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Week Ending FRIDAY May 29, 2009---------------------------News Archive

Breastfeeding Duration and Weaning Diet May Shape Child's Body Composition
Variations in both milk feeding and in the weaning diet are linked to differences in growth and development, and they have independent influences on body composition in early childhood, according to a new study accepted for publication in The Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM)

Previous studies suggest that the early environment may be a significant factor in childhood obesity. This study used dual x-ray absorptiometry to make direct measures of body composition in children at four years of age whose diets had been assessed when they were infants. The findings showed that children who had been breastfed longer had a lower fat mass which could not be explained by differences in family background or the child's height.

"Most studies linking infant feeding to later body composition focus on differences in milk feeding, but our study also considered the influence of the weaning diet," said Dr. Siân Robinson, PhD, of the MRC Epidemiology Resource Centre, University of Southampton in the United Kingdom and lead author of the study. "We found that, independent of the duration of breastfeeding, children with higher quality weaning diets including fruits, vegetables, and home-prepared foods had a greater lean mass at four years of age."

In this study, researchers assessed the diets of 536 children at six and 12 months of age. Diet was assessed using a food frequency questionnaire that was administered by trained research nurses to record the average frequency of consumption of specific foods. The age at which solid foods were introduced into the infant's diet was also recorded. In this study 'weaning' is defined as the period of transition in infancy between a diet based on milk feeding to one based on solid foods. The subjects' body composition was assessed at four years by dual X-ray absorptiometry.

"These findings are enlightening," said Professor Cyrus Cooper, Director of the MRC Epidemiology Resource Centre. "An influence of qualitative differences in the weaning diet on childhood body composition had not been described before."

The article "Variations in infant feeding practice are associated with body composition in childhood: a prospective cohort study," will appear in the August 2009 issue of JCEM.

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Fetal Development Linked to Adult High Blood Pressure
High blood pressure in later life may be influenced during development in the womb, new research suggests

Studies of elderly people found those with high blood pressure were more likely to have high levels of aldosterone, a hormone linked to blood pressure control, regardless of lifestyle factors such as diet and obesity.

Researchers from the Universities of Southampton, Edinburgh and Glasgow also found that aldosterone levels were higher in those with low birth weights, which also predicts high blood pressure in later life. The findings suggest that the body’s system for regulating the hormone and blood pressure levels is established in the womb.

Dr Elaine Dennison and Professor David Phillips of the University of Southampton were involved in the study. Dr Dennison said: “This research highlights the importance of the early environment on the risk of high blood pressure in later life. It suggests that early life experience might be added to better known risk factors for high blood pressure such as stress, diet and obesity.”

The study involved more than 300 men and women born in Hertfordshire between 1920 and 1930 whose birth weights had been recorded. Blood samples were taken and tests carried out to analyse levels of aldosterone and how it was regulated. The findings also support the use of treatments for high blood pressure targeted at altering levels of aldosterone.

Funding for the study came from the Wellcome Trust and the British Heart Foundation.



The Role of Low Vitamin D in Cancer Development

In studying the preventive effects of vitamin D, researchers at the Moores Cancer Center at the University of California, San Diego, have proposed a new model of cancer development that hinges on a loss of cancer cells’ ability to stick together

The model, dubbed DINOMIT, differs substantially from the current model of cancer development, which suggests genetic mutations as the earliest driving forces behind cancer.

“The first event in cancer is loss of communication among cells due to, among other things, low vitamin D and calcium levels,” said epidemiologist Cedric Garland, DrPH, professor of family and preventive medicine at the UC San Diego School of Medicine, who led the work. “In this new model, we propose that this loss may play a key role in cancer by disrupting the communication between cells that is essential to healthy cell turnover, allowing more aggressive cancer cells to take over.”

Reporting online May 22, 2009 in the Annals of Epidemiology, Garland suggests that such cellular disruption could account for the earliest stages of many cancers. He said that previous theories linking vitamin D to certain cancers have been tested and confirmed in more than 200 epidemiological studies, and understanding of its physiological basis stems from more than 2,500 laboratory studies.

“Competition and natural selection among disjoined cells within a tissue compartment, such as might occur in the breast’s terminal ductal lobular unit, for example, are the engine of cancer,” Garland said. “The DINOMIT model provides new avenues for preventing and improving the success of cancer treatment.”

Garland went on to explain that each letter in DINOMIT stands for a different phase of cancer development. “D” stands for disjunction, or loss of intercellular communication; “I,” for initiation, where genetic mutations begin to play a role; “N” for natural selection of the fastest-reproducing cancer cells; “O” for overgrowth of cells; “M” for metastasis, when cancer cells migrate to other tissues, where cancer can kill; “I” refers to involution, and “T” for transition, both dormant states that may occur in cancer and potentially be driven by replacing vitamin D.

While there is not yet definitive scientific proof, Garland suggests that much of the evolutionary process in cancer could be arrested at the outset by maintaining vitamin D adequacy. “Vitamin D may halt the first stage of the cancer process by re-establishing intercellular junctions in malignancies having an intact vitamin D receptor,” he said.

According to Garland, other scientists have found that the cells adhere to one another in tissue with adequate vitamin D, acting as mature epithelial cells. Without enough vitamin D, they may lose this stickiness along with their identity as differentiated cells, and revert to a stem cell-like state.

Garland said that diet and supplements can restore appropriate vitamin D levels, and perhaps help in preventing cancer development. “Vitamin D levels can be increased by modest supplementation with vitamin D3 in the range of 2000 IU/day,” he noted.

The researchers noted that many studies show an apparent beneficial effect of vitamin D and calcium on cancer risk and survival of patients with breast, colorectal and prostate cancer. However, there are some studies that have not found such benefit, especially when taking smoking, alcohol and viruses into account. While more research needs to be done, Garland recommends that individuals should have their vitamin D level tested during an annual check up.

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Adult Bone Marrow Stem Cells Injected into Skeletal Muscle Can Repair Heart Tissue
University at Buffalo researchers have demonstrated for the first time that injecting adult bone marrow stem cells into skeletal muscle can repair cardiac tissue, reversing heart failure

Using an animal model, the researchers showed that this non-invasive procedure increased myocytes, or heart cells, by two-fold and reduced cardiac tissue injury by 60 percent.

The therapy also improved function of the left ventricle, the primary pumping chamber of the heart, by 40 percent and reduced fibrosis, the hardening of the heart lining that impairs its ability to contract, by up to 50 percent.

"This work demonstrates a novel non-invasive mesenchymal stem cell (MSC) therapeutic regimen for heart failure based on an intramuscular delivery route," said Techung Lee, Ph.D., UB associate professor of biochemistry and senior author on the paper.

Mesenchymal stem cells are found in the bone marrow and can differentiate into a variety of cell types.

"Injecting MSCs or factors released by MSCs improved ventricular function, promoted myocardial regeneration, lessened apoptosis (cell death) and fibrotic remodeling, recruited bone marrow progenitor cells and induced myocardial expression of multiple growth factor genes," Lee said.

"These findings highlight the critical 'cross-talks' between the injected MSCs and host tissues, culminating in effective cardiac repair for the failing heart."

The paper reporting this development appears online in the Articles-in-Press section of the American Journal of Physiology -- Heart Circulation Physiology at http://ajpheart.physiology.org/cgi/reprint/00186.2009v1.

