Week Ending FRIDAY September 25, 2009-------------------------News Archive / Return to News Alerts

Targeting Auto-Immune Diseases Wins Major Award
Dr. Hilde Cheroutre focuses on specific molecular and genetic events that lead to autoimmune disease, and wants to eventually treat for these diseases - right after birth - to prevent the disease from occurring
"Leaps in knowledge often result from exceptional minds exploring ideas that were considered risky at their inception, especially in the absence of strong supportive data," said an NIH statement describing the Pioneer Awards. "The changing face of biomedical research calls for support of aggressive risk-taking and innovation that will produce tomorrow's conceptual and technological breakthroughs."
With these words, National Institutes of Health (NIH) announced Hilde Cheroutre, Ph.D., as one of the 18 scientists nationwide chosen for the 2009 Pioneer Award prize from more than 2,300 applicants. Her award - $4.7 million - will fund her innovative research proposal that, which if successful, would create a new way of detecting, treating and possibly preventing autoimmune diseases, with the potential for identifying high risk for autoimmunity in newborns.
Dr. Cheroutre's proposal will work toward developing innovative treatment, and even more far-reaching approaches, that might prevent autoimmunity in those susceptible individuals. Autoimmunity occurs when the body's white blood cells mistakenly attack normal cells. This leads to a host of disorders such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis.
"Normally, the immune system provides us protection against pathogens and the generation of transformed cancer cells," said Dr. Cheroutre. "But in autoimmunity, the immune system does not seem to be able to distinguish bad from good cells. It's like the body gets caught in friendly fire. It can cause incredible self-destruction."
If Dr. Cheroutre's premise is correct - and she proves that certain cellular defects underlie autoimmunity - it could allow for early detection of those individuals at high risk. "If true, it would enable us to detect at birth whether an individual is genetically prone to autoimmunity."
The second part of her groundbreaking proposal would then come into play through the development of new therapies that could potentially prevent autoimmunity in those people identified as highly susceptible. Theoretically, similar treatments could also be used for those who have already developed autoimmunity.
"If successful, an individual could be treated very early on right after birth-- to prevent the disease from occurring or they could be closely observed (medically) and the moment they start to show signs of autoimmunity, treatment could begin," said Dr. Cheroutre. "This would enable treatment before autoimmunity starts up and gets out of hand. It is so important to stop or control these diseases before too much damage has occurred. They are kind of like cancer, in that once it gets too far along, it takes a huge toll."
Dr. Cheroutre's bold proposal is not her first venture into unconventional thinking. She is a world renowned expert on mucosal immunity, whose findings over the years have frequently bucked conventional wisdom on the immunology of the intestines or broken new ground in immunology in general. Such was her 2007 discovery that retinoic acid, a vitamin A derivative, can play a critical role in controlling inflammation in the body, which is the chief cause of inflammatory bowel disease, rheumatoid arthritis and several other autoimmune diseases. Nature Medicine named it one of the key biomedical research advances of the year. The finding was a departure from current understanding and opened a new frontier in inflammation research.
Dr. Cheroutre said her proposal is based on logic, reason and previous information she garnered in her studies of the mucosal immune system. "It really is my knowledge from the mucosal immune system, and the mechanisms by which the body chooses to tolerate or attack certain substances, that I used to reason and make this proposal," she said.
Dr. Cheroutre finds the Pioneer award both exhilarating and challenging. "The NIH is giving recipients the chance to explore our most imaginative concepts. It's a once in a lifetime opportunity. I hope that the opportunity given to me with this award will ultimately lead to innovative and advanced knowledge that can help to prevent autoimmunity from occurring and effectively treat those people who already suffer from autoimmune diseases."
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Babies See It Coming
New study shows mobile infants have established neural pathways to see looming danger
Do infants only start to crawl once they are physically able to see danger coming? Or is it that because they are more mobile, they develop the ability to sense looming danger?
According to Ruud van der Weel and Audrey van der Meer, from the Norwegian University of Science and Technology in Trondheim, infants’ ability to see whether an object is approaching on a direct collision course, and when it is likely to collide, develops around the time they become more mobile. Their findings1 have just been published online in the Springer journal Naturwissenschaften.
An approaching object on a collision course projects an expanding image on the retina, providing information that the object is approaching and how imminent the danger is. Looming stimuli create waves of neural activity in the visual cortex in adults. The authors investigated how, and where, the infant brain extracts and processes information about imminent collision.
They used high-density electroencephalography to measure brain activity in 18 five- to eleven-month-old infants, when a growing multicolored dot on a screen (the looming stimulus) approached the infants at three different speeds. The researchers also recorded the gaze of both eyes.
They found that infants’ looming-related brain activity clearly took place in the visual cortex. The more mature infants (ten to eleven months old) were able to process the information much quicker than the younger infants aged five to seven months.
These findings suggest that there are well-established neural networks for registering impending collision in ten- to eleven-month-olds, but not yet in five- to seven-month-olds. For the eight- to nine-month-old infants, they are somewhere in between.
The authors comment: “This could be interpreted as a sign that appropriate neural networks are in the process of being established and that the age of eight to nine months would be an important age for doing so. Coincidentally, this is also the average age at which infants start crawling. This makes sense from a perspective where brain and behavioral development go hand in hand. Namely, as infants gain better control of self-produced locomotion, their perceptual abilities for sensing looming danger improve.”

Children Who Are Spanked Have Lower IQs
Children who are spanked have lower IQs worldwide, including in the United States, according to new groundbreaking research by University of New Hampshire professor Murray Straus
"All parents want smart children. This research shows that avoiding spanking and correcting misbehavior in other ways can help that happen," Straus says. "The results of this research have major implications for the well being of children across the globe."
"It is time for psychologists to recognize the need to help parents end the use of corporal punishment and incorporate that objective into their teaching and clinical practice. It also is time for the United States to begin making the advantages of not spanking a public health and child welfare focus, and eventually enact federal no-spanking legislation," he says.
Straus and Mallie Paschall, senior research scientist at the Pacific Institute for Research and Evaluation, studied nationally representative samples of 806 children ages 2 to 4, and 704 ages 5 to 9. Both groups were retested four years later.
IQs of children ages 2 to 4 who were not spanked were 5 points higher four years later than the IQs of those who were spanked. The IQs of children ages 5 to 9 years old who were not spanked were 2.8 points higher four years later than the IQs of children the same age who were spanked.
"How often parents spanked made a difference. The more spanking the, the slower the development of the child's mental ability. But even small amounts of spanking made a difference," Straus says.
Straus also found a lower national average IQ in nations in which spanking was more prevalent. His analysis indicates the strongest link between corporal punishment and IQ was for those whose parents continued to use corporal punishment even when they were teenagers.
Straus and colleagues in 32 nations used data on corporal punishment experienced by 17,404 university students when they were children.
According to Straus, there are two explanations for the relation of corporal punishment to lower IQ.
First, corporal punishment is extremely stressful and can become a chronic stressor for young children, who typically experience corporal punishment three or more times a week. For many it continues for years. The research found that the stress of corporal punishment shows up as an increase in post-traumatic stress symptoms such as being fearful that terrible things are about to happen and being easily startled. These symptoms are associated with lower IQ.
Second, a higher national level of economic development underlies both fewer parents using corporal punishment and a higher national IQ.
The good news is that the use of corporal punishment has been decreasing worldwide, which may signal future gains in IQ across the globe.
