealed the strength of correlations in the eye movement predictions derived from pairs of simultaneously recorded neurons, and suggests, the researcher say, either that a small number of neurons are sufficient to drive the behavior at any given time or that many neurons operate collectively at each moment.

The finding, says Lisberger, underscores the importance of recording for more than one neuron at a time. “There is a lot that we can learn from how multiple neurons interact.”

Published April 24, 2008 in the journal Neuron
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AMPK Signaling: Got Food?

Reuben Shaw, assistant professor in the Molecular and Cell Biology Laboratory and the Dulbecco Laboratory for Cancer Research, reports that when mammalian cells sense that glucose and other nutrients are running short, they muffle a cellular protein called raptor, causing cells to slow their growth. Not only do these studies reveal survival strategies likely common to complex and simple organisms alike, but they suggest an extremely intriguing link between cancer and diabetes.

His work centers around a human tumor suppressor named LKB1. Interestingly, LKB1 encodes a threonine kinase that serves to activate a number of downstream kinases, including the AMP-activated protein kinase (AMPK), which is a critical regulator of metabolism, and the par-1/MARK family of kinases that regulate cell polarity. Using mouse and human cells, Shaw and colleagues observed that when cells are kept hungry in a culture dish, the watchdog enzyme AMPK jumps into action and attaches a chemical phosphate group to a target protein named raptor. As a result, raptor, whose job is to cradle a growth-promoting protein called mTOR, is disabled, inactivating mTOR and halting cell division. Cells then safely switch into energy conservation mode until plentiful times return.

Previously, Shaw and others had shown that although AMPK performs a critical growth-slowing function, it takes its orders from a biochemical big boss, the protein LKB1. LKB1 is a so-called tumor-suppressor, meaning that its loss correlates with formation of benign growths, called hamartomas, and some types of malignant lung and colon cancer. Once growth-regulating LKB1 was out of the picture, many of these tumors showed very high levels of unregulated mTOR activity.

Knocking out LKB1 in liver showed that loss of LKB1 led to a complete loss of AMPK activation and severe diabetes-like phenotypes in in the mice. Metformin, one of the most-widely prescribed type-2 diabetes therapeutics in the world, requires LKB1/AMPK signaling in the liver in order to exert a therapeutic benefit. Metformin activates AMPK, suggesting that the LKB1/AMPK pathway is a molecular link between diabetes and cancer. "This circuit could in part explain the increased cancer risk seen in type 2 diabetic patients," says Shaw, noting many are predisposed to breast, prostate or colon cancer.

Published April 24, 2008 in the journal Molecular Cell
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Maternal Gene Flow Out Of Africa

A team of Genographic researchers and their collaborators have published the most extensive survey to date of African mitochondrial DNA (mtDNA). Over 600 complete mtDNA genomes from indigenous populations across the continent were analyzed by the scientists, led by Doron Behar, Genographic Associate Researcher, based at Rambam Medical Center, Haifa, and Saharon Rosset of IBM T.J. Watson Research Center, NY and Tel Aviv University. Analyses of the extensive data presented in this study provide surprising insights into the early demographic history of human populations before they moved out of Africa, illustrating that these early human populations were small and isolated from each other for many tens of thousands of years.

MtDNA, inherited down the maternal line, was used to discover the age of the famous 'mitochondrial Eve' in 1987. This work has since been extended to show unequivocally that the most recent common female ancestor of everyone alive today was an African woman who lived in the past 200,000 years. Paleontology provides corroborating evidence that our species originated on this continent approximately 200,000 years ago.

The migrations after 60,000 years ago that led modern humans on their epic journeys to populate the world have been the primary focus of anthropological genetic research, but relatively little is known about the demographic history of our species over the previous 140,000 years in Africa. The current study returns the focus to Africa and in doing so refines our understanding of early modern Homo sapiens history.

Doron Behar, Rambam Medical Center, Haifa, said: "We see strong evidence of ancient population splits beginning as early as 150,000 years ago, probably giving rise to separate populations localized to Eastern and Southern Africa. It was only around 40,000 years ago that they became part of a single pan-African population, reunited after as much as 100,000 years apart."

Recent paleoclimatological data suggests that Eastern Africa went through a series of massive droughts between 135,000-90,000 years ago. It is possible that this climatological shift contributed to the population splits. What is surprising is the length of time the populations were separate - as much as half of our entire history as a species.

Saharon Rosset, IBM T.J. Watson Research Center, NY and Tel Aviv University, said: "The analysis of such a massive dataset presents statistical and computational challenges as well as great opportunities for discovery of the events that shaped our history and genetic landscape. For example, we can see evidence of a population expansion period starting around 70,000 years ago, perhaps leading to the out of Africa dispersal shortly afterward."

The timing of these events coincides with the onset of the Late Stone Age in Africa, a change in material culture that many archaeologists believe heralds the beginning of fully modern human behavior, including abstract thought and complex spoken language.

Previous studies have shown that while human populations had been quite small prior to the Late Stone Age, perhaps numbering fewer than 2,000 around 70,000 years ago, the expansion after this time led to the occupation of many previously uninhabited areas, including the world beyond Africa.