The heart disease death rate has dropped significantly in the last three decades due to better treatments, resulting in large numbers of people living with heart failure. This advance has lead to another health hurdle: The only therapy available to reverse the decline in cardiac function is heart transplantation, and donor hearts are very scarce.

Clinical trials of myocardial stem cell therapy traditionally have relied on surgery -- infusing the stem cells directly into the heart or injecting them into the myocardium, the heart muscle -- invasive methods that can result in harmful scar tissue, arrhythmia, calcification or small vessel blockages.

"In our research with a swine model of heart failure," said Lee, "we've found that only 1-to-2 percent of MSCs infused into the myocardium grafted into the heart, and there was no evidence that they differentiated into heart muscle cells. In addition, diseased tissue is not a healthy environment for cell growth.

"For these reasons, and because patients with heart failure are not good surgical risks, it made sense to explore a non-invasive cell delivery approach," said Lee. "An important feature of MSCs is their ability to produce a plethora of tissue healing effects, known as "tropic factors," which can be harnessed for stem cell therapy for heart failure.

Lee noted that the multiple trophic factors produced by MSCs have been shown in the literature to be capable of reducing tissue injury, inhibiting fibrosis, promoting angiogenesis, stimulating recruitment and proliferation of tissue stem cells, and reducing inflammatory oxidative stress, a common cause of cardiovascular disease and heart failure.

"Since skeletal muscle is the most abundant tissue in the body and can withstand repeated injection of large number of stem cells, we thought it would be a good method to deliver MSCs," Lee said. "We hypothesized that MSCs, via secretion of these functionally synergistic trophic factors, would be able to rescue the failing heart even when delivered away from the myocardium.

"This study proves our hypothesis," said Lee. "We've demonstrated that injecting MSCs, or trophic factors released by MSCs, into skeletal muscle improved ventricular function, promoted regeneration of heart tissue, decreased cell death and improved other factors that cause heart failure.

"This non-invasive stem cell administration regimen, if validated clinically, is expected to facilitate future stem cell therapy for heart failure."

Lee said the next step is to use genetic and pharmacological engineering to make the stem cells more active, so good therapeutic effects can be achieved with fewer cells.

"That is our goal. It would reduce the cost of stem cell therapy and make it more affordable for patients in the future."



Award for Pioneering Stem Cell Research to Mend Broken Bones
A new study led by scientists from the University of Southampton could allow the development of new and better treatments for broken bones and other orthopaedic problems associated with ageing.

Researchers at the University, working alongside colleagues from Keele, Imperial College London and Nottingham universities, will combine stem cell science and tissue engineering to look at the development and repair of human skeletal tissue.

Funding of £4 million has been awarded by the Biotechnology and Biological Sciences Research Council (BBSRC) for the research.

Fractures, bone loss due to trauma or disease and other orthopaedic conditions pose a significant clinical and socioeconomic problem, especially with an ageing population, but as yet there is no large scale effective treatment for replacing or repairing damaged bones.

Professor Richard Oreffo, from the University’s School of Medicine, is leading the study. He said: "Despite intense research, significant challenges for the reconstruction of tissues such as bone remain. Bone and cartilage tissue repair is a highly complex development process. A key requirement for these regeneration strategies to succeed remains our ability to understand skeletal cell activity, develop appropriate scaffolds and to understand how the environment the cells find themselves in affects their ability to interact with other cells to form new bone or cartilage."

Over the next five years, the scientists will combine their expertise in skeletal stem cells, scaffolds (which is a material structure on which cells grow) and the physical environment to identify the key growth factors, matrix proteins and physical conditions that will enhance tissue regeneration and ultimately lead to more effective skeletal repair strategies.

"We believe a paradigm shift in approach is required if we are to lead internationally in regenerative medicine. Our findings of how stem cells, scaffolds and the physical environment can be combined to induce new bone and cartilage will be used to augment and accelerate bone repair. This will allow us to develop new regimes for cartilage and bone regeneration ultimately leading to more effective treatments" explained Professor Oreffo.

Commenting on the award, Professor Douglas Kell, BBSRC Chief Executive said: "Fractures, particularly among older people, are a major cause of morbidly and mortality, and costs the NHS billions of pounds each year. This truly multidisciplinary approach to the basic research necessary to improve our scientific understanding opens up exciting possibilities in the area of skeletal development and repair, an area where advancement is becoming increasingly urgent on both a quality of life and an economic level as our population gets older."


THURSDAY May 28, 2009---------------------------News Archive

A Genetic Link to Premature Ejaculation
Premature ejaculation can be embarrassing, but a new study suggests that it might be a genetic disorder.

Researchers from Turku, Finland, interviewed more than three thousand men - all pairs of male twins and their older or younger brothers - about the first time they had sex. Many participants in the study reported that they had suffered from erectile dysfunction and premature ejaculation at their first sexual encounter.

These common problems are often attributed to external factors, such as intoxication or nervousness due to peer pressure. This research confirms that such factors do cause erectile dysfunction. On the other hand, premature ejaculation appears to be strongly linked to genetic factors, and is not just psychological.

In an earlier study, researchers in The Netherlands linked premature ejaculation to a gene for serotonin regulation in a group of two hundred men. The new data from Finland independently show a genetic link to premature ejaculation in a much larger group, and rule out environmental factors.

Faculty of 1000 Medicine member David Goldmeier notes that the increasing evidence for a genetic cause of premature ejaculation opens the way for the development of new drug treatments - something that many men might benefit from.

However, both Goldmeier and reviewer Taylor Segraves emphasize that drug therapy is not the only solution: psychotherapy will continue to be a valuable and useful form of treatment for sexual dysfunctions - even those with a genetic cause.

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Viruses are Sneakier Than We Thought
Viruses are molecular marauders, plundering cells for the resources they need to multiply

Of central importance for viruses is the ability to commandeer cellular gene expression machinery. Several human herpesviruses put the breaks on normal cellular gene expression to divert the associated enzymes and resources towards their own viral genes.

Kaposi's sarcoma-associated herpesvirus (KSHV), which causes several AIDS-associated cancers, has now been shown to do this in an unexpected way, using a process that is normally protective, called polyadenylation.

Cells decode genetic information in a process called transcription, during which the DNA is unzipped and read by enzymes.

The product of this process is a piece of messenger RNA, which then emerges from the cell's nucleus (the section of the cell containing DNA) into the cell cytoplasm (the main cellular compartment) and is translated there into the protein corresponding to the DNA's message.

Polyadenylation is the process whereby Poly(A) tails are added to messenger RNAs (mRNAs) in the nucleus before they are transported into the cytoplasm.

These tails serve several purposes, including protecting the messages from degradation and enhancing the translation to protein. The effects of KSHV on cells was known to be caused by one of it's proteins – called SOX – but how the protein influences host cells transcription process has previously been unclear.

I
n a study published in this week's issue of PLoS Biology, researchers at UC Berkeley found that the presence of SOX led to an unexpected increase in the length of cellular mRNA poly(A) tails.

Mutant KSHV viruses that can't make SOX protein are unable to block cellular gene expression. SOX mutants fail to increase poly(A) tail length. This suggests that the virus uses a process normally involved in enhancement of gene expression to instead inhibit gene expression.

"We suspect that by aberrantly lengthening the poly(A) tails, the virus is sending the cell a signal that something is wrong with its messages and as a consequence they are held back in the nucleus," says Dr. Britt Glaunsinger, one of the researchers involved in this study. Indeed, similar results have been observed in yeast when mRNAs are improperly made or cannot traffic appropriately.