"The worldwide trend away from corporal punishment is most clearly reflected in the 24 nations that legally banned corporal punishment by 2009. Both the European Union and the United Nations have called on all member nations to prohibit corporal punishment by parents. Some of the 24 nations that prohibit corporal punishment by parents have made vigorous efforts to inform the public and assist parents in managing their children. In others little has been done to implement the prohibition," Straus says.
"Nevertheless, there is evidence that attitudes favoring corporal punishment and actual use of corporal punishment have been declining even in nations that have done little to implement the law and in nations which have not prohibited corporal punishment," he says.
Widely considered the foremost researcher in his field, Straus is the co-director of the Family Research Laboratory and professor of sociology at the University of New Hampshire. He has studied spanking by large and representative samples of American parents since 1969. He is the author of "Beating The Devil Out Of Them: Corporal Punishment In American Families And Its Effects On Children."
He has been president of three scientific societies including the National Council on Family Relations, and has been an advisor to the National Institutes of Health and the National Science Foundation. Much of his research on spanking can be downloaded from http://pubpages.unh.edu/~mas2.
Straus's research was supported, in part, by a grant from the National Institute of Mental Health.
Social Cues Confuse Babies/Dogs In a Classic Hiding Game
Are babies and dogs equally intelligent, not as intelligent as thought, or hiding something?
A study by developmental scientists at the University of Iowa and Indiana University challenges the conclusions of two recent studies on how babies and dogs respond to certain social cues. The new findings, published in this Friday's edition of the journal Science, indicate that babies and dogs may not be as clever as the other studies suggest.
Last year, a surprising study led by József Topál of the Hungarian Academy of Sciences showed cues from adults - like nodding, speaking and pointing - cause babies to perform worse in a classic toy-hiding game. The September 2008 report in Science suggested that babies have a unique ability to "read" social cues in a way that misled them in this particular task. Then, in a follow-up paper published earlier this month, the same research team reported that dogs, like babies, are confused by social cues - but wolves aren't. The authors concluded that dogs have become sensitive to social cues from humans due to our shared evolutionary past.
Today's UI and Indiana study used a 10-year-old theory based on how the brain works to provide another explanation for these hiding-and-finding mistakes. Led by John Spencer, professor of psychology in the UI College of Liberal Arts and Sciences and director of the UI Delta Center, the work indicates that babies age 10 months or younger are distracted by social cues - they focus on adults' faces and gestures rather than paying attention to where the object is hidden and do not have a unique ability, as the earlier study suggested.
Because dogs show a similar pattern of behavior with social cues present, the computer model used by Spencer's team can explain their behavior, too. Spencer and his colleagues suspect that wolves succeed in this task for the same reasons older babies do - they can form a robust memory for the hiding location. They say this makes particular sense given that the experimenters hid bits of food in the study with wolves.
"You don't often see cases in which the same data are interpreted in such fundamentally different ways," he said. "We say the infants and the dogs are easily distracted by social cues and the wolves are the clever ones; they say the infants and the dogs have a special ability to process social cues, and the wolves are inferior. It's exactly the opposite. It will be interesting to see where that tension takes us."
The studies in question examine a classic error made by babies up to 10 months old. When they repeatedly see an object hidden in one spot, they look for it there. Even when they witness it being hidden somewhere else, they continue to search in the original hiding location. By age 1, babies figure it out. This odd "A-not-B" error is the subject of five decades of research. Discovered by child psychologist Jean Piaget, it's a staple topic in developmental psychology courses and covered in parenting books.
Topál and his team are among the first to investigate how social cues influence babies' and other animals' performance on the task. Spencer considers the studies provocative but has concerns.
"It's against our intuition that social cues seem to hurt the infants' performance - you'd think encouragement from adults would be helpful. And it shows that social cues make a difference," he said. "But we disagree with the explanations put forth that are not grounded in what we know about infants' perceptual and cognitive abilities. This is, after all, a hiding and finding game - attention and memory should matter."
To show how attention and memory matter in this task, Spencer and colleagues ran computer simulations of a theory that was originally published in 1999 by co-author Linda Smith and her colleagues from Indiana University. This theory has explained infants' performance in many different versions of the A-not-B task. In the paper published this Friday in Science, Spencer and colleagues show that when the computer model fails to focus on the hiding event because distracting social cues are present, it shows the same behavior as infants.
"Research indicating that infants or dogs are extraordinary in some way tends to make a splash. We like to think our kids and pets are special, and in many ways they are," he said. "But in our view, there is no special ability at play here. Using neural network models, we demonstrated that other mundane things underlie infants' behavior. Infants and dogs are simply being distracted by social cues in this hiding game."
Spencer and his co-authors, UI postdoctoral researcher Evelina Dineva and Linda B. Smith, a chancellor's professor of psychological and brain sciences at Indiana University, propose a particular lesson from the debate. They want to see a move away from explanations that only explain a specific result - how infants interpret social cues in a hide-and-seek game - toward more comprehensive explanations that bring a host of findings together.
"This has been one of the really powerful aspects of our theory - it has unified a diverse array of findings with infants in this task and with older children in related memory tasks. Our paper nicely illustrates a new extension into the social domain," Spencer said. "In our view, this is something to celebrate - that we can bring social cognition together with basic cognitive processes. The downside, of course, is that infants, and by analogy dogs, don't have a special mind-reading ability. For some people, that's an unpleasant pill to swallow."
THURSDAY September 24, 2009-------------------------News Archive / Return to News Alerts

Why Hunger Triggers Infertility
Scientists have long known that calorie restriction increases longevity in animals but at an evolutionary cost the animals become infertile
Yale University researchers report in the September 7 to 11 issue of the Proceedings of the National Academy of Sciences that they have discovered the molecular switch in the brain that turns off the reproductive system in times of severe hunger. The same molecule also may play a key role in obesity, drug addiction and depression.
The scientists found that a peptide active in the hypothalamus called melanin-concentrating hormone or MCH can inactivate the reproductive system in times of hunger.
“Brain neurons that make MCH are quiet most of the time, but when the body is in negative energy balance, MCH neurons become active and can shut down reproduction, said Meenakshi Alreja, senior author the paper and Associate Professor of Psychiatry and Neurobiology at the Yale School of Medicine.
The Yale team found that MCH prevents a key reproductive molecule called kisspeptin from acting. Kisspeptin triggers puberty and helps maintain fertility. Hunger or excessive exercise activates the MCH system and delays puberty by blocking kisspeptin.
Scientists and drug companies are interested in MCH for many other reasons. MCH is implicated in depression and drug addiction as well. And mice bred without MCH remain lean and fertile which has made it a popular candidate for anti-obesity drugs as well.
In addition to fighting obesity and depression, MCH may now play a role in human fertility, Alreja said.
Other Yale authors in the study include Min Wu, Iryna Dumalska, Elena Morozova, and Anthony van den Pol of the Yale School of Medicine.
The research was funded by the National Institutes of Health.
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New Treatment in Advanced Melanoma Shrinking Tumours
Metastatic malignant melanoma one of the most difficult cancers to treat once it has started to spread is responding dramatically to a new treatment
According to a study to be presented at Europe’s largest cancer congress, ECCO 15 ESMO 34 [1], in Berlin on Thursday, in a phase I study, researchers have seen rapid and dramatic shrinking of metastatic tumours in patients treated with a new compound. The compound blocks the activity of a mutation of the BRAF gene, which is implicated in about 50% melanomas and 5% of colorectal cancers.
In new results from 31 melanoma patients with the BRAF mutation who were treated, 64% (14) of the 22 patients who could be evaluated so far met the official criteria for partial response (this involves the diameter of tumours shrinking by at least 30% for at least a month). A further six of the 22 patients also showed a response, but, at the time of the congress presentation, it was too early to say whether the tumours would shrink far enough to meet these criteria.