Published April 24, 2008 in the National Geographic
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THURSDAY - April 24, 2008--------------------------------------------------News Archive/Return to Today's News Alerts

Exercise May Reduce Risk of Preterm Birth

Women who are physically active during pregnancy may lower their chances of delivering prematurely, according to findings from a Danish study,

Using the Danish National Birth Cohort database, Mette Juhl, of the National Institute of Public Health, in Copenhagen, and colleagues analyzed physical activity information reported by 87,232 pregnant women between 1996 and 2002.

Overall, about one-third of the women said they participated in physical exercise, such as swimming, or low-impact leisure time activity such as aerobics, dancing, walking or hiking, bicycling, and yoga during early pregnancy.

Most of these women engaged in such activities for 1 to 2 hours per week, and somewhat fewer reported the same during later pregnancy, the investigators note.

Juhl and colleagues found that women who engaged in swimming or low-impact physical activities while pregnant were less likely to give birth before term than women who did not exercise during pregnancy.

Neither the type of exercise nor the level of exercise altered this association.

In a report in the American Journal of Epidemiology, Juhl and colleagues say their findings confirm the physical activity recommendations from health authorities in Denmark, Norway, Great Britain, and the United States that suggest pregnant women exercise at levels similar to non-pregnant women.

Presented at the February 25, 2008, in the American Journal of Epidemiology
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Eliminating Germline Cells Lengthens Fly Lifespan - And Ours?

New research by Brown University biologists shows that fruit flies live longer when they don’t produce germline stem cells – the cells that create eggs and sperm.

The work suggests a provocative general principle at work: Signals from reproductive tissue directly control lifespan and metabolism in the whole organism. The work, which appears in the Proceedings of the National Academy of Sciences, also offers a first glimpse of how this control in the fly might occur at the molecular level.

“For more than 50 years, scientists have known that there is a link between reproduction and lifespan,” said Thomas Flatt, a postdoctoral research associate in the Department of Ecology and Evolutionary Biology at Brown and the lead author of the research article. “When reproduction is delayed, animals live longer. Why? Our research suggests that signals from the reproductive system can regulate aging in animals – including, possibly, humans.”

The Brown findings follow a seminal discovery made 10 years ago by acclaimed aging biologist Cynthia Kenyon at the University of California, San Francisco. Kenyon found that eliminating germline stem cells in roundworms extended their lifespan.

“We wanted to see if Kenyon’s findings could be duplicated in the fly,” said Marc Tatar, the senior scientist on the project and a professor in the Department of Ecology and Evolutionary Biology. “If so, we’d know that reproductive control of lifespan was a general principle in biology.”

In their experiments, Flatt and Tatar over-activated a gene that controls germline stem cells in flies, a move that eliminated the cells’ production. These sterile flies lived 20 to 50 percent longer than typical flies – results that matched Kenyon’s finding in worms.

Flatt and Tatar speculated that these flies might live longer because they are insensitive to the effects of insulin. Past research at Brown and other universities shows that animals such as flies, worms and mice live longer when they produce or receive less insulin.

Yet, to their surprise, Flatt and Tatar found that when germline cells were eliminated, and flies lived longer, insulin-producing cells in the fly brain actually make more – not less – insulin. These results posed a paradox: How can flies be longer-lived when they’re making more of a life-shortening hormone? When the researchers studied the flies’ tissues, they discovered something intriguing: Even though the brains were making more insulin, the bodies were responding as if there was less insulin present.

Tatar said the team found a possible explanation for the paradox. In reaction to the flies’ brains boosting insulin production, the insects’ gonads – their ovaries or testes – produce a protein that acts like a sponge. This protein binds to the insulin and blocks its signals throughout the body. So the flies respond as if there is low, not high, insulin circulation inside their bodies.

“This suggests that the gonad and the brain are in a synchronized hormonal feedback loop,” Tatar said. “It’s not just the brain affecting the gonad, but also the other way around.”

“We think that in mammals, a similar communication occurs between the brain and the gonad, communication which controls insulin signaling,” Flatt said. “And when insulin signaling is reduced, the body goes into a state of high repair. The body becomes more stress resistant. Tissues protect themselves really well – and that increases longevity.”

Published April 23, 2008 in the Proceedings of the National Academy of Sciences
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Dinosaurs Had No Brown Fat

A team of researchers at New York Medical College has discovered why birds, unlike mammals, lack a tissue that is specialized to generate heat. A paper published April 21, 2008 in the online peer-reviewed journal BMC Biology contains the surprising implication that the same lack of heat-generating tissue may have contributed to the extinction of dinosaurs.

The paper, “The brown adipocyte differentiation pathway in birds: an evolutionary road not taken,” was written by Stuart A. Newman, Ph.D., professor of cell biology and anatomy, Nadejda Mezentseva, a Ph.D. candidate at New York Medical College, and Jaliya Kumaratilake, Ph.D., University of Adelaide, Australia.

Humans, like all mammals, have two kinds of adipose tissue, white fat and brown fat. White fat is used for storing energy-rich fuels, while brown fat generates heat. Hibernating bears have a lot of brown fat, as do human infants, who have much more than adults, relative to their body size. Infants’ brown fat protects them from hypothermia. Clinicians would like to find ways of making adult white fat behave more like brown fat so that we could burn, rather than store, energy.