The researchers showed that SOX has more than one trick to play on cells. As well as preventing the export of new cellular mRNAs, SOX targets the existing messages that were made in a cell before the KSHV could turn on its SOX protein.

mRNA poly(A) tails are normally bound by the cell's poly(A) binding protein (PABP), which helps guard them from degradation and facilitates their translation into protein. During KSHV infection, however, SOX removes PABP from the cytoplasm and causes it to instead accumulate in the nucleus.

PABP re-localization correlates with destruction of cytoplasmic mRNA in SOX-expressing cells, perhaps because these transcripts have been 'stripped' of an important protector.

"I find it fascinating that this single viral protein targets a key mRNA stabilizing element from two different angles to block cellular gene expression," says Glaunsinger. "It's yet another example of how viruses have evolved to interface so exquisitely with their hosts."



Stem Cells Used to Restore Sight for Corneal Disease Sufferers

THREE Australians have had their sight restored thanks to their own stem cells and ordinary contact lenses

Although the novel technique was used to reverse blinding corneal disease, it promises to be a quick, painless and cheap treatment for other visual disorders. It may even be useful for repairing damaged skin, the researchers reported today in the journal Transplantation.

The team leader, UNSW stem cell scientist Nick Di Girolamo said: “We're quietly excited. We don't know yet if (the correction) will remain stable, but if it does it's a wonderful technique”.

According to team member Stephanie Watson - an opthalmic surgeon with Sydney's Prince of Wales Hospital - two of the three patients were legally blind in the treated eye; they can now read big letters on the eye chart. The third could read the top few rows of the chart but is now able to pass the vision test for a driving license.

Although it's early days yet, commented Peter McCluskey, an opthalomogist with Sydney University and director of the Save Sight Institute: “But I think it's really exciting, innovative and novel”.

Dr Di Girolamo said the idea to team stem cells with contact lenses came from an observation by opthalogist and POWH co-author Minas Coroneo that stem cells from the cornea, or front of the eye, stick to contact lenses.

To obtain the stem cells, Dr Watson took less than a millimeter of tissue from the side of each patients' cornea. Working with colleagues at POWH and UNSW, he cultured stem cells from the tissue in extended wear contact lenses.

Dr Watson then cleaned the surface of the patients' corneas and inserted the lenses. Within 10 to 14 days the stem cells began to attach to the cornea, replenishing damaged cells. Satisfied that the stem cells were doing their job, Dr Watson removed the lenses and the patients have been seeing with new eyes for the last 18 months.

Dr Di Girolamo said the group has applied for funds to continue the project, which he thinks will be welcomed particularly in poor nations: “It's simple and easy for the patient and you don't need fancy equipment; just an opthalmic surgeon and a lab for cell culture."

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Research Suggests New Cellular Targets for HIV
Focusing HIV drug development on immune cells called macrophages instead of traditionally targeted T cells could bring us closer to eradicating the disease, according to new research from University of Florida and five other institutions

In the largest study of its kind, researchers found that in diseased cells — such as cancer cells — that are also infected with HIV, almost all the virus was packed into macrophages, whose job is to "eat" invading disease agents.

What's more, up to half of those macrophages were hybrids, formed when pieces of genetic material from several parent HIV viruses combined to form new strains. Such "recombination" is responsible for formation of mutants that easily elude immune system surveillance and escape from anti-HIV drugs.

"Macrophages are these little factories producing new hybrid particles of the virus, making the virus probably even more aggressive over time," said study co-author Marco Salemi, Ph.D., an assistant professor in the department of pathology, immunology and laboratory medicine at the UF College of Medicine. "If we want to eradicate HIV we need to find a way to actually target the virus specifically infecting the macrophages."

The work was published recently in the journal PLoS ONE.

At least 1.1 million people in the United States and 33 million in the world are living with HIV/AIDS, according to the Kaiser Family Foundation.

The researchers set out to see if HIV populations that infect abnormal tissues are different from those that infect normal ones, and whether particular strains are associated with certain types of illness.

They tackled the question using frozen post-autopsy tissue samples, pathology results and advanced computational techniques. They analyzed 780 HIV sequences from 53 normal and abnormal tissues from seven patients who had died between 1995 and 2003 from various AIDS-related conditions, including HIV-associated dementia, non-Hodgkin's lymphoma and generalized infections throughout the body. Four patients had been treated with highly active antiretroviral therapy, called HAART, at or near the time of death.

The researchers compared brain and lymphoma tissues, which had heavy concentrations of macrophages, with lymphoid tissues - such as from the spleen and lymph nodes - that had a mix of HIV-infected macrophages and T cells.

The analyses revealed great diversity in the HIV strains present, with different tissues having hybrid viruses made up of slightly different sets of genes. A high frequency of such recombinant viruses was also found in tissues generally associated with disease processes, such as the meninges, spleen and lymph nodes. The researchers concluded that HIV-infected macrophages might be implicated in tumor-producing mechanisms.

The higher frequency of recombinant virus in diseased tissues likely is because macrophages multiply as a result of an inflammatory response, the researchers said.

"The study points to macrophages as a site of recombination in active disease," said neurobiologist Kenneth C. Williams, Ph.D., a Boston College associate professor and AIDS expert who was not involved in the study. "So people can say this is one spot where these viruses come from."

T cells - the so-called conductors of the immune system orchestra, whose decline is the hallmark of HIV disease - are an obvious target for HIV drug development because they die soon after infection, and are readily sampled from the blood and cultured. But although current drugs are effective at blocking infection of new cells and lowering viral loads to barely detectable levels, they never reduce the viral level in an infected person to zero.

"Where is it coming from?" said Michael S. McGrath, the University of California, San Francisco, professor who led the research team. "We believe it's coming from these macrophages."

Macrophages, like T cells, can be infected multiple times by HIV. But unlike T cells, when they get infected, they don't die within days, but live for several months, all the while being re-infected with multiple viruses of different genetic makeup. That situation is ripe for the emergence of hybrids.

"Most people who look at viral sequences assume that evolution of the virus is linear. In the real world that doesn't happen - large parts of the virus are swapped in and out. This group has shown that in this model," Williams said. "It sort of overturns the old way of trying to match virus sequence with pathology."

McGrath's group is now developing macrophage-targeting drugs that, through a grant from the National Institute of Mental Health, should be in human clinical trials in a few years.

"This is one of the last frontiers — killing off what we believe is a so far untouched reservoir," he said.




Should I Stay or Should I Go? Neural Mechanisms of Strategic Decision Making
A new study demonstrates that when faced with a difficult decision, the human brain calls upon multiple neural systems that code for different sorts of behaviors and strategies

The research, published by Cell Press in the May 28th issue of the journal Neuron, provides intriguing insight into the mechanisms that help the human brain rise to the formidable challenge of adaptive decision making in the real world.

"When faced with a complex decision, many individuals engage in simplifying strategies, such as choosing based on the probability of a positive outcome," explains senior study author Dr. Scott Huettel from the Brain Imaging and Analysis Center at Duke University.

"Although we now know much about how the brain encodes specific decision factors like risk and reward, much less is known about the brain selects among multiple strategies for managing the computational demands of a complex decision-making task."

To distinguish brain regions that predict specific choices from those areas that predict an individual's preferred strategy, Dr. Huettel and colleagues used behavioral tests and functional magnetic resonance imaging (fMRI) to study participants engaging in a complex risky choice task.