Dr Paul Chapman, an attending physician on the Melanoma/Sarcoma service at Memorial Sloan-Kettering Cancer Center (New York, USA) and who was one of the leaders of the trial, told a news briefing: “We are very excited about these results. Of the 22 patients we have been able to evaluate so far, 20 have had some objective tumour shrinkage.
This is impressive as they all had metastatic disease and most of them had failed several prior therapies. A lot of these patients were pretty sick but many of them had a significant and rapid improvement in the way they function. We’ve had patients come off oxygen and we’ve got several patients who have been able to come off narcotic pain medication soon after starting treatment.”
The phase I extension data reported at ECCO 15 ESMO 34 focuses on a sub group of 31 patients who were all treated at the maximum tolerated dose of the drug (a 960 mg pill twice a day). All the patients had the BRAF mutation.
Dr Chapman said: “What makes this treatment different from standard chemotherapy is that standard chemotherapy attacks the machinery involved in cell division; so to stop the cancer cells dividing uncontrollably, most standard chemotherapy aims to block the mechanism of division by interfering directly with DNA replication or with microtubules in the dividing cells.
PLX4302 is different because it attacks the genetic program that is causing the cells to divide uncontrollably, and we think the BRAF mutation is driving that program. The drug is blocking the genetics of the tumour, rather than trying to interfere with the proliferation of the cells and, as a result, there are fewer side effects, although there are some. We are seeing some pretty dramatic and rapid responses, and they are occurring in sites where we rarely see responses to chemotherapy, such as in the bone.
“There are some important caveats. All these patients had failed previous therapies, either chemotherapy or treatment with Interleukin 2, as well as surgery. However, we know that only 10-30% of patients will respond to standard chemotherapy, so it’s not surprising that our patients had not responded, or have responded and then the cancer has recurred.
In our study 64% of patients have had a partial response, but because we are only treating patients with the BRAF mutation, we are cutting out about 40% of melanoma patients who do not have this mutation and whom we know will not respond to this treatment. That is one reason why we are seeing a much higher response than with conventional treatments.
“Also, we don’t know yet how long these responses will last, and we have had patients whose cancer has progressed after initially responding; so we are putting a lot of effort in to studying the patients who do relapse, trying to understand how their tumours have become resistant.
“In addition, one of the main side effects we’ve seen is that some patients develop early, non-melanoma skin cancers such as squamous cell skin cancer. We are very vigilant about this and although they are very easy to cut out, it’s something we are keeping a close eye on.”
Dr Chapman and his colleagues are planning a phase II trial of 90 patients starting at the end of this year. In addition, a large phase III randomised controlled trial involving several hundred patients is planned to start either at the end of this year or beginning of next year involving centres in North America, Europe and Australia.
Dr Chapman said it was too early to be talking about a cure for advanced melanoma, but that this drug had potential. “Most of us think that a drug like this would ultimately be part of the regimen, but that we might need additional drugs with it to complete the cure. Right now we are seeing dramatic responses but it’s too early to say whether we’ve actually cured people because most patients still have evidence of some level of tumour on their skin. I think this is a huge step forward; whether or not it will be sufficient by itself really remains to be seen.”

The Secrets of Cilia
Cilia have become unlikely stars in an unfolding scientific drama that promises new treatments for kidney disease, birth defects, blindness, and neurological and cardiac disorders. They may even be involved in the control of cell division and cancer
At Yale and labs across the country, scientists are proving that cilia, which exist on almost every mammalian cell, are not just tiny oars that move sperm or keep fluids moving over the surface of tissues in the oviduct or the throat and lungs.
These tiny structures play a profound role in sensing the environment outside the cell in many biological processes. Malfunctions of the cilia have now been associated with so many maladies infertility, obesity, mental deficits, and diseases of the pancreas, liver, heart and kidney that they have been given their own name: The Ciliopathies.
Joel Rosenbaum's seminal study of cells found in pond scum, have changed our understanding of how biological systems develop from embryos and function in adults. The story illustrates the power of translational research, or how unforeseen insights into our own health can be found within the simplest of organisms.
Rosenbaum wanted to know how proteins in the cytoplasm could travel all the way up to the tip of the cilium, where assembly occurs. "It was a basic biology question involving molecular motors and transport," Rosenbaum says. He and his colleagues came to describe the journey of molecules like riders on a roller coaster, travelling from the interior of the cell up and down the length of flagella. They named this system, which is responsible for flagellar assembly, intraflagellar transport or "IFT." They also found that when genes that code for the IFT transport proteins are mutated, cilia fail to form.
Polycystic Kidney Disease (PKD)
And now with easy access to catalogues of genes from a variety of species at their computer, the researchers entered a key gene involved in this intraflagellar transport system in Chlamydomonas into the gene bank and came up with an exact match: a gene found in a mouse model of a disease called polycystic kidney disease (PKD).
"In the lab, we just stared at each other and said, ‘What the hell is going on here?'" Rosenbaum recalls.
What could a gene involved in IFT in green algae possibly have to do with a common and devastating disease, marked by growth of large cysts in the kidney? These cysts are the fourth leading cause of kidney failure and afflict more than 600,000 people in the United States and 12 million worldwide.
Rosenbaum and his colleagues at UMass and Bradley Yoder at the University of Alabama-Birmingham examined the kidneys of mice with PKD by electron microscopy and found their kidney tubules (through which urine flows) lacked cilia evidence that suggested that this simple appendage might play a role in the disease.
"What really happened here is that apparently unrelated fields of research coalesced into something unexpected," Somlo says. Rosenbaum explains "When you observe similarity in structure, there is likely a similarity in function."
In 1998, Stefan Somlo, Professor of Medicine, and chief of the Section of Nephrology at the Yale School of Medicine, identified one of two genes known to cause PKD. Rosenbaum approached Somlo and suggesting that PKD was in fact a disease of the cilia. Somlo's skepticism soon vanished when Rosenbaum and his colleagues showed PKD genes discovered by Somlo were located on the cilia themselves. This finding gave rise to the current "Ciliary Hypothesis of PKD."
But how, exactly, were the cilia functioning that would cause this devastating disease?A major breakthrough in answering this question was the finding by r
Researchers at the National Institutes of Health then showed that mechanically bending the cilium of the kidney cell would cause calcium to flow into a cell.How did this mechanically-induced calcium flow cause PKD? Somlo and Michael Caplan, Yale professor of cellular and molecular physiology, determined that cilia act like sensors, detecting urine flow through the kidney. When the urine flow decreases, cilia do not bend, calcium does not flow in and a signal is sent to the cell that "not all is right." This in turn signals the formation of more cells. The result is that in mice lacking cilia, excessive cell division causes the cysts in the kidney tubules that are the hallmark of PKD.
It turned out that those lab mice with PKD not only lacked cilia in the kidneys, but in other cells as well. The mice had other health problems as well. Revelations of cilia's role in a host of diseases began pouring out from labs at Yale and around the globe.
Telling the Fetal Heart Right from Left
Dr. Martina Brueckner, associate professor of pediatrics and genetics at Yale and a pediatric cardiologist, found defects in cilia can lead to severe heart defects in children. Brueckner's lab in the late 1990s was investigating why some children are born with hearts on the right side of their chest rather than the correct position on the left. In this condition, the heart and other organs in the developing fetus cannot tell right from left. In severe cases when these organs end up misaligned along the left and right sides of the body, many children die before the age of five.