While most mammals have a key gene called UCP1, which is responsible for the heat-generation function of brown fat, birds do not. The researchers found they could induce a specific type of stem cell in chicken embryos to produce differentiated cells that are structured and behave like brown fat. These chicken cells can even activate a UCP1 gene if presented with one from a mouse.

The ability to produce brown fat evolved in a common ancestor of birds and mammals, but the ability to generate heat was lost in the group that gave rise to birds and lizards after it separated from the mammalian lineage (the researchers found the lizard genome similarly lacks a UCP1 gene). This strongly implies that dinosaurs, which diverged from birds even later than lizards, also lacked brown fat.

Published April 21, 2008 in the journal BMC Biology
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Maternal Diet Before Pregnancy Linked to Child's Gender

A woman's diet at the time of conception could influence whether her child is a girl or a boy, researchers suggest.

Women with the highest energy intake before pregnancy were more likely to have a boy than women with the lowest caloric intake (56% versus 45%), reported Fiona Mathews, D.Phil., of the University of Exeter, and colleagues, online in the Proceedings of the Royal Society B: Biological Sciences.

However, diet during pregnancy had no link with the sex of the baby, they found in the blinded observational study. If a true association, such as skipping breakfast, could account for the small but steady decline in male birth rates in the United States and other developed countries over the past 40 years, they said.

"Determining whether infant sex is 'naturally' influenced by maternal conditions is of direct relevance to the current debate about the artificial selection of the sex of an embryo during fertility treatment and in commercial 'gender clinics'," they added.

Studies have shown that many animals produce more sons when a mother has plentiful resources or is high ranking. The researchers explained this in terms of an evolutionary drive to produce descendants, because "sons are more costly to produce in both the short and long terms than daughters" but can potentially have more offspring.

If women were also able to unconsciously manipulate sex ratios in response to resource availability, then diet before and shortly after conception would be expected to be related to offspring gender, the researchers said. So, they looked at the effect among 740 women who were pregnant for the first time and who had no medical problems, including obesity. The women were recruited from a single general hospital in England at their first clinic visit at about 14-weeks' gestation. These women kept prospective food diaries in early pregnancy and retrospectively reported their usual diet in the year before conception.

Most of the women (661) reported their usual diet later in pregnancy at 16- to 28-weeks' gestation. All women were 'blind' to the sex of their offspring at the time because the hospital policy was to not disclose offspring sex at ultrasound scans.The r Researchers found that diets high in nutrients including protein, fat, vitamin C, folate, and minerals were linked to offspring gender before conception, whereas diets in early and later pregnancy were not.

Women who had the highest energy intake before conception were 1.5 times more likely to have a boy than women who had the lowest. Energy intake was the only factor independently associated with offspring sex in the analysis, although potassium was significant in a stepwise regression. "Thus, an increased prevalence of male fetuses was associated with high maternal nutrient intakes, but not with high-nutrient density," the researchers said.

Among all the individual food items reported on the food frequency questionnaires, breakfast cereal intake before pregnancy was the only one strongly associated with infant sex. Women who ate more than one bowl of cereal a week were 1.87 times more likely to have a boy than those who ate cereal once a week or less. This likely represents a pattern of eating breakfast or not, the researchers said, because cereal is the main food eaten for breakfast in England and is rarely consumed at other times of day.

One potential mechanism could be glucose, which has been seen to favor growth and development of males while inhibiting that of females, they said. "Skipping breakfast extends the normal period of nocturnal fasting, depresses circulating glucose levels and may be interpreted by the body as indicative of poor environmental conditions."

This may be true even for women who are overweight or obese, because glucose levels and other factors are influenced more by recent intake than fat reserves, the researchers said.

Since all of the women in the study were white and never had given birth before, the potentially confounding effects of race and birth order, both of which are associated with sex ratio, were avoided.

Published April 5, 2008 in the Proceedings of the Royal Society B: Biological Sciences
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WEDNESDAY - April 23, 2008------------------------------------------------News Archive/Return to Today's News Alerts

Fetal Exposure to Substance Abuse Changes Brain Structure

Babies born to women who use cocaine, alcohol or tobacco during pregnancy may have brain structure changes that persist into early adolescence, a new U.S. study says.

Researchers at Children's Hospital Boston and the Boston Medical Center used MRI scans to study the brains of 35 children, average age 12, who were exposed to the substances while in the womb.

"We found that reductions in cortical gray matter and total brain volumes were associated with prenatal exposure to cocaine, alcohol or cigarettes," study first author Dr. Michael Rivkin, a neurologist at Children's Hospital Boston, said in a prepared statement.

The more substances a child was exposed to, the greater the reduction in brain volume.

The study, published in the April issue of the journal Pediatrics, is the first to document joint long-term effects of prenatal cocaine, alcohol and tobacco exposure on brain structure, Rivkin said.

Previous studies that documented brain effects of prenatal alcohol exposure were mostly limited to children with fetal alcohol syndrome. Children with that condition were excluded from this new study.

Rivkin noted that his study was too small to find statistically significant effects of single substances after factoring in exposure to other substances, and was also too small to document the effects of different levels of prenatal exposure.