The task involved economic gambles with multiple outcomes ranging from large monetary losses to large monetary gains. Subjects chose between different ways of changing the gambles: they could maximize the best possible gain, minimize the worst possible loss, or increase the overall probability of winning.

Choices that maximized gains or minimized losses were predicted by fMRI activation in the ventromedial prefrontal cortex or anterior insula, respectively, whereas probability-maximizing choices were associated with activation in the parietal and lateral prefrontal cortices. However, individuals differed in their strategic bias: some people were very focused on gains and losses, while others were very focused on the probability of winning.

Whether an individual expressed these biases in a particular decision was predicted by activation in the dorsomedial prefrontal cortex, which exhibited functional connectivity to the regions associated with specific choices. Further, the intrinsic strategic bias of each person - whether they were focused on rewards or probabilities - was predicted by an independent measure of how strongly their brain responded to unexpected gains and losses.

Importantly, decision parameters estimated using traditional economic models of risky choice were poor predictors of choices in this new experimental paradigm, supporting the idea that individuals indeed engaged in simplifying strategies.

"Our findings indicate that the neural mechanisms of choice reflect more than competition between decision variables; they additionally involve strategic influences that guide decisions differently across individuals," offers Dr. Huettel.


WEDNESDAY May 27, 2009---------------------------News Archive

Strict Maternal Feeding Practices Not Linked to Child Weight Gain
A new study published online in the journal Obesity provides further evidence that strict maternal control over eating habits – such as determining how much a child should eat and coaxing them to eat certain foods – during early childhood may not lead to significant future weight gain in boys or girls. Instead, this behavior may be a response to concerns over a child’s increasing weight

“Our findings suggest that controlling maternal feeding practices probably do not cause increased weight gain, as some previous studies have proposed. In fact, some degree of control may actually be beneficial in helping certain children maintain their weight,” says lead author Kyung E. Rhee, MD, MSc, a researcher with the Weight Control and Diabetes Research Center at The Miriam Hospital. Rhee is also a pediatrician with Hasbro Children’s Hospital and an assistant professor of pediatrics (clinical) at The Warren Alpert Medical School of Brown University.

Controlling or restrictive feeding practices have been associated with disinhibited child eating, increased caloric intake and excessive weight gain, prompting some experts to recommend that parents avoid these overly restrictive behaviors when helping children control their weight. However, as the study authors point out, research on the relationship between controlling feeding practices and child weight has been inconsistent and has not conclusively determined whether these practices cause, or are a consequence of, weight gain.

In the study, researchers examined the data of 789 children who participated in the National Institute of Child Health and Human Development’s Study of Early Child Care and Youth Development. The group included almost equal numbers of girls and boys, which the authors say is significant, since many prior studies have only focused on girls.

Child heights and weights were obtained at ages 4, 7 and 9 and changes in body mass index (BMI) were measured between 4-7 years and 7-9 years. Maternal feeding practices were measured at each age interval by asking mothers the question, “Do you let your child eat what he/she feels like eating?”

Although statistical analyses did not find an association between increases in controlling maternal feeding practices and later child weight gain, it did reveal some interesting gender differences. Researchers found that in boys, increases in restrictive feeding practices between the ages of 4 and 7 were associated with a decreased risk of increased BMI by the time the boys were 7-9 years old. But on the flip side, mothers seemed to increase their control when it appeared their daughters had gained significant amounts of weight between the ages of 4 and 7.

“Our findings mirror those of other studies that have found that parents are much less likely to recognize or be concerned about the overweight status of sons compared to daughters,” says Rhee. “These behaviors may represent a sensitivity to societal values that girls should be slim while boys have a physical or social advantage in being larger.”

Based on these findings, the researchers say restrictive feeding practices may actually be necessary for some children to help regulate their food intake, promote healthier eating habits and limit excessive weight gain. “There has been some concern about the negative impact of restrictive feeding practices and that we should be more lax and let the child determine how much, when and what to eat. However, some degree of control may not be harmful and may actually help certain children maintain their weight,” says Rhee.

However, she adds that further research is needed to define what this type of control looks like. The researchers also call for additional definition and exploration of restrictive feeding practices and their relationship with child weight gain to better inform recommendations for obesity treatment and prevention.

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Well Water Should Be Tested Annually to Reduce Health Risks to Children
Private well water should be tested yearly, and in some cases more often, according to new guidance offered by the American Academy of Pediatrics (AAP)

Researchers at the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health, took a lead role in working with the AAP to develop these recommendations and draft a new AAP policy statement about the things parents should do if their children drink well water.

The recommendations call for annual well testing, especially for nitrate and microorganisms such as coliform bacteria, which can indicate that sewage has contaminated the well. The recommendations point out circumstances when additional testing should occur, including testing when there is a new infant in the house or if the well is subjected to structural damage.

“Children are especially vulnerable to waterborne illnesses that may come from contaminated wells,” said Walter J. Rogan, M.D., an epidemiologist at NIEHS and lead author on the policy statement and technical report that appears in the June issue of Pediatrics. The new policy statement, “Drinking Water from Private Wells and Risks to Children,” offers recommendations for inspection, testing and remediation of wells providing drinking water for children.

“With few exceptions, well owners are responsible for their own wells,” said Rogan. Private wells are not subject to federal regulations and are only minimally regulated by states. With proper care, well water is safe; however, wells can become contaminated by chemicals or pathogenic organisms.

Nitrate, which comes from sewage or fertilizer, is the most common contaminant in wells. The presence of nitrates can be a problem particularly for infants under three months who can not metabolize nitrate. Water with a nitrate concentration of more than 1.0 milligrams per liter should not be used to prepare infant formula or given to a child younger than one year. The policy statement suggests using bottled water for infants when nitrate contamination is detected, or when the source of drinking water is not known.

The policy statement and accompanying technical report point out that water contamination is inherently local, and that families with wells need to keep in contact with state and local health experts to determine what should be tested in their community. For example, some parts of the country may have arsenic, radon, salt intrusion or agricultural runoff that may get into the water supply.

“As people move out of urban and suburban areas into areas that are not reached by municipal water supplies, it is more important than ever that people know who to contact in their local health department to get information about local groundwater conditions,” said N. Beth Ragan of NIEHS, who served as consultant on these reports. A compilation of state by state telephone and Web-based resources of local experts is included in the technical report. Approximately one-sixth of U.S. households now get their drinking water from private wells.

NIEHS Director Linda Birnbaum, Ph.D., says she is pleased that NIEHS researchers took the lead in writing this statement, and continue their longstanding liaisons with the American Academy of Pediatrics to develop state-of-the-science technical reports that can have a direct impact on public health.

“This statement will be extremely useful to many audiences — especially pediatricians,” Birnbaum said. “Pediatricians needed a one-stop shopping document that they can share with parents who have concerns about their children’s sources of drinking water.”



Neurobiology of Musicality Related to Intrinsic Attachment?
In the study of University of Helsinki and Sibelius Academy, Helsinki, the neurobiological basis of music in human evolution and communication was evaluated using candidate genes associated in the earlier studies with social bonding and cognitive functions

The data consisted of 343 family members from 19 Finnish families with at least some professional musicians and/or active amateurs. The musical aptitude was assessed using three music tests: the auditory structuring ability test (Karma Music test) and Carl Seashore's pitch and time discrimination subtests.

Additionally participants filled in an extensive web-based self-report questionnaire and blood samples were collected from the study subjects over 12 years of age. One part of the questionnaire was devised to chart the participants creative functions in music –composing, improvising and arranging of music.

