FRIDAY - April 18, 2008--------------------------------------------------News Archive/Return to Today's News Alerts
Just How Dangerous is Bisphenol-A?
A U.S. federal agency's draft report on the health risks of bisphenol-A, a chemical found in some plastics, is stirring new controversy about the hormonelike substance. Although the report mostly mirrors an outside group's conclusions of last year, it increases concerns about certain risks to fetuses and children. Environmentalists praise the report, but it's unclear whether the findings will initiate regulation.
Bisphenol-A (BPA) is found in polycarbonate bottles, including some water and baby bottles, and the liners of some metal food cans. It has been detected in the blood of most Americans. At high levels, BPA acts like a hormone, causing lower birthweight and delayed puberty in offspring.
In August 2007, a panel of outside experts convened by the federal National Toxicology Program (NTP) found many of BPA studies unconvincing, even while expressing "some concern" about changes in the brain of the developing fetus. Adding to the controversy, a contractor hired to help draft the report had received industry funding.
Now the NTP's own scientists have "some concern" not only for neurobehavioral effects, but for potential precancerous breast and prostate lesions, and delayed puberty in females. Michael Shelby, director of the NTP Center for the Evaluation of Risks to Human Reproduction, explains that new research papers led NTP to "give a little more credence" to reports of prostate changes in newborn animals. The NTP also noted saw that low-level BPA did alter breast development, and concluded that certain mouse studies on accelerated puberty in females were convincing.
Although Shelby says it is unusual for the NTP to depart from an outside panels' conclusions, it is not unprecedented. "The comments and controversy sure were an impetus to look a little closer." However, as both panels had only "some concern," about BPA, this is less likely to trigger regulatory action than a higher level of concern, note Shelby.
Sonya Lunder, senior analyst at the Environmental Working Group, an advocacy group, lauds the NTP's decision to include many studies discarded by the earlier panel. She feels the Food and Drug Administration "will have to take another look at the literature." The NTP draft report will now go through a comment period and peer review.
However, Canadian scientists are expected to issue their report about BPA risks that could lead to the first national limit or ban on the chemical.
Released April 14, 2008, the DRAFT NTP BRIEF ON BISPHENOL A
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Bacterial Species Teaches Us About Cell Shape and Polarity
Christine Jacobs-Wagner joined the lab of Lucy Shapiro at Stanford University in 1996, where she spent four productive years exploring how Caulobacter crescentus - a bacteria - coordinates its development.
When Caulobacter divides, it does so asymmetrically, producing daughter cells that have different fates. One daughter, the swarmer cell, grows a polar flagellum and swims off. The other daughter, the stalk cell, attaches itself to a rock - grows and at some point divides to produce another swarmer. Each swarmer cell eventually differentiates into a stalk cell and begins the cycle again.
In Shapiro's lab, Jacobs-Wagner studied a histidine kinase involved in initiating some of the differentiation events in swarmer cells. To determine where in the cell the kinase would go, Jacobs-Wagner tagged the protein with green fluorescent protein and then took her samples to Losick's Harvard lab, which was set up to do fluorescence microscopy. "At the time they had only one microscope," she recalls. "Since I was the outsider, I got to use it from two o'clock in the morning until 6:00, which was the only time it was free. So I was working all night e-mailing Lucy my results."
She found that the kinase changes its location during the cell cycle. "At certain times it was going to one pole, at other times to both poles, and at one point it actually delocalizes," she says. That movement was key for the cell's growth and survival.
Says Lucy Shapiro: "It was the first that we knew that a regulatory protein was dynamically localized. This is a bacterial cell. It's two microns long. Everybody thought any protein could get anywhere by diffusion and that no protein needed to be anywhere in particular." "Still to this day it amazes me," says Jacobs-Wagner. "Bacterial cells are so tiny. So what's the point of a protein being 'here' when it only takes milliseconds for it to go anywhere?" She continued to explore this question. "We've made some progress in understanding that certain bacterial proteins are localized," she says. "But we still don't know why they do it, or how."
While pursuing the question, Jacobs-Wagner and her postdoc, Nora Ausmees, discovered crescentin, the protein that gives Caulobacter its characteristic crescent shape. Ausmees was searching for mutants in which a few proteins of interest were no longer localized. Instead she stumbled across a cell that was no longer curved. "We thought it was intriguing," says Jacobs-Wagner. So they studied these straight cells and found that they lacked crescentin - a protein that forms a filament along the inner curvature of the bacterium. Even more stunning, crescentin polymerizes into a structure called an intermediate filament, a cytoskeletal element seen before only in animal cells.
"It was a big surprise," says Yale's Thomas Pollard, an expert on the cytoskeleton. "It's always fun when someone outside the field — Christine was definitely not working on intermediate filaments before this — shocks everybody in the field by finding something they thought didn't exist."
Since the crescentin discovery in 2003, Jacobs-Wagner has gone on to identify and characterize other interesting Caulobacter proteins, including one that serves as a landmark as it allows cells to figure out which end of the bacteria is which. Reasoning that any protein that acted as a cell-pole marker probably works by recruiting other proteins: ".. we decided to search the genome for proteins rich in protein-interaction domains." Of the nine proteins they identified, three localized to specific sites, and one they named TipN. "It was a pretty weak rationale," she says, "but it worked."