The culprit for this form of congenital heart disease turned out to be a gene coding for a part of the cilium in embryonic cells. These cilia actually move in an unusual way and direct the flow of fluid from left to right acting almost like traffic cops by helping direct cells to form organs along a left-right axis. In the case of mice with heart abnormalities closely resembling those found in humans with abnormal left-right development, the cilia were no longer able to direct this left-right flow and the proper body asymmetry was not formed.
"We had no idea when we started where this was going," Brueckner says. She also suspects that cilia found in heart cells may be responsible for orchestrating other important cardiac functions.
Cancer
The insight that malfunctioning cilia might trigger cyst formations has led to some interesting possibilities for research on cancer, which is marked by uncontrollable cell division. Scientists wondered: Was it possible that cancer somehow destroyed cilia to promote proliferation? Several labs are now investigating this possibility. It is based on a 50-year-old observation that cells with cilia do not divide until the cilia are lost.
Mood, Learning, Memory
Now, the profound effects of cilia are being recognized in many other areas of research. For instance, a Yale team led by neuroscientist Pasko Rakic recently described how cilia play a role in creating molecular signals that spur creation of neurons in an area of the brain involved in mood, learning and memory.
Blindness
Ironically, Rosenbaum and his colleagues at UMass are also finding evidence that cilia may indeed be involved in a form of blindness, just as his Ph.D. adviser suggested more than 40 years ago. Rod cells in the retina are crucial to sight. They are formed from cilia, and these cilia play a key role in transporting molecules that repair the rods as they age. If material does not reach these key portions of the rod cells (called "rod outer segments"), they die and blindness can result.
It turns out that the transport mechanism that delivers these key materials to rod cells is the same intraflagellar transport system Rosenbaum studied in the green algae Chlamydomonas. In one form of sight loss, called Joubert's Syndrome, scientists have now identified a genetic defect that causes a blockage at the base of the cilium that prevents transport of these repairing molecules and have identified the particular part of the cilium that is defective. Using gene therapy to correct the defect, scientists have now succeeded in restoring sight in some animals with Joubert's Syndrome.
In 40 years since Rosenbaum began his lonely study of these microscopic marvels, cilia have taken a place among science's most fascinating and rewarding structures
WEDNESDAY September 23, 2009-------------------------News Archive / Return to News Alerts

Obesity Hinders Chemotherapy in Children with Leukemia
Obesity is associated with increased incidence and mortality of many types of cancer
Obesity is an important factor contributing to chemotherapy resistance and increasing relapse rates among children with leukemia, according to recent findings published online first in Cancer Research, a journal of the American Association for Cancer Research.
Obesity is associated with increased incidence and mortality of many types of cancer. Leukemia is the most common cancer in children, affecting more than 2,000 children each year in the United States alone, according to background materials in the study.
Given the increasing prevalence of obesity worldwide, these findings could have important implications for cancer treatment and may help explain the increased leukemia relapse rate in obese patients, according to the study's lead researcher Steven D. Mittelman, M.D., Ph.D. Mittelman is the fellowship research director with the Division of Endocrinology at Childrens Hospital Los Angeles, and assistant professor of pediatrics, physiology and biophysics at the Keck School of Medicine, University of Southern California.
"Obesity could increase cancer incidence and mortality through a variety of ways. It may impair the immune system's ability to stop cancer, or predispose cells to become cancerous," Mittelman suggested. "Once you have cancer, and if you are obese, the fat cells themselves may impair the ability of chemotherapy to fight cancerous cells."
This study was inspired by a previous study led by a colleague, Anna Butturini, M.D., associate professor of clinical pediatrics in the Division of Hematology-Oncology at Childrens Hospital, which showed that obese children diagnosed with leukemia have a 50 percent higher chance of relapsing compared with lean children.
Using preclinical models, Mittelman and colleagues investigated the reason why obese children were more at risk of relapse. They developed a mouse model of obesity and leukemia, cultured fat and leukemia cells together, and treated the leukemia cells with traditional chemotherapy drugs used in children vincristine, nilotinib, daunorubicin and dexamethasone.
Obese mice with leukemia had higher relapse rates than lean mice after treatment with the first-line chemotherapeutic agent vincristine. The chemotherapy treatments all worked less effectively in culture when fat cells were nearby. When the mice relapsed from the leukemia, the researchers found leukemia "hiding out" in the fat tissue during chemotherapy, according to Mittelman.
"These four drugs attack leukemia cells by different routes, so when we saw fat cells blocking them we realized there could be an important mechanism promoting their ability to live and divide," he said. "We were surprised to find leukemia cells in the fat tissue."
David Hockenbery, M.D., member of the Fred Hutchinson Cancer Research Center and professor of internal medicine at the University of Washington, said "this study provides striking experimental support for the clinical observations that obesity is associated with poor prognosis in multiple cancers."
The researchers demonstrated that co-culture of leukemia cells with adipocytes diminishes response to multiple chemotherapeutic agents. Therefore, adipose tissue may function as a "safe haven" for leukemia cells during therapy, according to Hockenbery. Based on the finding that adipocytes accumulate chemotherapeutic drugs, he advised that careful attention be paid to dose adjustments based on pharmacokinetic measurements.
"In addition, by highlighting a potential communication between adipocyte and leukemia cells, this research will stimulate efforts to find a diffusible factor that protects leukemia cells from chemotherapy," said Hockenbery.
More research is needed to figure out how fat cells are a part of the tumor microenvironment and how they block potentially lifesaving treatments, according to Mittelman. The researchers are currently conducting additional studies to evaluate other chemotherapeutics, how obesity may or may not affect treatment and the effect of fat cells found in bone marrow on leukemia.
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Linking Alcohol Abuse, Depression, Obesity in Young Women
There is new evidence that depression, obesity and alcohol abuse or dependency are interrelated conditions among young adult women but not men
Using data collected when young adults were 24, 27 and 30 years of age, a team of University of Washington researchers found that nearly half the sample of 776 young adults tracked during the study met the criteria for one of these conditions at each of these time points.
"The proportion of people with all three of these conditions at any one point is small," said Carolyn McCarty, the lead author of a new study and a UW research associate professor of pediatrics and psychology. "For women there is a great deal of overlap between these common emotional and health problems that span early adulthood. Men may develop one of these conditions but they don't tend to lead another one later on."
"These conditions are major public health problems. They take a toll on families and community and are not subject to quick fixes. It requires a lot of time, money and energy to treat them."
The study found that:
• Women with an alcohol disorder at age 24 were more than three times as likely to be obese when they were 27.
• Women who are obese at 27 were more than twice as likely to be depressed when they were 30.
• Women who are depressed at 27 were at increased risk for alcohol disorders at 30.
• Obesity offers men some protection against later developing depression.
McCarty said the research did not uncover any step-by-step progression from one these disorders to another. However, she said clinicians treating women with one of these conditions should be aware that patients might develop another disorder.
McCarty said there are two possibilities as to why women with alcohol disorder at 24 were more likely to be obese at 27.
"The caloric intake associated with drinking alcohol may increase metabolic processes leading to weight gain. Or there may be an underlying connection to levels of dopamine, a neurotransmitter, in the reward pathway in the brain because the same pathways reward both food and alcohol intake. It also may be that some people substitute food for alcohol, leading to obesity."
She said body image may play a key role in why women who are obese at 27 are more likely to report depression three years later.
"Body image is particularly important for women. There seems to be a transfer that when women feel bad they eat more. That can have devastating effects emotionally and physically. But for men experiencing obesity, the reverse is true, and obesity seems to be protective against depression. It's the so-called 'jolly fat man' theory, which suggests that overweight people are actually happier."