In the study high music test scores were significantly associated with creative functions in music (p< .0001), suggesting composing, improvising and arranging music demands musical aptitude. Creativity is a multifactorial genetic trait involving a complex network made up of a number of genes and environment. Here was shown for the first time that the creative functions in music have a strong genetic component (h2 =.84; composing h2 =.40; arranging h2 =.46; improvising h2 = .62) in Finnish multigenerational families. Additionally the heritability estimates of the musical aptitude were remarkable.

To elucidate the neurobiological basis of music in human evolution and communication the researchers demonstrated an association of arginine vasopressin receptor 1A (AVPR1A) gene variants with musical aptitude. In the previous studies the AVPR1A gene and its homologies have been associated with social, emotional and behavioral traits, including pair bonding and parenting.

The results suggest that the neurobiology of music perception and production is related to the pathways affecting intrinsic attachment behavior.

Music is social communication between individuals. Darwin proposed that singing is used to attract the opposite sex. Furthermore, lullabies are implied to attach infant to a parent and singing or playing music together may add group cohesion.

Thus, it is justified to hypothesize that music perception and creativity in music are linked to the same phenotypic spectrum of human cognitive social skills, like human bonding and altruism both associated with AVPR1A. We have shown for the first time in the molecular level that music perception has an attachment creating impact, says Liisa Ukkola.




Gene Discovered for Cornelia de Lange Syndrome, a Disabling Genetic Disease
An international team of researchers has discovered the gene for Cornelia de Lange syndrome, a disabling, multisystem genetic disease that affects an estimated one in 10,000 children.

The finding is expected to lead to a genetic test, enabling rapid and definitive diagnosis of the syndrome, as well as prenatal testing for families who already have one child with the disease.

Geneticists from The Children's Hospital of Philadelphia and Drexel University College of Medicine in Philadelphia led the study, which received advance online publication on May 17 on the web site of Nature Genetics. In pinpointing the gene, they used an innovative research approach that may lend itself to investigations of other genetic conditions, particularly "orphan diseases:" rare, poorly understood disorders.

The lead researchers, Ian D. Krantz, M.D., of Children's Hospital, and Laird G. Jackson, M.D., of Drexel University College of Medicine, together maintain the world's largest database of patients with Cornelia de Lange syndrome (CdLS), drawing on clinical records and genetic samples first gathered 30 years ago.

Named for a Dutch physician who first described it in 1933, the syndrome often includes mental retardation, impaired growth, heart defects, gastroesophageal reflux and feeding problems, impaired vision, hearing loss, and upper limb abnormalities, including missing fingers or hands. There are typically distinctive facial features, such as thin eyebrows that join together, long eyelashes, thin lips and excessive body hair. In the past, CdLS was often fatal in infancy; now, most children with the condition live into adulthood.

Although CdLS has been known for decades, the disease is a challenge to scientists. "This syndrome has been confusing for a long time, because it's been difficult to trace one source for its multiple effects on many organs," said Dr. Krantz, the lead author and principal investigator of the study. The
disease is also variable - some patients have much milder forms of CdLS. In addition, because few individuals with CdLS had children, it is rare to find parents and children who both have the disease.

In the current study, the researchers analyzed the genomes (the entire genetic makeup in an individual's DNA) of 12 families having more than one member with CdLS. Through a process of elimination, they were able to identify four candidate regions for the CdLS gene. Further analysis narrowed the search to a region of chromosome 5. They combined this knowledge with cytogenetic data - the details of chromosomal rearrangements in a child with CdLS.

The team identified a large gene on chromosome 5, which they named NIPBL. Mutations giving rise to Cornelia de Lange syndrome occur at different locations within that gene.

NIPBL stands for Nipped B-like, because the human gene produces proteins similar to those produced by the Nipped-B gene in fruit flies. "The insect gene was called `Nipped' because a mutation in that gene produces an abnormal fly wing that looks like it had a small bite taken out of it," said Dr. Jackson. Both the fruit fly gene and the human gene regulate biological signals that have wide-ranging effects during development, on a variety of organ systems.

"This discovery is exciting for a number of reasons," said Julie Mairano, executive director of the Cornelia de Lange Syndrome Foundation, based in Avon, Conn. "It will pave the way for genetic tests to confirm a diagnosis and provide comfort for parents who already have one child with the syndrome. It will raise awareness of the disease among physicians and scientists, and, most importantly, focus interest on better treatments for children with Cornelia de Lange syndrome."

When a genetic test for CdLS is developed, said Dr. Krantz, physicians will be able to provide a definitive diagnosis to confirm or rule out a clinical diagnosis. The test will also assist genetic counselors. "Fortunately," says Dr. Krantz, "the disease has a low recurrence risk. Families having one child affected by CdLS have only a one percent chance that a subsequent child will be affected. When a prenatal test is developed, we will determine before birth whether the fetus is among that one percent."

At Children's Hospital, Dr. Krantz directs a full-service clinic for children with CdLS, the only program in the world offering comprehensive services for children with the condition. At this clinic, which attracts patients from around the globe, specialists from a variety of medical disciplines treat each child's specific constellation of symptoms. Treatments may include heart medications, tube feeding and hand surgery.

The long-term goal of the gene discovery, of course, is to improve clinical treatments for the syndrome. "One cannot predict the exact path science takes from a basic discovery to a practical therapy," said Dr. Jackson. "However, better understanding of the specific biological pathways by which a gene mutation affects health and development may lead to new therapies to intervene at different points along the path."


TUESDAY May 26, 2009---------------------------News Archive

Identification of Genetic Variants Affecting Age at Menopause Could Help Improve Fertility
For the first time, scientists have been able to identify genetic factors that influence the age at which natural menopause occurs in women

Ms Lisette Stolk, a researcher from Erasmus MC, Rotterdam, The Netherlands, told the annual conference of the European Society of Human Genetics today ( Monday 25 May) that a greater understanding of the factors influencing age at menopause might eventually help to improve the clinical treatment of infertile women.

Ms Stolk and her team performed a Genome-Wide Association Study (GWAS) in 10,339 menopausal women. The data analysed were taken from 9 different studies undertaken in The Netherlands (the Rotterdam Study 1 and 2), the UK (the TwinsUK study), USA (the Framingham study, the Cardiovascular Health Study, the ARIC study, the HAPI Heart Study), Iceland (AGES-Reykjavik) and Italy (the InCHIANTI study).

The scientists found 20 single nucleotide polymorphisms (SNPs) in four different places on chromosomes 19 and 20. SNPs are common genetic variants that influence how humans look, behave, develop disease or react to pathogens. In genetics they are used to compare regions of the genome between different groups of individuals and to identify those regions that are associated with a particular disease or characteristic.

The SNPs the researchers found had not been identified before, and the part of the body where they might have an effect has yet to be identified, though the researchers speculate that this is likely to be in the ovaries or brain.

"We found that the 20 SNPs were all related to a slightly earlier menopause", said Ms Stolk, "and women who had one of them experienced menopause nearly a year earlier than others. We know that ten years before menopause women are much less fertile, and five years before many are infertile. In Western countries, where women tend to have children later in life and closer to menopause, age at menopause can be an important factor in whether or not a particular woman is able to become a mother."

In addition to its effect on fertility, earlier menopause has other deleterious effects on women such as an increased risk for osteoporosis, osteoarthritis and cardiovascular disease, while it has a protective effect on the risk of breast cancer.