About the same time, another team identified TipN in a genetic screen. "We were looking for genes that regulate flagellar function or positioning," says Patrick Viollier of Case Western Reserve University, who overlapped with Jacobs-Wagner as a postdoc in Shapiro's lab. "We looked for mutants that didn't swim properly and isolated a bunch of genes," one of which turned out to be TipN. Caulobacter that lack TipN assemble their flagella in the wrong place.
Their complementary approaches, made for a strong story, and both groups published their findings in back-to-back in the journal Cell in 2006.
"That discovery was as significant, perhaps even more so, than the work on [crescentin] curving," says Margolin. "Most cells, including eukaryotic cells, are polar: They have a top and bottom, but it's not well understood how that happens." Approaching the problem in simpler organisms, such as Caulobacter, he says, "could bring us closer to understanding how any cell can make each of its ends different."
Published March 10, 2006 in the journal Cell
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Premature Baby's Fate Depends On More Than Age
Four factors beyond gestational age influence whether an extremely premature baby will survive and grow up healthy, U.S. researchers reported.
Girls, babies that weigh more and babies that do not have a twin all survived premature birth better, as did babies whose mothers were treated with steroids to hasten the development of the lungs, the researchers reported in the New England Journal of Medicine. These factors also lowered the risk of neurodevelopmental problems such as blindness, hearing loss, thinking problems and cerebral palsy.
"Using the five factors in combination really gives you a better idea of how children are going to do, rather than singling out a single factor," Dr. Rosemary Higgins of the National Institute of Child Health and Human Development (NICHD), who worked on the study, said in a telephone interview. The findings are designed to help doctors and patients decide whether to give aggressive treatment or only comfort care to such children.
Usually, doctors treat an extremely premature infant primarily on the basis of its gestational age, but they cannot always tell with certainty when a child was conceived. Researchers, led by Jon Tyson of the University of Texas Medical School at Houston, studied 4,446 infants born 22 to 25 weeks after conception. Full-term pregnancy lasts 40 weeks. Forty-nine percent of the infants in the study died and 21 percent survived without a disability based on tests done when they were about two years old. "We found that about half of the infants survived and that about half of those who survived had neurodevelopmental impairments. This is a very, very high risk group of babies," Tyson said in a statement.
The NICHD, which funded the study, has used the data to create a Web site that outlines the odds of healthy survival in specific cases. A calculator here is designed to guide doctors and families. For example, the site estimates that a 23-week-old girl weighing 28 ounces (800 grams) who received steroid treatment and was born alone has a 36 percent chance of survival without a neurodevelopmental impairment. At 22 weeks, the likelihood drops to just 12 percent.
"Sometimes gestational age can be off by a week or two, depending on dating or ultrasound," said Higgins. "As you can see from the study, a week makes a big difference." So does gender. A boy born at 23 weeks under those circumstances has a 22 percent chance of surviving without impairment, although the researchers stressed these numbers are just estimates based on the new data. "There clearly appears to be a biologic difference that gives girls a week advantage over the boys for the same gestational age. It's a difference that's unexplained," Higgins said.
Published April 17, 2008 in the New England Journal of Medicine
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Brain-Freeze Reveals Auditory Pathways
The brain's sound processing areas are split into two distinct regions - one which determines what a sound is, the other which tracks where it's coming from, according to research published online (April 13) in Nature Neuroscience.
Physiological recordings in animals, including humans, have been consistent with two pathways in auditory regions, but conclusive evidence was lacking. Now, researchers have separated the "what" and the "where" of hearing, and shown that dual-processing does exist in the auditory cortex.
"The brain breaks down information into two fundamental dimensions," said Stephen Lomber of the University of Western Ontario in London, Canada, who led the study. "This could be a defining principle for sensory information."
Lomber and his colleague, Shveta Malhotra of the University of Texas at Dallas, placed cooling coils on the surface of the brains of three cats to deactivate specific areas of the auditory cortex as the cats listened and responded to different sounds - a reversible procedure. They found that when they deactivated a region called the posterior auditory field, the cats failed to locate a sound; however, they could still discriminate between different sound patterns, indicating that only the "where" auditory pathway was affected. Conversely, when the nearby anterior auditory field was deactivated by cooling, cats could find where the sound was coming from, but they couldn't tell what type of sound it was, showing only the "what" pathway was affected.
David Moore of the MRC Institute of Hearing Research in Nottingham, England, who was not involved in the research, said the study shows a clear functional segregation of the hearing tasks tested, but he's not convinced by the conclusions that all "what" and "where" related auditory functions will be processed in the same regions. "There's a difference between the two particular sorts of test, but it doesn't necessarily give any more information that that."
Jyrki Ahveninen of Harvard Medical School said the approach is a powerful way of causing temporary lesions in a healthy brain, but he worries that the technique may not be truly "reversible," and that longer term effects could interfere with the data. "If you cool part of the brain, it takes some time to heat back up," he said.
Also, it remains to be seen whether the dual pathway Lomber describes in cats also occurs in primates. Micah Murray of Vaudois University Hospital Center in Lausanne, Switzerland, described the cooling method as a "very interesting technique for emulating the behavioral consequences of stroke" in humans, but he cautioned that different functional regions of the brain might be involved in human hearing.
Published April 13, 2008 in the journal Nature Neuroscience doi: 10.1038/nn.2108, Article
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THURSDAY - April 17, 2008----------------------------------------------News Archive/Return to Today's News Alerts
Health Risks, Benefits Come With Delayed Umbilical Cord Clamping
Waiting just a few minutes to clamp the umbilical cord after a baby is born could boost iron stores in the newborn’s blood, but delayed cord clamping comes with an increased risk of jaundice, according to a new review of studies.