The link between obesity at 27 and subsequent depression at 30 among women may develop as a result of individuals self-medicating themselves.
"People who feel more emotionally down may use alcohol for a quick lift or a short-term boost. The two conditions may be connected by an underlying stress mechanism. Stress is linked to depression, so women under stress potentially eat and drink more," she said.
The study also showed that income has a significant effect on obesity at age 24 and those with higher incomes had a lower risk for weight problem.
McCarty said that finding is not surprising since many of the least nutritional items are inexpensive, and low income areas do not have the same sources of fresh fruits and vegetables that more affluent ones have.
"It costs more to eat well," she said.
McCarty believes that intervention programs are needed and can play a key role in reducing the growing public health burden caused by these conditions.
"Early prevention is important because the sooner we start the more impact we can have. Interventions should include stress management so we can provide young people with tools to cope with situations and emotions. We also need to explore underlying factors that predispose people to these conditions, such as a family background that is not supportive or is toxic."

'Lies My Parents Told Me'
Research shows parents use deception to influence their children
Parents say that honesty is the best policy, but they regularly lie to their children as a way of influencing their behavior and emotions, finds new research from the University of Toronto and the University of California, San Diego.
Surprisingly little scholarship has been published on the subject of parental lying, so Gail Heyman, professor of psychology at UC San Diego, Diem Luu, a former UCSD student, and Kang Lee, professor at the University of Toronto and director of the Institute of Child Study, Ontario Institute for Studies in Education, set out to explore the under-researched phenomenon. They asked U.S. participants in two related studies about parents lying to their children either for the purpose of promoting appropriate behavior or to make them happy.
In one of the studies, many parents reported they told their young children that bad things would happen if they didn't go to bed or eat what they were supposed to. For example, one mother said she told her child that if he didn't finish all of his food he would get pimples all over his face. Other parents reported inventing magical creatures. One explained, "We told our daughter that if she wrapped up all her pacifiers like gifts, the 'paci-fairy' would come and give them to children who needed them...I thought it was healthier to get rid of the pacifiers, and it was a way for her to feel proud and special."
In the other study, the researchers surveyed college students' recollections about their parents' lying and obtained similar results: parents often lie to their children even as they tell them that lying is unacceptable.
The researchers refer to this practice as "parenting by lying."
"We are surprised by how often parenting by lying takes place," said Lee. "Moreover, our findings showed that even the parents who most strongly promoted the importance of honesty with their children engaged in parenting by lying."
Though Heyman thinks that there are occasions when it is appropriate to be less than truthful with a child "telling a two-year-old you don't like their drawing is just cruel," she said she urges parents to think through the issues and consider alternatives before resorting to the expedient lie.
"Children sometimes behave in ways that are disruptive or are likely to harm their long-term interests," said Heyman. "It is common for parents to try out a range of strategies, including lying, to gain compliance. When parents are juggling the demands of getting through the day, concerns about possible long-term negative consequences to children's beliefs about honesty are not necessarily at the forefront."
The research also examined "parenting by lying" among Asian-American and European-American parents. Asian-American parents were more likely to report lying to their children for the purpose of influencing their behavior. According to the researchers, one possible explanation for this finding is that as compared to European-American parents, Asian-American parents tend to place a greater emphasis on the importance of teaching children to be respectful and obedient, and they use a range of parenting strategies to meet these ends.
The research is published in the current edition of The Journal of Moral Education and was supported by a grant from the National Institute of Child Health and Human Development.
Heyman and Lee are now preparing an international study to explore the subject further, and they are also beginning to study the possible consequences of "parenting by lying": Does it create confusion about right and wrong? Does it undermine a child's trust?
Epigenetic Changes That Influence Abnormal Fetal Growth
The National Institutes of Health (NIH) has awarded Albert Einstein College of Medicine of Yeshiva University two grants totaling $3.5 million to study epigenetic changes chemical modifications of genes caused by stress, diet or other environmental influences and how they contribute to human diseases and biological processes
The NIH will award approximately $62 million to medical institutions over the next five years to study the impact of epigenetic changes on a number of diseases and conditions, including tumor development, hardening of the arteries, autism, glaucoma, asthma, aging, and abnormal growth and development. The grants will build on the work of the NIH Roadmap for Medical Research's Epigenomics Program.
Einstein's grants will focus on epigenetic modifications related to abnormal fetal growth and to chronic kidney disease, led, respectively, by Francine H. Einstein, M.D., assistant professor of obstetrics & gynecology and women's health and Katalin Susztak M.D., Ph.D., associate professor of medicine. Their research will illuminate the total repertoire of epigenetic influences referred to as the "epigenome" that characterize each of these conditions.
"The goal of epigenomics research is in part to understand how human diseases are caused and how environmental factors affect them," says John M. Greally, M.B., B.Ch., Ph.D., associate professor of genetics and of medicine at Einstein, who directs Einstein's Center for Epigenomics. "This research is also driven by the fact that epigenetic processes are inherently reversible and could therefore respond to therapies that reverse long-term damage to the cells. These pioneering studies by Drs. Einstein and Susztak are the first steps towards this ultimate goal."
"The goal of epigenomics research is in part to understand how human diseases are caused and how environmental factors affect them."
John M. Greally, M.B., B.Ch., Ph.D."Epigenomics represents the next phase in our understanding of genetic regulation of health and disease," says NIH Director Francis Collins, M.D., Ph.D. "These awards will address the extent to which diet and environmental exposures produce long-lasting effects through changes in DNA regulation." Dr. Collins notes that the initiative "is expected to profoundly alter the way we understand, diagnose and treat disease."
The main epigenetic modification being studied in these projects is DNA methylation, the addition of methyl groups to the cytosine bases of DNA, often associated with silencing of nearby genes. DNA methylation is one of a number of epigenetic regulatory mechanisms that control gene expression in normal cells but can become altered in disease. For example, epigenetic changes have been found in every type of cancer that researchers have studied.
The larger of the two grants awarded to Einstein, for $2.03 million over five years, will address the epigenetic changes that influence abnormal fetal growth.
"We know that very small and very large newborns have a higher chance of developing problems like diabetes or cardiovascular disease later in life," says Dr. Einstein. "So, we are trying to determine the epigenetic changes in these babies that make them more susceptible to chronic disease and premature death."
The researchers hypothesize that conditions during fetal development alter epigenetic patterns of DNA methylation in stem cells. These changes may be a marker for, or contribute to, susceptibility to type 2 diabetes and other age-related diseases. Dr. Greally and Cristina Montagna, Ph.D., assistant professor of genetics and of pathology at Einstein, are co-principal investigators on this study.
The second grant, for $1.49 million over four years, will address the epigenetic landscape of chronic kidney disease, which affects some 20 million people in the U.S. and is associated with a three-to-five-fold increase in mortality. The researchers suspect that unfavorable environmental conditions, such as poor nutrition during pregnancy, can imprint abnormal DNA methylation patterns on the fetal kidney.
Epigenetic changes may also explain why diabetes is the leading cause of renal (kidney) failure. "People with diabetes who control blood glucose levels develop fewer complications," says Dr. Susztak. "But they still face a greater risk for kidney failure and other complications probably because their bodies remember periods from long ago when their glucose was not well controlled. We want to learn whether this so-called hyperglycemic memory is coded in DNA methylation patterns."