However, Rivkin said the overall findings are highly suggestive, and he and his colleagues would like to continue their research into this important public health matter. It's estimated that more than one million babies born each year in the United States have been exposed to at least one of these substance while in the womb.

Health-care providers should offer pregnant women comprehensive care to help them reduce the use of all harmful substances. And public health campaigns shouldn't ignore the risks of some substances while focusing on others, since the greater the number of total prenatal exposures, the more likely there will be harmful and lasting effects on a baby's developing brain, the study authors said.

Presented at the April 12, 2008, in the journal Pediatrics
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Scientists Discover Mechanism That Can Send Cells On To Cancer

Using a common virus as a tool for investigating abnormal cell proliferation, a team led by scientists at Cold Spring Harbor Laboratory (CSHL) has succeeded in clarifying an intricate series of biochemical steps that shed light on a way that cancer can begin.

The team’s findings are the latest involving adenovirus, a type of virus that causes the common cold in people, but whose genome contains known oncogenes - genes that when expressed can promote cancer under certain conditions.

“Adenovirus carries a number of cooperating genes that modulate cell growth in ways we’re interested in,” said William Tansey, Ph.D., who, along with CSHL professors Scott Lowe, Ph.D., and Gregory Hannon, Ph.D., is one of the team’s co-leaders and corresponding author. Other team members include molecular biologists from Stony Brook University in New York.

The team focused on an adenoviral oncogene called E1A, and E1A protein that it codes for. Said Dr. Tansey, “...adenovirus, a DNA tumor virus - is useful to us.  We use them as you would use a flashlight, to illuminate important processes inside the cell that help us understand what goes awry in oncogenesis.”

Viruses can’t reproduce on their own. It must find a way to enter the nucleus of a living cell and hijack the cell’s reproductive machinery in order to reproduce itself. “It’s not adenovirus itself, but the things it does when it enters a cell, that really interest us,” Dr. Tansey explained.  “By looking, in particular, at the activity of the proteins adenovirus codes for - proteins like E1A - we are tapping into a kind of natural growth-control mechanism.”

Because a tumor virus needs to commandeer the reproductive machinery of a living cell to survive, it must force the host cell to enter the reproductive, or S-phase, of its cycle. Past research has demonstrated that a protein called E2F is central in the process by which S-phase is activated. When the cell is not reproducing, E2F is known to be inhibited by its binding to another protein, called Rb, or retinoblastoma protein.

Recently, it’s been shown that E1A’s cancer-promoting activity is more extensive, involving a gene-regulating protein called p400. Until the CSHL/Stony Brook team published its current paper, no one knew how E1A’s binding with p400 affected the process. Prior studies had shown that when E1A and p400 proteins are bound together, cellular growth control is disrupted into over growth. Why does this potentially oncogenic effect occur? What mechanisms are set in motion by binding these two proteins?

E1A, when present in a cell, binds to p400. That protein then forms a complex with Myc which accounts for Myc’s stability in cells in which E1A is present. Close study showed that “the piece of the E1A protein important for stabilizing Myc was the same piece that bound to p400,” Dr. Tansey said. And just as E1A can pull the Rb protein away from E2F, the ability of E1A to bind p400 - and thus to engage Myc - stabilizes that oncoprotein and opens the door to tumorigenesis.

“We know now that the interaction of E1A and p400 is very important in terms of regulating cell growth in normal and cancer cells,” Dr. Tansey said. “So we’re taking a cue from the history of work on adenoviruses and we’re leaving E1A behind to concentrate on Myc and p400. For us, now, the next step is to learn more about the p400-Myc connection.”

Published April 22, 2008 in the Proceedings of the National Academy of Sciences
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Prenatal Exposure to Smoking May Bring on Early Menopause

Women who were exposed to cigarette smoke prenatally may go through menopause earlier than other women, a study has found.

Researchers found that among more than 4,000 U.S. women followed since the 1970s, those whose mothers had smoked during pregnancy were 21 percent more likely to have gone through menopause at any given age.

The findings suggest that maternal smoking during pregnancy may have a role in "programming" female children's eventual age at menopause, the researchers report in the American Journal of Epidemiology. Dr. William C. Strohsnitter, of Tufts-New England Medical Center in Boston, led the study.

Studies have long shown that women who smoke tend to go through menopause at a younger age. Researchers suspect that this is due to the effects of cigarette smoke on estrogen production or on ovarian follicles, structures that produce a woman's eggs each month. Women are born with a certain number of ovarian follicles, Strohsnitter and his colleagues note in their report, but little is known about the prenatal factors that might influence this number.

To investigate, the researchers used data from a study begun in 1975 to study the effects of prenatal exposure to DES, an oral estrogen that was once prescribed to prevent miscarriages but was later found to be linked to a rare vaginal cancer in young women whose mothers used the hormone. Strohsnitter's team focused on 4,025 study participants who were followed through 2001 and had complete information on their mothers' smoking habits. The women were born between 1939 and 1968.

By 2001, 15 percent of the study participants had gone through menopause. The researchers found that, at any given age, women whose mothers had smoked during pregnancy were more likely to have reached menopause. This remained true even when the researchers accounted for other factors, including the women's own smoking habits and whether they had been exposed to DES in the womb.