Clamping the cord within 30 to 60 seconds after birth is one of three steps in an “active management” approach to the third stage of labor, a time when a new mother is vulnerable to excessive blood loss. Studies show that active management reduces the risk for hemorrhage, but now lead review author Susan McDonald and other investigators are refining that research.
“We’ve started to ask ‘Is it necessary that we do all three? Which part of this is most important? Did timing of clamping the cord make a difference?’” said McDonald, a professor of midwifery at La Trobe University and the Mercy Hospital for Women in Melbourne, Australia. Of the studies included in the review: “We found in terms of the amount of bleeding, delayed clamping did not increase the mother’s risk of bleeding,” said McDonald.
The review appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.
The review of 11 studies evaluates the maternal and infant benefits of delaying cord clamping until after the cord stops pulsing, a sign that blood is no longer flowing between the mother’s placenta and the baby. McDonald said in most cases the time difference between early and late cord clamping is just one or two minutes, but the delay allows for an additional infusion of blood from mother to child. His analysis found that newborns in the delayed-clamping group had larger stores of iron in their blood. The amount of iron in the blood at birth can influence health, particularly an infant’s risk for anemia in the first months of life.
However, the study also found that infants in the delayed-clamping group were more vulnerable to jaundice. Many babies get a mild form of jaundice at birth because the liver is immature and cannot process bilirubin, a yellow byproduct of the breakdown of old red blood cells. “When the liver can’t process all the bilirubin it tends to get pushed out to the tissue and the baby looks a little bit yellow,” McDonald said. Most newborn jaundice subsides without treatment or is treated with simple exposure to sunlight. The review found that infants in the delayed-clamping group had a higher risk for jaundice that needed extra treatment with phototherapy.
“In most places in Western countries where there is a higher income, people have access to hospitals where babies can get that therapy,” McDonald said. “But if you are working in an area where you don’t have easy access to treat a child with more severe jaundice, then as a clinician you would need to weigh up the benefits and risks. Allowing the baby to get the extra blood and maybe become jaundiced is a particular problem if you don’t have the facilities. In that case, perhaps, you would err on the side of clamping the cord a little earlier,” she said.
“There’s a happy medium you try to strike,” said Joyce Roberts, a certified nurse midwife, professor and coordinator of the Nurse-Midwifery Track at the University of Michigan School of Nursing. Roberts said many midwives put the baby on the mother’s abdomen, above the level of the placenta, so blood continues to flow, but not to excess.
Published April 16, 2008 in the Cochrane Database of Systematic Reviews.
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Sperm and Eggs From Stem Cells ‘In 15 Years’?
Human sperm and eggs will be grown from stem cells within five to fifteen years but the technology will not allow gay and lesbian couples to conceive children with genes from each partner, an international panel of scientists predicted recently.
While artificial gametes (reproductive cells) could be used to treat infertility, the biological barriers to creating sperm from female cells and eggs from male ones will make same-sex conception impossible for the foreseeable future, according to the Hinxton group of leading stem-cell researchers.
Mouse sperm grown from stem cells have already been used to fertilise eggs and produce live pups, and the success has suggested that the technique could allow men and women who make no gametes of their own to have children.
Cells from an infertile man or woman would first be reprogrammed into an embryonic state, or used to make cloned embryonic stem cells. The resulting stem cells would then be turned into sperm or eggs, which would carry the patient’s DNA.
The research has prompted speculation that sperm could be produced from a woman or eggs from a man, allowing lesbian or gay couples to have children to whom both partners make an equal genetic contribution. Some who object to the technology have even argued that it could lead to “ultimate incest”, by which a single person becomes mother and father of a child. Researchers, however, dismissed the prospect of male eggs and female sperm as science fiction in the new Hinxton group report.
Human sex is determined by the inheritence patterns of the X and Y chromosomes: women have two copies of the X, while men have one X and one Y. As several genes that are critical to sperm production are carried on the Y chromosome, this will make it “difficult or even impossible” to turn female cells with two X chromosomes into sperm under any circumstances currently known to science. The production of eggs from male cells is a little less problematic, but even this is likely to be “very difficult”, the report said.
Professor Robin Lovell-Badge, of the National Institute for Medical Research in London, a member of the Hinxton group’s steering committee, said: “It would be very difficult to get eggs from XY cells, and even more difficult to get sperm from XX cells – my own view, indeed, is that the latter is impossible.”
Under the Human Fertilisation and Embryology Bill currently passing through British Parliament, laboratory experiments with these cells will be permitted, but it will be illegal to use them in fertility treatment. Members of Parliment are expected to table an amendment that would allow Parliament to approve their clinical use in the future, without recourse to primary legislation. Professor Lovell-Badge said he would support such an amendment. An American scientist has suggested that a new method for reprogramming adult cells into an embryo-like state could be used to produce genetically engineered children. Stem cells produced with the technique could be added to human embryos, so that they developed into “chimeras” that contain cells with two distinct genetic signatures, according to Robert Lanza, of Advanced Cell Technologies
Other scientists, however, questioned the usefulness of this approach, which would in any case be banned in Britain. Professor Lovell-Badge said: “I cannot think what might be gained by doing this.”