TUESDAY September 22, 2009-------------------------News Archive / Return to News Alerts

Treating Depression in Pregnancy
Depression is not uncommon in pregnant women
A new report from the American Psychiatric Association (APA) and the American College of Obstetricians and Gynecologists, which is published by Elsevier in the September-October 2009 issue of General Hospital Psychiatry(http://journals.elsevierhealth.com/periodicals/ghp/home), explores the management of pregnancy and depression.
Between 14 and 23% of pregnant women will experience a depressive disorder while pregnant. In 2003, approximately 13% of pregnant women took an anti-depressant at some point during their pregnancy. This rate has doubled since 1999. Many women go untreated due to concerns regarding the safety of treating pregnant women.
"The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists" describes results from an unusual collaboration of authors from the American Psychiatric Association and American College of Obstetricians and Gynecologists, as well as a consulting developmental pediatrician. These authors reviewed the world's English-language literature and reported results describing the association of depressive symptoms and anti-depressant treatment on fetal and neonatal outcomes.
Both depressive symptoms and anti-depressant exposure were found to be associated with fetal growth changes and shorter gestations. Short-term neonatal irritability and neurobehavioral changes were also linked with both maternal depression and anti-depressant treatment. Some, but not all, studies reported low rates of fetal malformations with first trimester exposure, but there was no specific pattern of defects for individual medications or class of agents.
"This timely article by Yonkers and colleagues reviews the data on the potential effects of both anti-depressant medications and depressive symptoms on birth and fetal outcomes," said Wayne J. Katon, MD, Editor-in-Chief of General Hospital Psychiatry.
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In Children, H1N1 Flu Vaccine Like Seasonal Flu Vaccine
A single 15-microgram dose of 2009 H1N1 influenza vaccine the same dose that is in the seasonal flu vaccine generates an immune response expected to protect against 2009 H1N1 influenza virus in most 10- to 17- year-olds eight to 10 days following vaccination
Early results from a trial testing a 2009 H1N1 influenza vaccine in children look promising, according to the trial sponsor, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Preliminary analysis of blood samples from a small group of trial participants shows that a single 15-microgram dose of a non-adjuvanted 2009 H1N1 influenza vaccine the same dose that is in the seasonal flu vaccine generates an immune response that is expected to be protective against 2009 H1N1 influenza virus in the majority of 10- to 17- year-olds eight to 10 days following vaccination. These results are similar to those recently reported in clinical trials of healthy adults. Younger children generally had a less robust early response to the vaccine.
"This is very encouraging news," says NIAID Director Anthony S. Fauci, M.D. "As we had hoped, responses to the 2009 H1N1 influenza vaccine are very similar to what we see with routinely used seasonal influenza vaccines made in the same way. It seems likely that the H1N1 flu vaccine will require just one 15-microgram dose for children 10 to 17 years of age. The 2009 H1N1 influenza virus is causing widespread infections among children, so these are welcome results."
The ongoing NIAID-sponsored trial began in mid-August at five sites nationwide. The trial is assessing the safety and immune responses to one and two doses of either 15 micrograms or 30 micrograms of vaccine. Data from the trial is being compared for three age groups: children 6 months to 35 months old; 3 to 9 years old; and 10 to 17 years old.
The preliminary results are based on blood samples taken eight to 10 days after the first vaccination. Immune responses were strongest among the oldest children, those 10 to 17 years old. In this group of 25 children, a strong immune response was seen in 76 percent who received one 15-microgram dose of vaccine. The immune responses in children nine years old and younger were not as strong. Among 25 volunteers aged 3 to 9 years old, a strong immune response was seen in 36 percent of those given 15 micrograms of vaccine. In the youngest group, 20 children between 6 months to 35 months old, a single 15-microgram dose of vaccine produced a strong immune response in 25 percent of recipients.
"These results are not unexpected and are both similar to what is seen with seasonal influenza vaccines and consistent with what we and our colleagues at the Food and Drug Administration anticipated," notes Dr. Fauci.
Study investigators are also collecting blood samples from the volunteers approximately three weeks after both the first and second injections. It is anticipated that the immune response to the 2009 H1N1 influenza vaccine will be similar to that of seasonal influenza vaccination and will continue to rise for several weeks following vaccination, says Dr. Fauci. The study is being closely monitored by the trial physicians and staff as well as by an independent safety monitoring committee.
The vaccine being tested in this trial is manufactured by Sanofi Pasteur in Swiftwater, Pa., in the same manner as its licensed seasonal vaccine, which is used every year in millions of children, and is the same formulation recently licensed by the FDA to protect against 2009 H1N1 influenza. Like inactivated seasonal influenza vaccines, the vaccine contains a purified part of a killed virus and cannot cause flu.
NIAID is conducting trials of 2009 H1N1 influenza vaccines through its longstanding vaccine clinical trials network, the Vaccine and Treatment Evaluation Units. Additional information about the NIAID-sponsored clinical trials in children is available in an Aug. 18 Bulletin http://www3.niaid.nih.gov/news/newsreleases/2009/H1N1pedvax.htm and a Q&A http://www3.niaid.nih.gov/news/QA/qaH1N1pedvax.htm. A detailed description of the trial protocol is at clinicaltrials.gov http://clinicaltrials.gov/show/NCT00944073.
For more information on influenza, including pandemic influenza and avian influenza, visit www.flu.gov. Also, see NIAID’s Web portal at http://www3.niaid.nih.gov/topics/Flu/.

Blood-Brain Barrier Used to Deliver Drug Therapy
Enzyme delivered through the bloodstream corrects deficiencies in the brain
The blood brain barrier is generally considered an obstacle to delivering therapies from the bloodstream to the brain. However, University of Iowa researchers have discovered a way to turn the blood vessels surrounding brain cells into a production and delivery system for getting therapeutic molecules directly into brain cells.
Working with animal models of a group of fatal neurological disorders called lysosomal storage diseases, the UI team found that these diseases cause unique and disease-specific alterations to the blood vessels of the blood brain barrier. The scientists used these distinct alterations to target the brain with gene therapy, which reversed the neurological damage caused by the diseases.
The findings, which were published Sept. 13 inNature Medicine's Advance Online Publication (AOP), could lead to a new non-invasive approach for treating neurological damage caused by lysosomal storage diseases.
"This is the first time an enzyme delivered through the bloodstream has corrected deficiencies in the brain," said lead investigator Beverly Davidson, Ph.D., UI professor of internal medicine, neurology, and molecular physiology and biophysics. "This provides a real opportunity to deliver enzyme therapy without surgically entering the brain to treat lysosomal storage diseases.
"In addition, we have discovered that these neurological diseases affect not just the brain cells that we often focus on, but also the blood vessels throughout the brain. We have taken advantage of that finding to delivery gene therapy, but we also can use this knowledge to better understand how the diseases impact other cell types such as neurons," she added.
Lysosomal storage diseases are individually quite rare, but as a group they affect approximately 1 in 8,000 live births. The diseases are caused by deficiencies in enzymes that break down larger molecules. Without these enzymes, the large molecules accumulate inside cells and cause cell damage and destruction.
Enzyme replacement therapy has been successful in treating one form of lysosomal storage disease called Gaucher disease. However, storage diseases that affect the central nervous system remain untreatable because it has not been possible, to this point, to get the missing enzymes past the blood-brain-barrier and into the brain.
"Our discovery allowed us to test the idea that the brain cells might be able to make use of the reintroduced enzyme to stop or reverse the damage caused by the accumulated materials," said Davidson, who also is the Roy J. Carver Professor in Internal Medicine. "In the treated mice, the affected brain cells go back to looking normal, the brain inflammation goes away and the impaired behaviors that these mice have is corrected."