It's possible, according to Strohsnitter and his colleagues, that prenatal exposure to tobacco smoke affects the early development of ovarian follicles. However, they write, more studies are needed to understand how prenatal exposures may affect women's reproductive life.

Published March 15, 2008 in the American Journal of Epidemiology
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Fertility Expert Finds Genetic Markers of an Egg’s Maturity

Fertility expert Pasquale Patrizio, M.D. of the Yale School of Medicine has long been interested in understanding why so few human eggs harvested during in vitro fertilization result in pregnancies.

“The two big questions are why so few eggs produce live births and can we one day identify the best one among the many that look alike?’’ Patrizio said. “To do so we needed to understand the genetic make up of eggs first.”

Patrizio, professor of obstetrics and gynecology and director of the Yale Fertility Center, and former Yale colleague Dagan Wells, now at the University of Oxford in the United Kingdom, have shown significant differences in gene activity among eggs at different stages of maturity in their recent paper analysing gene expression in immature eggs, mature eggs developed in culture in the laboratory, and eggs matured in the ovary within their own egg-shell.

They found that eggs matured in culture tend to lack gene activity normally involved in the development of the cytoplasm of the egg, or the area outside the nucleus. They also compiled a list of mRNA-mediated gene expression changes that take place as the eggs matured.

The study is significant for many reasons, say the researchers. First it provides the most comprehensive and detailed information about the genetic make-up of human eggs at different stages of maturity. Second, it provides gene expression profiles that will make it possible to identify eggs with exceptional developmental capacity. Third, it reveals that eggs harvested while still immature and then matured in lab dishes, a practice known as vitro maturation, display significant differences in gene activity when compared to already mature eggs.

The findings of significant differences in the genetic profiles of eggs matured in lab dishes as opposed to eggs matured within the ovary may be a clue that the current culture conditions are suboptimal, and explain the lower pregnancy rates seen with the process of in vitro maturation, Patrizio said. Fertility clinics have started to offer in vitro maturation to some patients because it requires fewer drugs and therefore has fewer side effects such as ovarian hyperstimulation.

“However, the advantage of using fewer days of stimulation and fewer drugs, may be negated by the observation that these eggs are unable to properly complete their maturation process and that important proteins manufactured during in vivo maturation are missing,” Patrizio said.

The results of this study will help researchers develop ways to better culture immature eggs and pave the way to identify which ones might be most likely to lead to live births, he said.

Published April, 2008 in the American Journal of Obstetrics and Gynecology
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TUESDAY - April 22, 2008------------------------------------------------News Archive/Return to Today's News Alerts

Epilepsy Treatment No Obstacle for Breastfeeding

Children exposed to epilepsy drugs in breastmilk had slightly higher cognitive scores at age two than those who were bottlefed, reported Kimford Meador, M.D., of the University of Florida at Gainesville, and colleagues, in the ongoing Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study.

Good evidence from the general population supports a benefit from breastfeeding for immune function and many other outcomes whereas the risks during epilepsy treatment are only theoretical, Dr. Meador said at the American Academy of Neurology meeting here. "My approach has been to encourage women to breastfeed if they want to do that."

However, women should still use caution until the findings are confirmed by other studies, he said. The NEAD study included a limited number of families and only common antiepileptic agents. "It's not definitive, but at least it's a start," he said. "This is a question I am frequently asked by moms." However, there's been virtually no evidence with which to answer this question, he said.

Antiepileptic drugs are known to kill neurons in the developing animal brain, but studies suggested estradiol blocked this apoptosis or cell death process, Dr. Meador said. Breastfeeding was thought to present a unique channel for neurodevelopmental damage because a child is virtually bathed in the mother's estradiol in utero but then not protected by the hormone after birth, he said.

The NEAD study was designed to determine long-term cognitive effects of in utero exposure to the most commonly used antiepileptic drugs. It enrolled American and British women with epilepsy taking monotherapy carbamazepine (Carbatrol, Epitol, Equetro, Tegretol), lamotrigine (Lamictal), phenytoin (Dilantin, Phenytek), or valproate (Depakote, Depakene) during pregnancy. Their children will be tested for neuropsychological effects through age six.

Research had previously reported that the rate of serious adverse events (defined as death or major congenital malformation) differed between drug groups. Lamotrigine was associated with the lowest rate at about 1% whereas valproate was associated with the highest rate at about 20%. Dr. Meador presented data from cognitive testing at age two years on the 187 children still in the study of the original 311 live births, showing that after adjustment for maternal IQ and epilepsy drug dose exposure, cognitive scores were lower for valproate than any of the other drugs studied.

Mental Developmental Index (MDI) scores from the Bayley Scales averaged 84 for valproate-exposed children but 93 to 95 for all other groups. The majority of children were not breastfed (58%), but those who were had better MDI cognitive scores overall and for each individual epilepsy drug exposure group. Dr. Meador concluded that there was no overall deleterious effect from breastfeeding during antiepileptic therapy, but he cautioned that the study was underpowered to look show a difference in the individual drug categories.