The age of menopause varies greatly among Caucasian women, ranging between 40 and 60 year of age, with an average at around 50. The reasons for this variation are unknown, but there is evidence from studies of twins that this could be due to inheritable genetic factors. However, until now, GWAS had not been used to study the effect of genetic variants on age at menopause.

The scientists intend to follow up their work with an even larger sample of menopausal women to identify more chromosomal loci. "GWAS gives you SNPs connected with menopausal age, and a possible indication of the gene involved, but not a total proof of function", said Ms Stolk. "When we have a larger group of loci we intend to perform functional studies to study the exact biology and effect of this association."

The scientists say that it may be several year before they have enough information to make genotyping for earlier menopause available to patients, and even then this may not be helpful to all women with fertility problems.

"However, if these studies give us a better understanding of the function of the genetic variants involved in early menopause, we might one day be able to screen women who have problems getting pregnant to see if they have one or more of these variants which might relate to their sub-fertility, and perhaps interfere with the relevant physiological pathways in order to delay their total infertility", said Ms Stolk.

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Neural Tube Defects in Mice Linked to Enzyme Deficiency
Women of childbearing age can reduce the risk of having a child born with a neural tube defect such as spina bifida by eating enough folate or folic acid. However, folate prevents only about 70 percent of these defects

New research using mice at Washington University School of Medicine in St. Louis confirms the importance of another nutrient, inositol, to protect against the development of neural tube defects.

A research team led by Monita Wilson, Ph.D., found neural tube defects in some mouse embryos from female mice genetically modified to have low levels of ITPK1, an enzyme involved in the metabolism of inositol, a compound important for neural development and function. The finding suggests that inositol depletion is linked to these birth defects.

The research is published May 25 in the Proceedings of the National Academy of Sciences Early Edition.

In humans, neural tube defects usually occur during the first three to four weeks of pregnancy, before most women know they are pregnant. Certain cells in an embryo form the neural tube, which becomes the foundation of the brain, spinal cord and the bone and tissue surrounding it. A defect forms if the tube does not close properly.

The two most common neural tube defects are spina bifida and anencephaly. Spina bifida affects 1,500 to 2,000 babies born in the United States annually, causing paralysis, spine abnormalities, incontinence and other problems. Anencephaly occurs when the head end of the neural tube fails to close, resulting in the absence of a major portion of the brain, skull and scalp. That condition is fatal.

Wilson, research assistant professor of medicine, and her collaborators created genetically modified mice to have low levels of one of the inositol kinases, then took a close look at their embryos during each day of the 21-day gestation period.

"Because of the short gestation period, a mouse embryo looks very, very different from day to day," Wilson says. "When we looked at the mutant embryos, between the ninth and 12th days of gestation, we noticed that about 12 percent to 15 percent had spina bifida and exencephaly, similar to anencephaly in humans."

Some of the mutant mouse embryos had kyphoscoliosis or other skeletal deformities.

That led the team to consider that there are birth defects that don't respond to folic acid but may respond to inositol treatment, says Wilson, whose research is being funded by the National Institutes of Health and the Children's Discovery Institute at Washington University and St. Louis Children's Hospital.

"Previous animal studies suggest that administration of inositol can further reduce the incidence of neural tube defects, but the mechanism for the protective effect of inositol remains an enigma," says David B. Wilson, M.D., Ph.D., an associate professor of pediatrics and of developmental biology at Washington University and senior author of the study. "By studying these mice we hope to gain insight into the role of inositol in normal and abnormal embryonic development and on gene-nutrient interactions that underlie neural tube defects in humans."

A few studies of human mothers with low inositol levels have shown an increased risk of having children with spina bifida. A clinical trial is under way in the United Kingdom in which women who have a history of one or more pregnancies with neural tube defects and wish to become pregnant again are given folic acid plus inositol or folic acid and a placebo.

Next, Wilson and her colleagues plan to give the genetically modified mice increased doses of inositol to determine if that can prevent these neural tube defects.



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How Genetics Influences Humans to Choose Their Mates
New light has been thrown on how humans choose their partners, a scientist told the annual conference of the European Society of Human Genetics Monday May 25

Professor Maria da Graça Bicalho, head of the Immunogenetics and Histocompatibility Laboratory at the University of Parana, Brazil, says that her research had shown that people with diverse major histocompatibility complexes (MHCs) were more likely to choose each other as mates than those whose MHCs were similar, and that this was likely to be an evolutionary strategy to ensure healthy reproduction.

Females' preference for MHC dissimilar mates has been shown in many vertebrate species, including humans, and it is also known that MHC influences mating selection by preferences for particular body odours. The Brazilian team has been working in this field since 1998, and decided to investigate mate selection in the Brazilian population, while trying to uncover the biological significance of MHC diversity.

The scientists studied MHC data from 90 married couples, and compared them with 152 randomly-generated control couples. They counted the number of MHC dissimilarities among those who were real couples, and compared them with those in the randomly-generated 'virtual couples'. "If MHC genes did not influence mate selection", says Professor Bicalho, "we would have expected to see similar results from both sets of couples. But we found that the real partners had significantly more MHC dissimilarities than we could have expected to find simply by chance."

Within MHC-dissimilar couples the partners will be genetically different, and such a pattern of mate choice decreases the danger of endogamy (mating among relatives) and increases the genetic variability of offspring. Genetic variability is known to be an advantage for offspring, and the MHC effect could be an evolutionary strategy underlying incest avoidance in humans and also improving the efficiency of the immune system, the scientists say.

The MHC is a large genetic region situated on chromosome 6, and found in most vertebrates. It plays an important role in the immune system and also in reproductive success. Apart from being a large region, it is also an extraordinarily diverse one.

"Although it may be tempting to think that humans choose their partners because of their similarities", says Professor Bicalho, "our research has shown clearly that it is differences that make for successful reproduction, and that the subconscious drive to have healthy children is important when choosing a mate."

The scientists believe that their findings will help understanding of conception, fertility, and gestational failures. Research has already shown that couples with similar MHC genes had longer intervals between births, which could imply early, unperceived miscarriages. "We intend to follow up this work by looking at social and cultural influences as well as biological ones in mate choice, and relating these to the genetic diversity of the extended MHC region", says Professor Bicalho.

"We expect to find that cultural aspects play an important role in mate choice, and certainly do not subscribe to the theory that if a person bears a particular genetic variant it will determine his or her behaviour. But we also think that the unconscious evolutionary aspect of partner choice should not be overlooked. We believe our research shows that this has an important role to play in ensuring healthy reproduction, by helping to ensure that children are born with a strong immune system better able to cope with infection."




Nervous System May be Culprit in Deadly Muscle Disease
Brain may win out over brawn as the primary cause of breathing problems in children with a severe form of muscular dystrophy known as Pompe disease

Researchers at the Powell Gene Therapy Center at the University of Florida have discovered that signals from the brain to the diaphragm — the muscle that controls breathing — are too weak to initiate healthy respiration in mouse models of the disease.

The discovery for the first time shifts responsibility to the nervous system for the severe breathing problems experienced by infants with Pompe disease, a rare genetic disorder that causes extreme muscle weakness. Children born with the disorder usually die before age 2.

"For years what we have thought is principally a muscle disease may actually be caused by problems with signaling between the spinal cord and the muscle," said Dr. Barry Byrne, a UF pediatric cardiologist, a member of the UF Genetics Institute and the director of the Powell Gene Therapy Center. "As we've treated children with this disease, we found many of them have become ventilator-dependent, so we went back to the laboratory and found that a significant part of the respiratory deficit is in the spinal cord and not in the diaphragm alone."