In early 2004, members of the Stem Cell Policy and Ethics Program (SCOPE) at the The Johns Hopkins Berman Institute of Bioethics began developing a new project, aspiring to bring together an esteemed, international and interdisciplinary group to explore the ethical and policy challenges of transnational scientific collaboration raised by variations in national regulations governing embryo research and stem cell science. While this project was originally planned as a single meeting in Hinxton, UK, the delegates, calling themselves the ‘Hinxton Group’, decided that there were additional challenges they would be able and willing to address, and that this group should not dissolve. Coordinated by a US/UK steering committee, the Hinxton Group is an informal collection of individuals interested in ethical and well-regulated science.
Referenced April 15, 2008 to the Hinxton Group, UK
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Stem Cell Marker Controls Two Key Cancer Pathways
Researchers at Georgetown University Medical Center have discovered that a gene associated with human breast stem cells can stimulate development of mammary cells by activating two critical cancer pathways. They say this finding, reported at the annual meeting of the American Association for Cancer Research (AACR), provides new evidence that breast cancer can arise from stem cells and that targeting this gene might provide a new way to treat cancers of the breast as well as other tumor types.
“This is the first time any role has been attributed to this gene, and it turns out to be one that is surprisingly powerful,” says the study’s lead author, Xiaoyang Wang, Ph.D., Postdoctoral Fellow at Georgetown’s Lombardi Comprehensive Cancer Center.
Specifically, Wang and the researchers show for the first time that this gene, Musashi1 (Msi1), switches on Wnt and Notch cell signaling. Both of these pathways help control stem cell growth, and are known to be critically important to the development of many cancers. Msi1 was named after a famous 17th century Japanese swordsman, Miyamoto Musashi, by Japanese researcher Hideyuki Okano, Ph.D., who identified it in fruit flies in 1994. Okano currently collaborates with the Georgetown scientists. Recent studies have shown Msi1 to be a marker of human stem cells in general because it has been found in human breast, colon, brain, skin, and other cells, says Robert Glazer, Ph.D., a professor of Oncology and Pharmacology and the study’s senior author.
So Glazer and Wang decided to probe the gene’s function. “Msi1 is known to be a marker of stem cells, but no one knows what it does. We wanted to see if it had a function in the mammary gland,” Glazer says. They were especially interested in whether Msi1 is associated with cancer development because recent studies have suggested that stem cells may be the causative root of some cancers – a notion that is vigorously debated among cancer researchers. “It is really critical to understand if stem cells are involved in cancer development because a lot of therapies used to treat cancer don’t target stem cells,” he says. “That may explain why tumors come back.”
In laboratory experiments, the scientists found that, in mammary cell development, Msi1 drives mammary cells along different lineages – in other words, it can decide what type of cell develops in the breast, be it muscle cells or cells that line milk ducts, etc. In cancer, the Wnt and Notch pathways are often activated, and the researchers found that Msi1 is expressed in particularly aggressive tumors. The researchers then tested whether Msi1 regulates these pathways in mammary cells and found that it did.
They then studied how Msi1 drives the Wnt and Notch pathways found that when Msi1 was over-expressed, there was an increased secretion of a growth factor known as proliferin, and reduced secretion of the Wnt pathway inhibitor, Dickkopf-3. Additionally, Msi1 programmed the expression of a number of genes that have a concerted effect on the cell cycle, Wang says.
“We believe that while Msi1 may contribute to cell proliferation, it is not the single gene that controls cancer development,” Glazer says. “This work suggests, but does not prove, that stem cells drive breast cancer formation,” he says. “Msi1 might make a good therapeutic target, and we are currently testing ways to interfere with its function in cells to see if it disrupts cancer cell proliferation.”
The study was funded by the Charlotte Geyer Foundation and the National Institutes of Health.
Presented April 12 - 16, 2008 at the annual meeting of the AACR - American Association of Cancer Research
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One Step Closer to Understanding the Causes of Sexual Difficulties in Women
Researchers at the Kinsey Institute for Research in Sex, Gender and Reproduction are shedding light on why some women experience sexual problems and others do not.
A study published in the April issue of the journal "Archives of Sexual Behavior" found connections between personality traits such as sexual inhibition and sexual problems.
While previous studies have explored the role demographics such as age, education and socio-economic status play in sexual functioning among women, few have explored the role differences in personality play in predicting current and lifetime sexual problems. In this study, women's sexual inhibition tendencies were more important than other factors in predicting sexual problems.
"Although further research is needed to confirm these findings with other samples, particularly clinical samples of women seeking help for sexual problems, these findings suggest that high scores on sexual inhibition may help predict which women are vulnerable to experience sexual problems," said Cynthia Graham, research fellow at the Kinsey Institute and co-author of the paper. "They may also be used as prognostic factors in treatment studies."
Researchers studied the responses of 540 women on the Sexual Excitation/Sexual Inhibition Inventory for Women that rated current and sexual problems, lifetime arousal difficulty and lifetime problems with low sexual interest. The strongest predictors of reports of sexual problems were women's sexual inhibition scores. Below are some of the findings:
Sexual inhibition scores were the strongest predictor of current and past sexual problems including lifetime arousal difficulty and low sexual interest. They were better predictors than demographic and background factors such as age, socio-economic status, and whether or not women were in a sexual relationship.
"Arousal Contingency" or the ease with which arousal can be disrupted by situational factors, and "Concerns about Sexual Function" were the two most predictive of women's sexual problems.
The Kinsey Institute has been developing, testing and fine-tuning the dual control model of sexual response, which is the basis for the Sexual Excitation/Sexual Inhibition Inventory for Women used in this study. This theoretical model reflects the idea that sexual response in individuals is the product of a balance between excitatory and inhibitory processes. Researchers believe these two systems operate somewhat independent of each other and are different in each person.