Presented at the April 12, 2008, 60th annual American Academy of Neurology Meeting
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Women's Networks Critical to Survival During Hurricane Katrina

More than 1,800 people perished in the wake of Hurricane Katrina in August 2005 - the largest hurricane death toll in the United States since 1928. For the most vulnerable - the urban poor with little money, no transportation and limited resources - Katrina threatened to take everything. According to a University of Missouri researcher, some of those people survived the hurricane because of quick action from key women who, through pre-existing social networks, were able to mobilize for successful evacuation.

Jacqueline Litt, associate professor and chair of the Department of Women's and Gender Studies, found that informal family and community networks coordinated by women are vital in emergency situations. More than 50 people were evacuated from New Orleans, La., through the efforts of two "core anchors," a 58-year-old woman and her daughter, who initiated communication and organization using established familial and social relationships.

"Women in normal times act as the glue for networks," Litt said. "They coordinate networks of care giving, oversee the pooling of resources and know how to find each other. In emergencies, they use those same skills. That pre-existing interdependence, trust and knowledge is what made successful evacuations happen."

Litt concurs with previous research that networks are central to survival in low-income families. The question she hoped to answer in her study was whether those networks crack under the pressure of emergency situations. Litt discovered the networks were successful during the Katrina evacuations for three reasons.

First, government warnings did not appear to carry the same authority as the passing of informal knowledge through trusted network members. Second, women were the key to "pulling together" network ties already embedded in their daily lives. Through those network ties, women had previously been organizing child care and sharing money or job information. Third, the network recognized personal ties and allowed for expansion to include other individuals. For example, one person would not leave another behind.

"The importance of respecting and maintaining family and kin ties in disaster response, something we now see the government had no capacity to do, cannot be overestimated," Litt said. "Any formal disaster planning should take into consideration, in a practical way, not only the existence but the usefulness of these networks. It's the order in the chaos."

Litt's study was based on two years of research on the "Katrina Diaspora" (the flight of storm refugees to other parts of the United States). Litt conducted interviews and attended focus groups with approximately 80 evacuees in mid-Missouri and Baton Rouge, La., examining the significance of women's work in emergency evacuation. Her research will be published in a special issue of the National Women's Studies Association Journal: New Orleans: gender, the meaning of place, and the politics of displacement.

Published in the LSU National Womens Studies Association Journal
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A Mutation that Makes Good Medicine

A genetic mutation might be extending the lives of many African Americans after heart failure by mimicking a common class of drugs called beta blockers. The findings could explain why clinical trials of beta blocker drugs have shown little benefit to African-American patients.

During heart failure, the heart doesn't stop beating but stops pumping blood efficiently. This can be caused by a number of diseases - including diabetes and hypertension. As the heart falters, the body releases adrenaline to keep the organ pumping. Too much adrenaline overworks the heart, and eventually the organ gives out.

Beta blockers halt the over production of adrenaline by blocking adrenaline receptors and slowing the heart rate. But studies suggest that the drugs don't work in many African Americans. Researchers at the University of Maryland, Baltimore, and Washington University in St. Louis, Missouri, took a close look at GRK5, one of the receptor proteins in the heart that responds to adrenaline to figure out what was happening. After sequencing DNA from 96 heart-failure patients, the team found that 40% of African Americans in the study had a mutation in GRK5 called Leu41. Only 2% to 3% of participants of European or Chinese descent had this variant.

They then followed 375 other African-American heart-failure patients with and without the Leu41 mutation until they died or received a heart transplant, an average period of 30 months. Some patients took beta blockers and some didn't. Of those who did, patients with Leu41 had the same survival rate as those without the mutation. But among patients who didn't take beta blockers, those with Leu41 lived almost twice as long as those without the mutation. Reporting online this week in Nature Medicine, the team says it believes the mutation mimics beta blockers, slowing heart rate by blocking GRK5's ability to respond to adrenaline.

"This work suggests that the reason it's been hard to demonstrate a benefit [of beta blockers] in African Americans is that almost half of them are already getting the benefit naturally,” says David Kass, a cardiologist at Johns Hopkins University in Baltimore, Maryland, who was not part of the study.

But that doesn't mean that beta blockers are useless for patients with Leu41, says Gerald Dorn, a senior author of the study and a cardiologist at Washington University School of Medicine. Beta blockers work against several different types of heart disease, so "I'm not willing to say that having the protective gene is equal in every way to beta-blocker therapy."

Published April 20, 2008 in the journal Nature Medicine
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Cancer Cells Spread by Releasing "Bubbles"

A fundamental mechanism of how tumor cells communicate has just been discovered by the team of Dr. Janusz Rak at the Research Institute of the McGill University Health Centre (MUHC) in collaboration with Dr Guha from the University of Toronto.

Cancer cells communicate with their more healthy counter-parts by releasing vesicles - bubble-like structures - containing cancer-causing (oncogenic) proteins that can trigger duplications when they merge into non or less-malignant cells. Findings were published on April 20 in the on-line edition of Nature Cell Biology.