The findings, which will be published the week of May 25 in the online early edition of the Proceedings of the National Academy of Sciences, also have a bearing on motor neuron diseases, a group of incurable brain disorders that destroy cells that influence essential muscle activity such as speaking, walking, breathing and swallowing. Notable among these is ALS, technically known as amyotrophic lateral sclerosis or, more commonly, Lou Gehrig's disease.

Although many laboratory discoveries never advance to the point where they can be confirmed in patients, scientists will be able to evaluate whether there is indeed a neural aspect to Pompe disease in a clinical safety study of a gene therapy in six infants with the disorder.

The clinical trial, which will begin this summer at UF, had previously advanced on its merits as a therapy for breathing problems in a group of patients who have very few treatment alternatives.

Children with Pompe disease cannot produce the enzyme acid alpha-glucosidase, or GAA. Without the enzyme, sugars and starches that are stored in the body as glycogen accumulate and destroy muscle cells, particularly those of the heart and respiratory muscles.

In this first-in-humans gene therapy for neuromuscular disease, scientists will incorporate the correct gene to produce GAA into an adeno-associated virus, which already exists in most people, and inject it into each patient's diaphragm. The intent is to "infect" cells of Pompe patients with the genetic machinery they have been missing since birth.

Now, in addition to testing the safety of the dosage and watching closely for signs of therapeutic effects, researchers will fortuitously be able to study the response of the phrenic nerve, which shuttles impulses from the brain to the diaphragm via the spinal cord.

In the PNAS study, UF researchers examined breathing in mice with a form of Pompe disease and in a line of mice genetically engineered to produce GAA only in muscle, not in the central nervous system. In both models, phrenic nerve bursts to stimulate breathing were substantially weaker than in normal mice. As a backdrop, they considered a detailed analysis of a Pompe disease patient's nervous system, finding similar unhealthy glycogen buildup in the spinal cord and deficient neural output to the diaphragm.

"Treatments that target muscle alone may be ineffective," Byrne said. "Fortunately the gene transfer we are attempting also affects the phrenic nerve, and we know in mice we can restore phrenic nerve stimulation of the diaphragm. Ultimately we hope that by restoring the function of this gene in both muscle and nerve the patients may have improved respiratory function and possibly breathe independently."

In addition to Pompe disease, this finding has relevance for congenital and other forms of muscular dystrophy, according to Xiao Xiao, a distinguished professor of gene therapy at the University of North Carolina Eshelman School of Pharmacy at Chapel Hill who was not involved in the research.

"People did not realize there was nerve involvement in these diseases until this study," Xiao said. "It provides us with a new target for therapy, but it also gives us a new challenge. Not only do we have to deliver therapy to the muscle and heart, we now have to deliver it to the nerve. Fortunately Dr. Byrne is very well-qualified and positioned to take this therapy from the bench to the bedside."

The general therapy for children with Pompe disease involves intravenous infusions to replace the missing GAA enzyme, according to Dr. Robert D. Steiner, a professor of pediatrics and molecular and medical genetics and vice chair for pediatric research at Oregon Health & Science University and OHSU Doernbecher Children's Hospital. In a subset of patients, the enzyme replacement therapy helps initially, but becomes ineffective over time.

"I think this study begins to explain some of the difficulties we've had in treating patients," said Steiner, who did not participate in the research. "The findings are clear that central nervous system involvement is likely to be important in Pompe disease, and that treatments that do not take this into account will not be 100 percent effective in the long-term. It is very reasonable to pursue gene therapy for treatment of this disease, because gene therapy makes it possible to target the central nervous system."


MONDAY May 25, 2009---------------------------News Archive

Low Levels of Vitamin D Linked to Common Vaginal Infection in Pregnant Women
Pregnant women with low levels of vitamin D may be more likely to suffer from bacterial vaginosis (BV) – a common vaginal infection that increases a woman’s risk for preterm delivery, according to a University of Pittsburgh study

Available online and published in the June issue of The Journal of Nutrition, the studymay explain why African-American women, who often lack adequate vitamin D, are three times more likely than white women to develop BV.

“Bacterial vaginosis affects nearly one in three reproductive-aged women, so there is great need to understand how it can be prevented,” said Lisa M. Bodnar, Ph.D., M.P.H., R.D., assistant professor of epidemiology, obstetrics and gynecology, University of Pittsburgh.

“It is not only associated with a number of gynecologic conditions, but also may contribute to premature delivery – the leading cause of neonatal mortality – making it of particular concern to pregnant women.”

The study, which included 469 pregnant women, sought to determine whether poor vitamin D status played a role in predisposing women, especially African-Americans, to BV.

Dr. Bodnar and colleagues at Magee-Womens Research Institute found that 41 percent of the study participants had BV and of these, 93 percent had insufficient levels of vitamin D. They also found that the prevalence of BV decreased as vitamin D levels rose.

Vitamin D may play a role in BV by regulating the production and function of antimicrobial molecules, which in turn may help the immune system prevent and control bacterial infection. However, only about one in four Americans gets enough vitamin D.

Vitamin D deficiency may be more common in African-Americans because dark pigmentation limits the amount of vitamin D that can be made in the skin through casual exposure to sunlight. African-American women also are less likely to meet dietary recommendations of vitamin D.

“Although this is a preliminary study, it points out an interesting connection between vitamin D and BV,” said Dr. Bodnar.

“We don’t recommend pregnant women take mega-doses of vitamin D based on these findings, but they should talk with their doctor if they have concerns about their vitamin D status. All women should be encouraged to eat a healthy diet and take a prenatal vitamin before they become pregnant or as soon as they find out they are pregnant.”

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Why the Thumb of the Right Hand is On the Left Hand Side
It is the concentration of a few signaling molecules that determines the fate of individual cells during the early development of organisms

In the renowned journal Current Biology, a team of molecular biologists led by Pia Aanstad of the University of Innsbruck reports that a variety of molecular mechanisms accounts for the interpretation of the concentration of the signaling molecule Hedgehog.

The development of an organism is a complex process to which a dozen or hundreds of signaling molecules contribute. Some of these molecules have dozens of functions in the fruit fly and in humans alike.

One of these molecules – Hedgehog – controls the development of, for example, the extremities, the central nervous system, the teeth, eyes, hair, lung and the gastrointestinal tract. "What is most remarkable: The cells are told what to do not only because the molecule is present but also by the different concentrations of the molecules in the tissue", says group leader Pia Aanstad of the Institute for Molecular Biology of the University of Innsbruck.

"The concentration of Hedgehog makes the thumb of the right hand grow on the left hand side and the thumb of the left hand grow on the right hand side." Thus, scientists define Hedgehog as a morphogen – a signal that is concentration-dependent and controls the pattern formation of an organism.

A mutation in this signaling pathway induces dramatic and embryonically lethal malformations in the early developmental stage such as the formation of just one central eye.

Defects in the Hedgehog signaling pathway in humans are a cause for one of the most common birth defects – holoprosencephaly.

"Hedgehog genes are not new in evolution and the signaling pathway functions in the fly, mouse, fish and in humans similarly", says Pia Aanstad. In her research work she focuses on the zebra danio or zebra fish. Due to the short developmental cycle, the scientists are able to observe the development of the small tropic fish in fast motion. "We want to better understand how the cells process the signals of the signaling molecules and how they react."