Researchers are using the dual control model to better understand such complex issues as sexual difficulties, sexual compulsivity and high-risk sexual behaviors. Prior studies have found that while sexual inhibition plays an important protective role in restraining sexual responses, individuals who score highly in inhibition might be more likely to experience sexual problems.
This particular study aimed to gain insight into the role of inhibition and excitation proneness in predicting sexual problems in a non-clinical sample of women.
Published April, 2008 in the journal Archives of Sexual Behavior
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WEDNESDAY - April 16, 2008----------------------------------------------News Archive/Return to Today's News Alerts
Possible Link Between Baby Swimming and Breathing Problems in Children
Children with mothers who have allergies or asthma have an increased risk of wheezing in the chest if they take part in baby swimming before 6 months of age. This is shown in a new study using data from the Norwegian Mother and Child Study (MoBa) at the Norwegian Institute of Public Health (NIPH). The results come from a study of 30 000 participants from MoBa. Approximately 25 percent of these children took part in baby swimming from 0-6 months of age.
Most children who take part in baby swimming show no increased incidence of lower respiratory tract infections, ear inflammation (otitis media) or tightness and wheezing in the chest. Between 6-18 months the incidence of lower respiratory tract infections and otitis media were 13 percent and 30 percent respectively, whilst the proportion of children who experienced tightness or wheezing in the chest was 40 percent.
Among children of mothers with asthma and allergy, 44 percent of those who did not go swimming had tightness or wheezing in the chest. This was compared to the 47 percent of children who swam and experienced tightness and wheezing who had mothers with asthma and allergies. The difference is not large but it indicates a tendency to respiratory problems, says Wenche Nystad, primary author and Department Director at the NIPH’s Division of Epidemiology.
Earlier studies indicated that there can be a link between baby swimming and airway infections in children. It has been suggested that indoor environmental factors (airway irritants) such as volatile chlorination products for indoor swimming pools can affect lung epithelium and contribute to the development of respiratory illnesses like asthma among children.
The connection between respiratory problems and baby swimming was suggested by a pediatrician who asked whether children with increased risk of asthma, who took part in baby swimming, had a greater tendency to develop respiratory diseases. Earlier studies indicated a connection but the results were uncertain. Therefore we want to carry out a more thorough study, says Nystad. If mother and baby are healthy, the study shows that there is no increased risk of otitis media or respiratory problems with baby swimming before six months of age.
Published April 10, 2008 in the journal Acta. Paediatric.
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Molecule Prompts Blood Stem Cells to Help Repair Heart Damage in Animal Model
Researchers at UT Southwestern Medical Center have for the first time used drug-treated blood stem cells to repair heart damage in an animal model, results that might point to methods for healing injuries from heart attacks or disease.
In the study, researchers screened about 147,000 molecules to find one that could transform human blood stem cells into a form resembling immature heart cells. When they implanted blood stem cells activated by this compound into injured rodent hearts, the human cells took root and improved the animals’ heart function.
“The clinical potential is enormous,” said Dr. Jay Schneider, assistant professor of internal medicine and senior author of the study, which appears online this week and in a future issue of the Proceedings of the National Academy of Sciences.
Despite medical advances in treating and preventing heart attacks, once the heart is damaged it cannot repair itself, said Dr. Schneider, a cardiologist.
“Heart attack is a man-made problem,” he said. “It’s a function of increased longevity and atherosclerosis, which have occurred at no other time in human evolution.”
In the first stage of the current study, which involved mouse stem cells, the researchers screened some 147,000 compounds in UT Southwestern’s Small Molecule Library to see which ones would activate genes known to be at work in the early stages of heart development.
This initial screening sifted out about 1,600 compounds, but the researchers narrowed their focus to a related group of molecules, among the most potent and easy to make, called Shz for sulfonyl-hydrazone.
The researchers then tested the effects of one Shz compound, Shz-3, a molecular variant synthesized by chemists at UT Southwestern, on human blood stem cells. These cells, called PBMCs for peripheral blood mononuclear cells, were cultured with Shz-3 for three days, then for seven days without the drug.
Tests showed that the Shz-treated cells began to create RNAs and proteins found only in heart cells. They were then implanted into the hearts of rats with heart damage. After a week, the function of the rats’ hearts had significantly improved, and after three weeks, the organs contracted as strongly as they did before the damage. Tests showed that the human cells were alive and had incorporated themselves into the heart tissue, although the researchers could not tell whether the human cells had become fully functional, contracting heart cells.
“This functional test is a good first step,” Dr. Schneider said “What this shows is that this drug can act on blood stem cells that are already being used in other clinical trials. This may speed its movement into clinical trials for heart repair.”
Shz compounds do not appear to be toxic in mice, and because the human blood stem cells are washed for seven days after treatment, the compounds are likely not to be harmful to humans, although further tests are needed, Dr. Schneider said.
Further studies will examine precisely what the Shz drugs are doing to the cells, and to identify additional chemical signals that might drive the cells toward a more mature form of heart cell, the researchers said.
Published April 14, 2008 in the Proceedings of the National Academy of Sciences
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Fetal DNA Identifies Rh Incompatibility Between Mom & Baby
Rh-negative mothers may be able to avoid unnecessary prophylaxis with anti-Rh immunoglobulin with screening by high throughput fetal genotyping.