To develop their gene therapy targeting system, Davidson and colleagues used a technique called phage panning to identify peptides that hone in on the blood vessels surrounding the brain. Surprisingly, they found that peptides that targeted the brain blood vessels in mice with lysosomal storage diseases were distinct from the peptides that targeted brain blood vessels in healthy mice. Moreover, the peptides that targeted blood vessels in different diseases were distinct from each other, suggesting that each disease causes specific alterations to the blood vessels.
The team modified a deactivated virus used for gene therapy so that the virus expressed copies of the unique brain-targeting peptide on its outer coat, and also carried the genetic blueprint for the missing enzyme.
The study showed that the modified virus targeted the blood vessels in the brain and caused the blood vessel cells to produce the enzyme. Most importantly, the researchers found that the enzyme was secreted into the brain tissue in sufficient quantities to correct the disease symptoms and problems.
The team was able to use this approach to treat two types of lysosomal storage disease in mice, suggesting that the approach could be used for other types of lysosomal storage disease and possibly other neurological disorders.
Junk DNA and Quest for Gene Therapy
A protein enables sections of so-called junk DNA to be cut and pasted within genetic code - a finding which could speed development of gene therapies
Scientists have identified how a protein enables sections of so-called junk DNA to be cut and pasted within genetic code a finding which could speed development of gene therapies.
The study by researchers at the University of Edinburgh sheds light on the process, known as DNA transposition, in which shifted genes have a significant effect on the behaviour of neighbouring genes. In the human genome, rearrangement of antibody genes can enable the immune system to target infection more effectively.
The research identifies how the enzyme is able to cut out a section of DNA and reinsert it elsewhere in the genome. The study, published in the journal Cell, was funded by the Wellcome Trust and the Medical Research Council.
The cut-and-paste property of shifted DNA is now being used to develop tools for scientific research and medical applications. Learning more about transposition could help scientists understand how to control the process and speed the development of gene therapies which introduce into cells genes with beneficial properties that, for example, can fight hereditary diseases or cancer.
Junk DNA, which accounts for almost half of the human genome, was originally believed to have no purpose. However, it is now emerging that movement of junk DNA, in a cut-and-paste mechanism, can lead to beneficial changes in cells.
Dr Julia Richardson of the University's School of Biological Sciences, who led the study, said: "By forming a picture of the enzyme that causes DNA to shift, and discovering how this works, we understand more about how these proteins could be adapted and controlled. This may one day enable genes to be pasted into cells exactly where they are needed which could be of enormous benefit in developing gene therapies."
MONDAY September 21, 2009-------------------------News Archive / Return to News Alerts

Age at First Drink May Affect Genes and Risk for Alcoholism
The age at which a person takes a first drink may influence genes linked to alcoholism, making the youngest drinkers the most susceptible to severe problems
A team of researchers, led by scientists at Washington University School of Medicine in St. Louis, studied 6,257 adult twins from Australia. They wanted to learn whether twins who start drinking at an early age are more likely to develop a more heritable form of alcohol dependence than those who begin drinking later in life. The researchers found that the younger an individual was at first drink, the greater the risk for alcohol dependence and the more prominent the role played by genetic factors.
"There seemed to be a greater genetic influence in those who took their first full drink at a younger age," says first author Arpana Agrawal, Ph.D. "That's very consistent with what has been predicted in the literature and in the classification of types of alcohol dependence, but we present a unique test of the hypothesis."
Agrawal and her colleagues examined previously collected data from identical and fraternal, male and female twins, using statistical methods to measure the extent to which age at first drink changed the role of heritable influences on symptoms of alcohol dependence. Using the twin model, they were able to tease out genetic influences, shared environmental influences and non-shared environmental factors.
Agrawal's team found that when twins started drinking early, genetic factors contributed greatly to risk for alcohol dependence, at rates as high as 90 percent in the youngest drinkers. For those who started drinking at older ages, genes explained much less, and environmental factors that make twins different from each other, such as unique life events, gained prominence.
The twins in the study were 24 to 36 years old when they were interviewed, but some reported taking their first drink as young as age 5 or 6. The researchers found that those who were 15 or younger when they started drinking tended to have a greater genetic risk for alcohol dependence. Some who were 16 or older before they took their first drink later became alcohol dependent, but their dependence was related more to environmental factors.
"We don't have actual gene expression data in this study, but we could hypothesize that exposure to early-onset drinking somehow modifies the developing brain," Agrawal says. "Particularly frequent or heavy early drinking may influence gene expression and contribute to more severe outcomes. Our research cannot prove that, but it's something that neuro-imaging and gene expression studies certainly should investigate."
Another possibility is that early drinking exposes adolescents to certain environment influences, such as their peer groups, that somehow enhance genetic influences that contribute to risk for alcohol dependence.
"Something about starting to drink at an early age puts young people at risk for later problems associated with drinking," Agrawal says. "We continue to investigate the mechanisms, but encouraging youth to delay their drinking debut may help."
"Some early-onset drinkers do not develop alcohol problems and some late-onset drinkers do we are working on why that is the case, but it is important to note that this is one risk factor among many and does not determine whether a person will, or will not, develop alcohol dependence," says Agrawal, an assistant professor in the Department of Psychiatry. "But age at first drink is a well-known risk factor, and there have been two main hypotheses about why: One has been that common genetic and environmental factors contribute both to the risk for alcohol dependence and to the likelihood a person will be younger when consuming their first drink. A second hypothesis suggests starting to drink at a younger age exerts an influence on alcohol dependence that is independent of these shared factors. Our findings suggest there may be some truth to both hypotheses."
Agrawal says studying twins offers advantages when attempting to learn about genetic and environmental influences on alcohol dependence. Since identical twins share 100 percent of their DNA, differences in drinking behavior between a pair of twins must come from environmental factors. Similarities between identical twins tend to be influenced by genes and family environment.
"Particularly identical twins offer us the opportunity to study the perfect natural experiment of genetically identical individuals whose drinking trajectories are modified by their shared and unique life experiences," she explains. "They are important assets in the study of complex behaviors, such as alcohol consumption."
The study results will be published in the December issue of Alcoholism: Clinical & Experimental Research, but they are available online through the journal's Early View.
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Another Key Factor in Regulating Placenta/Fetal Growth
A common biological molecule is central to placental growth and could hold the key to growth restriction of babies in the womb
Scientists funded by the Biotechnology and Biological Sciences Research Council (BBSRC), in the United Kingdom, have shown that a common biological protein molecule called SHP-2 is crucial for encouraging placenta growth. The research is published today in Endocrinology.
Dr Melissa Westwood, one of the team at the University of Manchester said: "For fetuses to grow well in the womb they need to get nutrients and oxygen from their mother. These come via the placenta and so as the fetus grows and its demand on mum increases, the placenta also must increase in size. If the placenta doesn't grow properly, the fetus is unable to receive all it needs from the mother and its growth is restricted. This can impact seriously on the health of the newborn. Furthermore we have learned recently that it dramatically increases the risk of ill health in adult life."
The researchers have investigated a group of proteins called the insulin-like growth factors (IGF). They have discovered that SHP-2, a molecule within placental cells, is a crucial mediator of the effects of IGFs in stimulating the placenta to grow.
Dr Westwood continued: "We know that placentas need an array of factors to support their growth, but until now we didn't realise that SHP-2 was so important for ensuring that these factors do their job.