Mutants do not react to high concentrations
Already during her time as a post doc in San Francisco, U.S., Pia Aanstad discovered a mutated zebra fish whose Hedgehog signaling pathway was disrupted.

The fish showed a genetic alteration at the so-called Smoothened (Smo) protein, which is located at the cell membrane and transfers the Hedgehog signal into the cell. In 2005, Aanstad and her colleagues published a paper in the renowned journal Nature, in which they showed that Smo is concentrated at cilia (cellular projections) and also functions at the cilium.

"By using high-resolution fluorescence microscopy, we have now shown that in the new mutants a small genetic alteration at the extracellular part of this protein inhibits localization in the cilia and that while the cells identify the Hedgehog signals, they interpret the concentration incorrectly", explains Pia Aanstad.

"This is evidence for the notion that cells use various molecular mechanisms for interpreting different Hedgehog concentrations."

This fact may also be of importance for the diagnosis and treatment of certain cancers (basal cell carcinoma), where the constant up-regulation of the Hedgehog signal is responsible for uncontrolled cell growth.

Aanstad published the findings together with her colleagues from the University of California, San Francisco in the journal Current Biology.



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Yeast Missing Sex Genes Can Still Undergo Sexual Reproduction
An emerging form of the pathogenic yeast Candida is able to complete a full sexual cycle in a test tube, even though it's missing the genes for reproduction

And it may also do so while infecting us, according to Duke University Medical Center researchers.

"Sex contributes to the Candida yeast species' evolutionary success," said Joseph Heitman, MD, PhD, director of the Center for Microbial Pathogenesis in the Duke Department of Molecular Genetics and Microbiology and co-author of two papers that tell the story in Nature and Current Biology. "I think the fact that it has a complete sex cycle is likely to play a role in the evolution of drug resistance in this emerging pathogenic yeast species. "

Yeast infections are notoriously hard to treat and yeast are one of the most successful pathogens and commensals in nature, he said. A commensal is an organism that benefits from associating with another organism without affecting the other.

Humans are susceptible to three types of yeast infection: thrush (in the mouth and throat), vaginal infection, and a sometimes fatal systemic infection of bloodstream and organs, such as the kidney.

In a paper published online May 24 in Nature, Heitman's team reports that eight Candida species which have a sexual cycle were missing many of the genes related to reproduction found in other species.
"The unrecognized sex cycle could mean we need to develop new treatments to combat what is really happening in humans infected by yeast," said co-author Jennifer Reedy, MD, PhD.

With co-author Anna Floyd, Heitman and Reedy explored the question further in a study appearing in the May 14 Current Biology. The major question was: how could the yeast sexually produce spores when they lack so many genes responsible for meiosis, the process of sexual cell division that reduces chromosomes to half their number in the progeny?

By examining and defining the structure and functions of the mating-type genes in yeast, Reedy learned that forms of Candida yeast undergo meiosis but generate offspring of several types.

About two-thirds have the classic 50:50 division of chromosomes from the split parent cell, but a third of them have an extra chromosome or even double copies of all chromosomes.
"What we found is that the sexual cycle has a new way to create genetic diversity, and it provides a unique vantage point from which we can explore the mechanisms of sexual reproduction," Reedy said. "This provides a new way to study sexual reproduction and how chromosomal abnormalities arise."

Heitman said that Candida's meiosis without meiotic genes may be what gives rise to the progeny with unusual numbers of chromosomes. "Maybe the genes were lost for a reason, to provide a route to genetic diversity," Heitman said. "Or maybe these differing types of progeny are the unfortunate consequence of undergoing meiosis without the machinery that species normally have when they reproduce sexually."

Humans, too, have their share of oddly paired chromosomes.

"Experts estimate that about 10 to 30 percent of human eggs or fusion products may be aneuploid, with chromosomes from mother and father not paired exactly one to one, but the great majority of those fusions of sperm and egg don't make it to the implantation and pregnancy stage," Reedy said.

"That's why it is important to find models like this, so that we may shed light on related human conditions."

The Current Biology study was supported by National Institutes of Health/NIAID grants. Dr. Heitman's work in the Nature study was supported by grants from the NIH/National Institute of Allergy and Infectious Diseases (NIAID).




Cancer Cells Disrupt Key Immune System Pathway
Human immune cells communicate constantly with one another as they coordinate to fight off infection and other threats. Now researchers at the School of Medicine have shown that muffling a key voice in this conversational patter is an early step in the progression of human cancers

Silencing an inter-cell signaling mechanism called the interferon pathway may be one way newly developing cancers gain the upper hand. It may also explain the immune dysfunctions seen in many cancer patients and why cancer immunotherapies are often ineffective.

"Over half of cancer patients mount an immune response against their own cancer," said hematologist Peter P. Lee, MD, associate professor of hematology. "So, why does it so often fail? Our research indicates that cancers interfere with a critically important immune signaling pathway. There's a possibility that correcting this defect may one day become part of a useful treatment for many types of cancer."

Lee is the senior author of the research, which was published in the May 18 advance online version of Proceedings of the National Academy of Sciences.

Clues that the interferon pathway is important in fighting off cancers come from mouse models in which the pathway has been artificially disrupted. These animals develop spontaneous tumors at higher rates than normal animals with functional interferon signaling—showing that the immune system quashes many cancers in their infancy. Some viruses are also known to inhibit the interferon pathway.

"It's a very dynamic interaction," said Lee. "If the immune system is successful in stopping a developing cancer, we never know about it because no disease develops. If the cancer cell population overcomes the immune system, you get cancer." In other words, physicians and patients see only the immune system's defeats. This adds an additional hurdle for new cancer treatments called immunotherapies meant to work by stimulating the patient's immune system to attack tumor cells.

Lee and his colleagues had previously shown that the interferon signaling pathway was compromised in melanoma patients. In the current study, the researchers investigated whether patients with two other types of cancer—breast and gastrointestinal—also showed the same defect. They isolated immune cells called lymphocytes in blood samples from patients with three types of cancers (32 breast cancer patients, 12 melanoma patients and 11 gastrointestinal cancer patients) as well as from 28 age-matched healthy patients.

They then compared the response of three classes of lymphocytes-B cells, T cells and NK cells - to exposure to interferons. They found that lymphocytes from breast cancer patients, as well as melanoma and gastrointestinal cancer patients, expressed significantly lower levels of interferon-responsive signaling molecules than did lymphocytes from healthy patients.

"They have a clear defect in the interferon signaling pathway," said Lee. When the researchers looked more closely at the lymphocytes from breast cancer patients, they found that the defect was equally severe in samples from people with early- and late-stage cancers - indicating that the problem must arise soon after the cancer begins to develop - and that it was present regardless of whether the patient had ever been treated with chemotherapy. Finally, the researchers showed that the immune cells from the breast cancer patients responded less efficiently to external activation signals.

"It's now looking like the interferon pathway may harbor a general immune defect in many types of cancers," said Lee. He and his colleagues are working to pinpoint what exactly is going haywire in the pathway and why. They are also investigating whether the problems are likely to block the effectiveness of newer immunotherapies that rely on the presence of a functional immune system.

"Whatever functional defect these immune cells have likely impacts the effectiveness of both active immunotherapy, like cancer vaccines, and passive immunotherapy, like cellular therapies," said Lee. "If these forces are still at play in vivo, the patient's immune response to these types of treatments will be blunted."















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