A mother who is Rh-negative and is carrying an Rh-positive fetus may develop antibodies against the Rh antigen if fetal blood enters her bloodstream. If she becomes pregnant again and the fetus is Rh positive, the antibodies can cross the placental barrier and cause hemolytic disease of the newborn, which accounts for one death in every 21,000 births.
Most women who are Rh negative receive injections of anti-Rhesus-D immunoglobulin, which prevents the development of the antibodies, around 28 weeks of gestation as a precaution. Sensitizing events - those that lead to the development of antibodies - such as abdominal trauma or vaginal bleeding after 28 weeks result in a second injection. But this practice is expensive, according to the researchers, and many women who are carrying an Rh-negative fetus are treated unnecessarily.
Widespread application of this high throughput test for identifying fetal Rhesus-D status, the researchers wrote, "would avoid unnecessary treatment … and avert the associated discomfort, inconvenience, and risk of exposure to pooled donor blood products that such injections entail," they wrote.
To test the effectiveness of their technique, the researchers obtained blood from 1,997 pregnant women with a mean gestational age of 27.9 weeks. DNA was robotically extracted and placed into a polymerase chain reaction plate. Polymerase chain reactions were performed to detect the presence of fetal RHD, the gene that encodes the Rhesus-D antigen, the most common of the Rh-factor antigens. Genotyping results were then compared with Rh-D typing of cord blood samples after birth.
More infants had a positive Rh status than negative (59.8% versus 35.9%). The fetal genotyping test predicted the Rh status that was confirmed through testing the cord blood in 95.7% of cases. Inconclusive fetal genotyping results were obtained in 3% of samples.
If this model had been applied to guide treatment in the women in this study, only 2% of women would have received anti-Rh immunoglobulin unnecessarily, compared with 38% without genotyping, the researchers said.
Sailesh Kumar, M.B.B.S., of Queen Charlotte's and Chelsea Hospital in London, wrote in an accompanying editorial that "non-invasive detection of fetal RHD status using maternal plasma is one of the few real advances in fetal medicine or obstetrics in recent years." Accurate and inexpensive tests like Dr. Daniels and colleagues' high throughput method could lead to the abandonment of invasive procedures, which are associated with a small risk of pregnancy loss, he said. The results of this study, Dr. Kumar said, "demonstrate the reliability of the automated technique and the feasibility of large-scale antenatal testing."
He pointed out that costs of the technique were not addressed in the study, but said that mass testing would likely save money by reducing pharmacy and manpower costs. "Automated techniques should make mass testing easier and cost-effective, and they should minimize the risks of receiving an unnecessary blood product," he concluded. "If these techniques are shown to be as reliable earlier in pregnancy, the arguments for recommending universal testing will be compelling."The researchers said that they are about to start feasibility trials on testing maternal blood samples as early as eight to 16 weeks of gestation.
Published April 3, 2008 in the British Medical Journal - BMJ
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St. Jude's Finds Three Proteins that Halt Child Brain Tumors
A discovery by St. Jude scientists suggests a safer way to treat medulloblastoma, a rare but often fatal childhood brain tumor. The group found that one of the brain’s signaling pathways inhibits the growth of the highly aggressive cancer cells.
The researchers discovered that three proteins, designated BMP2, BMP4 and BMP7, halted the growth of medulloblastoma tumors and induced the malignant cells to develop into normal neurons.
“We think we have identified a pathway that can be used to prevent tumor formation and a potential target for therapy,” said Martine Roussel, PhD, Genetics and Tumor Cell Biology. A report on this work appears in the March 15 issue of Genes & Development. Roussel is the paper’s senior author.
Medulloblastoma occurs in the cerebellum, which is located in the lower, rear part of the brain. This cancer strikes about 350 young children in the United States annually. Although treated patients have an overall five year survival rate of 70 percent, conventional therapies combining surgery, irradiation and chemotherapy frequently lead to permanent neurocognitive impairment.
Several research teams are seeking to decipher the intricate signaling mechanisms that govern the proliferation of cells called granule neuron progenitors (GNPs). These cells go on to develop into neurons in the cerebellum during the first year of life. But the disruption of this differentiation process can trigger medulloblastoma.
“We were interested in whether there were signals that inhibited tumor formation,” Roussel said. “And if there were, which ones were they? Could they be used to identify new therapeutic targets?”
Previous research had shown that spurring GNPs to differentiate into neurons requires that BMPs bind to a set of receptors on the cell surface. This binding results in blocking the activity of a signaling pathway triggered by another molecule called Sonic hedgehog.
“What was not known, and what we now find, is that the effect of BMPs on normal GNP cells is almost exactly mimicked in GNP-like tumor cells,” Roussel said. In cell culture experiments, her group found that BMPs rapidly cause the degradation of a protein called Math1, which occurs in dividing GNPs but not in non-proliferating neurons. Twelve hours after BMP treatment, researchers could detect no Math1 and cell growth soon stopped.
The exact way Math1 works remains unknown. However, in mice the protein is vital to the formation of a normal brain. Mice genetically altered so they did not carry the gene for Math1 failed to develop cerebellums.
The St. Jude team also performed gene transfer experiments in mice to test BMPs as a possible medulloblastoma treatment. Using a genetically altered virus, scientists inserted the BMP gene into the cancer cells and showed that the transfer not only halted tumor growth, but induced the cancer cells to change into neurons.
BMPs, however, are extremely expensive to purify. Currently, the St. Jude researchers are searching for tiny, less expensive biological molecules that might mimic the action of BMPs in medulloblastoma.