Some brain tumor cells have long been known to express a mutated version of what is called the variant III epidermal growth factor receptor (EGFRvIII). Expressed only in a fraction of tumor cells, EGFRv III has a major impact on the malignancy of the whole tumor. EGFRvIII is an oncogenic mutant of the epidermal growth factor receptor and is implicated in glioma - a tumor of the central nervous system (CNS).

The study shows that the mutated EGFRvIII triggers production of small vesicles that project from the cell membrane carrying mutated copies of EGFRvIII on their surfaces. They have been baptised "oncosomes." Surprisingly oncoproteins are not always confined to the cell that produced them. The study reflects they will migrate until they fuse with another cell, healthy or benign tumor. Oncogenic protein AGFRvIII then becomes integrated in the membrane of the "recipient" cell and starts stimulating specific metabolic pathways to make it act in an aberrant and malignant way. Although this may be a transient event, the changes could impact tumor behaviour by more rapid increases in cell numbers and by stimulation of blood vessel growth, hallmarks of malignant brain tumors.

"With this information we can imagine that many mutant proteins are not necessarily confined to the cells that make them, but rather can migrate and spread around as cargo of oncosomes, a process that could be referred to as formation of the "oncogenic field effect," explained Dr. Rak. "It demonstrates that cancer is a multi-cell process, where the cells talk to one another extensively. This goes against the traditional view that a single 'mutated' cell will simply multiply uncontrollably to the point of forming a tumour. This discovery opens exciting new research avenues, but we also hope that it will lead to positive outcomes for patients."

The presence of oncosomes (containing EGFRvIII or other proteins) in the blood of cancer patients could become a clinical marker that doctors could screen for a tumor's molecular characteristics instead of having to perform invasive surgery or biopsy.

Currently in brain cancer, this very precise assessment cannot be performed without removing the tumor by opening a patient's skull. However, the assay and analysis of oncosomes would potentially require only a small sample of blood or cerebrospinal fluid. This would be a step forward in ensuring patient comfort and choosing the best therapeutic strategy for them, factors key in the journey towards personalized medicine.

Published April 6, 2008 in a letter to the journal Nature Cell Biology
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MONDAY - April 21, 2008-------------------------------------------------News Archive/Return to Today's News Alerts

Too Much Fiber and Too Little Fat Not Good For Toddlers

After a number of years of encouraging people to eat more fresh fruit and vegetables, surprising research from the UK is now warning that too much fibre and too little fat for toddlers is not healthy.

Nutritionists say applying the principles of adult healthy eating to young children can lead to vitamin deficiencies and even stunted growth.

According to consultant paediatric dietician Dr. Sarah Almond, who has analysed the results of a Trading Standards study into nursery food, a diet high in fibre and low in fat, with plenty of fruit and vegetables is unsuitable for toddlers.

Dr. Almond says the expectation was that the research would show nurseries were serving children food that was too high in calories, fat, saturated fat and salt, and low in vegetables and fruit. But in fact the opposite was true and the majority of nurseries had gone to the other extreme and appeared to be providing food that was too low in calories, fat and saturated fat and too high in fruit and vegetables. Such a regime puts children at risk of developing nutritional deficiencies says Dr. Almond.

The research also revealed that most nurseries were serving children portions which were too small and very few provided them with meals containing enough calories. The under-five age group has different and specific nutritional requirements to children of school age because they have a high energy and nutrient requirement.They also have With their small stomachs and relatively under-developed guts, they cannot consume large quantities of food at a time but need frequent small meals and snacks throughout the day.

Too much fibre such as that absorbed through over-consumption of fruit and vegetables can result in insufficient intake of other food groups and inhibit the absorption of key minerals.

Almond says because many children attend nurseries from 7am until 7pm, the food and nutrition they receive there are essential to their health. Unlike school meals, government regulations do not apply to the provision of toddlers' meals and nurseries are only offered general advice such as suggesting childcare agencies refer to the Food Standards Agency for advice on food and nutrition for young children.

Experts say many nurseries are confused or misinformed about what entails healthy eating for the under-five age group and the nutritional content of toddlers' meals is a proper science. They say nurseries are unaware of vital calories, fats, carbohydrate, sugars, fibre, protein, vitamins and minerals and the nutritional requirements for this particular age group.'

Study Released by the East Sussex County Council Trading Standards service of Scotland, February, 2008, titled Nippers' Nutrition
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Ovarian Cancer Stem Cells Identified, Characterized and Cloned

Researchers at Yale School of Medicine have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer’s recurrence and its resistance to chemotherapy.

“These results bring us closer to more effective and targeted treatment for epithelial ovarian cancer, one of the most lethal forms of cancer,” said Gil Mor, M.D., associate professor in the Department of Obstetrics, Gynecology & Reproductive Sciences at Yale School of Medicine. Mor presented his findings recently at the annual meeting of the American Association for Cancer Research (AACR) Meeting in San Diego, California.

Cancerous tumors are made up of cells that are both cancerous and non-cancerous. Within cancerous cells, there is a further subclass referred to as cancer stem cells, which can replicate indefinitely. “Present chemotherapy modalities eliminate the bulk of the tumor cells, but cannot eliminate a core of these cancer stem cells that have a high capacity for renewal,” said Mor, who is also a member of the Yale Cancer Center. “Identification of these cells, as we have done here, is the first step in the development of therapeutic modalities.”