"Research from our lab and others around the world suggests that the placentas of growth-restricted babies might not grow because they are resistant to the effects of growth factors. We know that in many tissues in the body, SHP-2 is involved with the action of other growth factors not just IGF. Targeting the mediators of growth factor actions rather than the growth factors themselves may be a good way to intervene in cases of growth restriction a bit like sending a positive email to all your friends at the same time.
"However, any therapy based on this finding would have to be designed carefully. Most tissues of the body have SHP-2 doing one or more important jobs and so we would need to restrict therapy just to the placenta. This is possible but certainly challenging."
Professor Janet Allen, Director of Research, BBSRC said: "This is a great example where understanding healthy growth and development can lead quickly to a better understanding of what goes on when things go wrong. This sort of fundamental research can underpin really important social and economic benefits in the future."

Antioxidant Controls Spinal Cord Development
Researchers at the Johns Hopkins School of Medicine have discovered how one antioxidant protein controls the activity of another protein, critical for the development of spinal cord neurons
The research, publishing this week in Cell, describes a never-before known mechanism of protein control. “This is the first time we’ve seen this type of chemical reaction control neuronal differentiation,” says Shanthini Sockanathan, Ph.D., an associate professor at the Johns Hopkins Solomon H. Snyder Department of Neuroscience. “And it’s probably not specific for motor neurons that we study, but also for development of a wide variety of neurons.”
Previous research had shown that the GDE2 protein can cause immature cells in the spinal cord to differentiate into motor neurons, the nerve cells that connect to and control muscle contraction. Too little GDE2 causes motor neurons to not develop, while too much GDE2 causes them to develop too quickly, depleting progenitor pools.
“We reasoned that there must be tight control of GDE2 so we set out to look for the regulator by looking for other proteins that can bind to GDE2,” says Sockanathan.
Using biochemical approaches to isolate all proteins that normally bind to GDE2 in the developing spinal cord, followed by proteomic analysis to identify all binding proteins, the research team found a few hundred proteins. One, Prdx1, had been reported by others to have tumor-suppressing abilities, which caught Sockanathan’s eye for further investigation.
The team first asked if the Prdx1 protein can affect motor neuron development by removing it from developing spinal cords of chick embryos. Embryos lacking Prdx1 showed loss of motor neurons similar to that seen in embryos lacking GDE2, suggesting that indeed Prdx1 is somehow involved in motor neuron development.
To figure out how Prdx1 and GDE2 interact to cause immature cells to develop into motor neurons, the team mutated the proteins and examined how the mutations affect the cells. Mutations that prevent the two proteins from binding resulted in no motor neurons. Similarly, mutations that disrupt the enzyme abilities of GDE2 and Prdx1 also resulted in no motor neurons. In fact, only when GDE2 and Prdx1 can bind each other and work as enzymes do motor neurons develop.
“So we thought maybe the antioxidant enzyme activity of Prdx1 is doing something to regulate GDE2 function,” says Sockanathan. Her team then looked into what already was known about Prdx1’s enzyme activity. They found that bacteria and yeast versions of Prdx1 are able to help alter certain chemical bonds in proteins that form between specific amino acids that contain so-called sulfhydryl or “-SH” groups.
That led them to reexamine the GDE2 protein for sulfhydryl groups. As it turns out, they found 4 in GDE2: Three are close together and one is clear on the other end of the protein. They first performed some biochemistry experiments to determine whether these sulfhydryl groups can form disulfide bondsthey can. Then, two at a time, the researchers engineered mutations to replace each -SH-containing amino acid in GDE2 and asked if the mutated protein could still bind to Prx1. They found one combination of mutations that did not behave the same as the unmutated control, leading them to conclude that Prx1 must break the chemical bond between those two specific amino acids.
“We think that Prx1 breaks this bond in GDE2, activating it to promote motor neuron differentiation,” says Sockanathan. “This suggests a new general control mechanism that regulates when cells divide and when they differentiate. We’re excited to see how widespread it might be.”
This study was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health, and the Muscular Dystrophy Association.
New Way to Calculate “Maximum Weight Limit”
Calculating your BMI is pretty hard - unless you use this new method proposed by a researcher at the University of Nevada, Reno
Most of us are familiar with the term, Body Mass Index, or BMI, as an index to determine healthy body weight. But, calculating BMI involves a complex formula: weight in pounds is multiplied by 703, and then divided by height in inches squared. Charts or online calculators are then used to show a “healthy weight range” given an individual’s height that corresponds to the “healthy range BMI.” For example, a BMI chart indicates that a healthy range BMI of 19 to 24 translates to a “healthy weight range” of 120 to 150 pounds for a 5-foot, 6-inch individual.
If this sounds way too complicated to you, you’re not alone. George Fernandez, a professor of applied statistics and director of the Center for Research Design and Analysis at the University of Nevada, Reno, set out to give people a simpler way of calculating their healthy weight, and one that wouldn’t require charts or online calculators. In addition, he doesn’t think the “range” approach sticks in individuals’ minds.
“We need a “Maximum Weight Limit, or MWL,” he said, “one number that we know we can’t go over, just like a speed limit.”
So, using SAS software and statistical procedures, he discovered a much simpler way of calculating a Maximum Weight Limit, which closely corresponds to weight recommendations listed on BMI charts. But, you don’t need to calculate or know your BMI, nor do you need a chart or online calculator to figure out your Maximum Weight Limit. Fernandez will present his Maximum Weight Limit calculation at the Nevada Public Health Association Conference, 1:30 p.m., Sept. 22 at the University of Nevada, Reno’s Joe Crowley Student Union, Room 423.
“It’s a very simple calculation that most of us can do in our heads,” he explained. For men and women, there is a baseline height and weight. For men, the baseline is 5-feet, 9-inches tall and a Maximum Weight Limit of 175 pounds, meaning that a 5-foot, 9-inch tall man should weigh no more than 175 pounds. For women, the baseline is 5-feet tall and a Maximum Weight Limit of 125 pounds.
“These are nice round numbers that people can easily remember: 5-feet, 9-inches tall, 175 pounds for man; and 5-feet tall, 125 pounds for a woman,” explained Fernandez.
From that starting point, you simply calculate how much taller or shorter you are, in inches. Then, if you are man, you add or subtract 5 pounds for every inch you are taller or shorter than 5 feet, 9 inches. So, if you are 5-feet, 11-inches tall, you are 2 inches taller than the baseline of 5 feet, 9 inches. You add 5 pounds for each of those 2 inches, 10 pounds, to the baseline Maximum Weight Limit of 175. So, your Maximum Weight Limit is 185 (175 pounds plus 10 pounds). Women add or subtract 4.5 pounds for each inch they differ from the baseline height of 5-feet tall.
These Maximum Weight Limits correspond very closely to BMIs of 25.5 for men and 24.5 for women. A BMI of 18.5 to 25 BMI is diagnosed as the “healthy range.” Fernandez used a slightly lower BMI base for women and a slightly higher one for men because, on average, women have less muscle mass than men. Although some have debated using BMI as a means for calculating healthy weight because it does not take into account factors such as muscle mass, for example, it has been shown to work as a basis for calculating a healthy weight for more than 90 percent of the population and is the most universally used index in weight management programs.
“Now people can calculate their own Maximum Weight Limit, based on the BMI index, but without any calculators or charts,” Fernandez said. “And, all they have to remember is that one number, 185 pounds for example, which is easier for most people than retaining a weight range, such as 155 to 185 pounds.”
Fernandez also noted that this simple formula could be very useful in medically underserved areas of the world, and for individuals without access to technology and charts.
“Anyone, anywhere can calculate their Maximum Weight Limit if they know their height and this simple formula,” he said. “People can calculate this in their heads and remember this.”
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