Roussel also suggests that the ability of BMPs to transform medulloblastoma cells into normal neurons, coupled with a discovery made earlier at St. Jude, could offer a combination treatment for the cancer. In 2004, a St. Jude team reported that an experimental drug called HhAntag, which inhibits Sonic hedgehog signaling, led to the deaths of medulloblastoma cells and the elimination of these tumors in treated mice. However, the team also found that treatment with HhAntag interfered with bone development in the animals, suggesting an unwelcome side effect in young children.
Roussel’s group reported that although both the Sonic hedgehog and BMP pathways play roles in regulating cell division, they do so in distinctly different ways. This led to testing the two in combination. “What we found is that using a lower dose of the Sonic hedgehog inhibitor in combination with BMP gives the same therapeutic effect as high doses of the hedgehog inhibitor,” Roussel said. “We hope that by reducing the levels of both compounds, we might prevent the secondary effects on bone of this potential therapy.”
Published March 15, 2008 in the journal Genes & Development
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TUESDAY - April 15, 2008--------------------------------------------------News Archive/Return to Today's News Alerts
Heart Disease Predetermined by Oxygen Levels in the Womb
The amount of oxygen available to a baby in the womb can affect their susceptibility to developing particular diseases later in life. Research funded by the UK Biotechnology and Biological Sciences Research Council and the British Heart foundation and presented at the annual Society for Endocrinology BES meeting in Harrogate shows that your risk of developing cardiovascular disease can be predetermined before birth, not only by your genes, but also by their interaction with the quality of the environment you experience in the womb.
Researchers at the University of Cambridge, led by Dr Dino Giussani, examined the role that oxygen availability in the womb plays in programming your susceptibility to different diseases. His group found that babies that don’t receive enough oxygen in the womb (e.g. due to pre-eclampsia or placental insufficiency) are more likely to suffer from cardiovascular disease when they are adult. A reduction of oxygen levels in the womb can lead to reduced growth rates in the baby and to changes in the way that their cardiovascular, metabolic and endocrine systems develop. Combined, these alterations to the development of key systems in the body can leave the baby more prone to developing cardiovascular disease later in life.
Dr Giussani’s research also indicates methods by which we can potentially combat this problem. The detrimental effects of low oxygen levels on the development of the unborn’s cardiovascular system appear to be due to the generation of oxidative stress. Treatment with antioxidants in animal pregnancies complicated by low oxygenation can reverse these effects on the developing cardiovascular system and this could form the basis for new therapeutic techniques to prevent the early origin of heart disease in complicated human pregnancy.
Cardiovascular disease is the most common cause of death in the UK, accounting for 4 in every 10 deaths. Almost 2.6 million people are affected by heart and circulatory conditions in the UK, with someone having a heart attack every 2 seconds.
Scientist Dr Dino Giussani said: “We have known for a while that changes in maternal nutrition can affect fetal development and influence disease susceptibility later in life, but relatively little work has investigated how low oxygen levels in the womb may affect infant development. Our research shows that changes to the amount of oxygen available in the womb can have a profound influence on the development of the fetus in both the short- and long- term, and trigger an early origin of heart disease.
Interestingly, the adverse effects on the developing heart and circulation of poor fetal oxygenation are due to oxidative stress. This gives us the opportunity to combat prenatal origins of heart disease by fetal exposure to antioxidant therapy. This may halt the development of heart disease at its very origin, bringing preventative medicine back into the womb.”
Published April 10, 2008 in the journal Endocrine Abstracts
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Too Many Choices - Good or Bad - Can be Mentally Exhausting
Each day, we are bombarded with options - at the local coffee shop, at work, in stores or on the TV at home. Do you want a double-shot soy latte, a caramel macchiato or simply a tall house coffee for your morning pick-me-up? Having choices is typically thought of as a good thing. Maybe not, say researchers who found we are more fatigued and less productive when faced with a plethora of choices.
Researchers from several universities have determined that even though humans' ability to weigh choices is remarkably advantageous, it can also come with some serious liabilities. People faced with numerous choices, whether good or bad, find it difficult to stay focused enough to complete projects, handle daily tasks or even take their medicine.
These findings appear in the April issue of Journal of Personality and Social Psychology, which is published by the American Psychological Association.
Researchers conducted seven experiments involving 328 participants and 58 consumers at a shopping mall. In the laboratory experiments, some participants were asked to make choices about consumer products, college courses or class materials. Other participants did not have to make decisions but simply had to consider the options in front of them.
The scientists then asked each group to participate in one of two unpleasant tasks. Some were told to finish a healthy but ill-tasting drink (akin to taking one's medicine). Other participants were told to put their hands in ice water. The tasks were designed to test how the previous act of choosing, or not choosing, affected peoples' ability to stay on task and maintain behaviors aimed at reaching a goal.
Researchers found that the participants who earlier had made choices had more trouble staying focused and finishing the disagreeable but goal-focused tasks compared to the participants who initially did not have to make choices.
In other experiments, participants were given math problems to practice for an upcoming test. The participants who had to make important choices involving coursework spent less time solving the math problems and more time engaging in other distractions such as playing video games or reading magazines, compared to participants who were not asked to make choices prior to that point. The participants who made choices also got more math problems wrong than participants not faced with decisions.
To further buttress their laboratory findings, the researchers conducted a field test at a shopping mall. The shoppers reported how much decision-making they had done while shopping that day and then were asked to solve simple arithmetic problems. The researchers found that the more choices the shoppers had made earlier in the day, the worse they performed on the math problems. The authors note they controlled for how long the participants had been shopping, and for several demographic categories such as age, race, ethnicity and gender.