Mor and colleagues isolated cells from 80 human samples of either peritoneal fluid or solid tumors. The cancer stem cells that were identified were positive for traditional cancer stem cell markers including CD44 and MyD88. These cells also showed a high capacity for repair and self-renewal. The isolated cells formed tumors 100 percent of the time. Within those tumors, 10 percent of the cells were positive for cancer stem cell marker CD44, while 90 percent were CD44 negative.

Mor and his team were able to isolate and clone the ovarian cancer stem cells. They found that these cells were highly resistant to conventional chemotherapy while the non-cancer stem cells responded to treatment. “Isolating and cloning these cells will lead to development of new treatments to target and eliminate the cancer stem cells and hopefully prevent recurrence,” said Mor.

Published February 15, 20086 in the journal Clinical Cancer Research
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Boys In Japan/USA Twice as Likely As Girls To Receive Growth Hormone

Boys are twice as likely as girls in the U.S. and Asia (mostly Japan) to receive recombinant human growth hormone (rhGH) for growth hormone deficiency, illnesses that affect height, and short stature of a non-medical nature.

A smaller gender difference exists in Europe, Australia and New Zealand, but in the rest of the world short boys and girls are treated at the same rate. This indicates a likely cultural bias for male height in some countries.

The study, by researchers from The Children's Hospital of Philadelphia and Pfizer, is electronically available prior to publication in the Journal of Clinical Endocrinology and Metabolism. All children entered in the Pfizer International Growth Study (KIGS), a database designed to document long-term outcomes and safety of Genotropin, one of the three leading commercial brands of rhGH, were categorized by gender, location, date and age of therapy initiation, and diagnosis. Measures of national health status, health care expenditures, general economic indices and mean adult heights were also compared. Children were categorized into four geographic regions including the U.S., Europe/Australia/New Zealand, Asia and the "Rest of the World."

Recombinant human growth hormone has been available since 1985. "Because reports found more U.S. males receiving rhGH in its first years of availability, and rhGH use has increased considerably over the past 20 years, we thought it was important to get an up-dated look at the gender-based patterns of use in the U.S. and how they compared to other countries," said Adda Grimberg, M.D., lead author of the study and a pediatric endocrinologist at The Children's Hospital of Philadelphia. "We suspect that social and cultural pressures, combined with financial constraints, contribute to the international differences in the gender distributions of children treated with rhGH."

Historical trends revealed a consistent overall male predominance among U.S. pediatric rhGH recipients at a nearly two-to-one ratio. The gender ratio did not change significantly across the more than 20 years of rhGH use. Males outnumbered females at all ages, especially during the second decade of life. Because boys typically start puberty later than girls and hit their growth spurt at a later stage of puberty, boys who lag behind their peers are more likely to be perceived as having a growth problem.

The factor that most consistently affected the gender distribution was the diagnostic indication for rhGH therapy. The greatest gender disparities occurred for diagnoses without an identifiable cause, such as idiopathic short stature and idiopathic GH deficiency because of the complexity of the diagnostic tests. Prader-Willi syndrome, a genetic disease with multiple benefits from rhGH therapy besides height, was the only indication with gender equality in the U.S. Dr. Grimberg hypothesized, "when the decision to treat involves an indication that relies more heavily on clinical judgment, treatment patterns are more likely to highlight underlying differences in social pressures for tallness."

Comparing the U.S. experience with global patterns revealed that Asia (mostly Japan) had the greatest male predominance at 65 percent, followed closely by the U.S. at 64 percent. Europe/Australia/New Zealand came third at 55 percent. All three world regions exceeded 50 percent males, while the rhGH recipients in the rest of the world regions, where rhGH is used far less frequently, were 47 percent male. Similar to the U.S. data, global gender distributions of rhGH depended on the specific reason the therapy was initiated. The United Kingdom had the lowest male percentage of the top 10 country-based children prescribed Genotropin?.

Dr. Grimberg's earlier research in referral patterns for growth failure evaluations at a U.S. pediatric endocrinology clinic showed a disturbing statistic: that 41 percent of the girls were found to have an underlying disease that made them short, compared to 15 percent of the boys. Conversely, 38 percent of the boys were within normal height ranges, compared to 20 percent of the girls, and boys were referred for evaluation about twice as often as girls.

A variety of diseases may cause growth failure - among them, hormone deficiencies, Turner syndrome (a chromosome abnormality found only in females) and gastrointestinal conditions such as celiac disease or inflammatory bowel disease. For some, growth failure is the only symptom. "Gender differences in the use of rhGH may be indicative of more general gender differences in the diagnostic rates of diseases that present solely with growth failure," cautioned Dr. Grimberg. Not all of these diseases are treated by rhGH. For example, celiac disease is treated with a gluten-free diet. If a short girl is less likely to be perceived as needing rhGH treatment, she may also be less likely to undergo the diagnostic evaluation that reveals her underlying celiac disease.

The manufacture of rhGH in 1985 changed the treatment of pediatric growth failure. Prior to 1985, only children with the most severe growth hormone deficiency were treated because of the very limited supply of human pituitary GH. In 2003, the U.S. Food & Drug Administration (F