Kathleen D. Vohs, PhD, the study's lead author and a member of the University of Minnesota's marketing department, concluded that making choices apparently depletes a precious resource within the human mind. "Maintaining one's focus while trying to solve problems or completing an unpleasant task was much harder for those who had made choices compared to those who had not," says Vohs. "This pattern was found in the laboratory, classroom and shopping mall. Having to make the choice was the key. It did not matter if the researchers told them to make choices, or if it was a spontaneously made choice, or if making the choice had consequences or not."
But what about making fun choices? How does that affect our mental acuity? In their last experiment, researchers determined that making a few enjoyable decisions, such as spending four minutes selecting items for a gift registry, was shown to be less mentally draining than when participants spent 12 minutes doing the same task. In other words, even if people are having fun making decisions, their cognitive functions are still being depleted with every choice they make.
Vohs says these experiments provide evidence that making choices, as opposed to just thinking about options, is what is especially taxing. "There is a significant shift in the mental programming that is made at the time of choosing, whether the person acts on it at that time or sometime in the future. Therefore, simply the act of choosing can cause mental fatigue," says Vohs. "Making choices can be difficult and taxing, and there is a personal price to choosing."
Published March 26, 2008 in the Journal of Personality & Social Psychiatry
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Heart Stem Cell Scientist Honors Dame Anne McLaren In Keynote Speech
Professor Christine Mummery, one of the world's leading heart stem cell experts, honored the memory of Dame Anne McLaren in the keynote lecture of the inaugural UK National Stem Cell Network Science Meeting in Edinburgh. Dr McLaren was an early pioneer of the study of embryonic germ cells and her research directly contributed to the development of IVF treatments and stem cell techniques.
Prof Mummery from the Netherlands is a leading expert in the study of cardiomyocytes - the beating cells of the heart - most particularly those derived from stem cells. She informed the delegates at the UKNSCN conference that Dr McLaren was a leading figure in guiding the stem cell research community in learning the language and ethics of working with early human embryos in research. She said that the UK regulations, which have allowed the country to take a strong lead in stem cell research, are in part due to Dr McLaren's thoughtful input to the various committees that first examined the laws needed to govern IVF treatment.
Speaking ahead of her lecture, Prof Mummery said: "Anne McLaren was one of the most thoughtful and sensitive stem cell scientists the scientific community has seen. Her views not only influenced the direction of UK regulation of the field - which has helped thousands of couples through IVF treatment - but also scientists considering ethical and regulatory questions across Europe.
"Anne was also an excellent communicator of her research and, as well as commemorating her work, my lecture will highlight some of the cutting edge advances in today's stem cell research field."
Prof Mummery's lab in The Netherlands is a world leader in the study of the basic development of the heart and how embryonic stem cells differentiate into the cardiac and vascular cells that make up the adult heart.
Prof Mummery said: "Stem cell therapies have the potential to help us to treat and manage a wide range of diseases and conditions. Using stem cells to repair hearts damaged by disease could be one of the most promising in the near future. There are hurdles still to overcome but we have made real progress in producing the right sort of cells that would be needed."
Speaking on behalf of Dr McLaren's family, Professor Susan Michie said: "We are delighted that Professor Mummery will give this important lecture in honour of Anne. The presentation of cutting edge stem cell research, which has such huge potential for improving the health and well-being of people the world over, would have delighted Anne. Anne thought that society was the poorer for often overlooking the huge talent amongst women scientists; it is therefore very appropriate that a world-renowned woman scientist is delivering this lecture."
Published April 10, 2008 in the journal Nature Cell Biology
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MONDAY - April 14, 2008--------------------------------------------------News Archive/Return to Today's News Alerts
Researchers Uncover Novel Process Behind Heart Muscle Contraction
Researchers from the University of Pittsburgh and the University of Chicago were able to control heart muscle function in a new way after discovering the previously unknown role of two enzymes in heart muscle contraction, as detailed in the April 11 cover story of the “Journal of Biological Chemistry.” Although in the early stages, the research provides fresh knowledge of how heart muscle functions and also holds early potential as a treatment for various heart diseases - including congestive heart failure - that is possibly less taxing on the heart than current regimens.
Experiments on slivers of heart muscle revealed that heart muscle contractions can be regulated by the enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs), explained Pitt professor Sanjeev Shroff, the Gerald McGinnis Chair of Bioengineering in the Swanson School of Engineering. Shroff and Pitt research associate Stephen Smith collaborated with Mahesh Gupta, an associate professor of surgery at the University of Chicago, and his research associate Sadhana Samant. The project was funded by a grant from the National Institutes of Health.
The team found that HATs and HDACs influence acetylation of certain heart muscle proteins, a process wherein a radical cluster of atoms called an acetyl group attach to a protein and change its function. HATs facilitate acetylation, and HDACs remove the acetyl group. The team discovered that acetylation renders the muscle fiber more sensitive to calcium, which causes the muscle to contract.
“This is a completely new process in the area of heart muscle contraction,” Shroff said. “Acetylation is widely known to regulate such events inside the cell nucleus as gene regulation, but it’s never before been associated with heart muscle contraction.”
Furthermore, Shroff and his colleagues could intervene in this microscopic process to control heart muscle contraction. By inhibiting HDACs, they increased the calcium sensitivity of the muscle fibers and strengthened contraction.
As a possible treatment for such conditions as congestive heart failure, this technique could present an alternative to current therapies that counteract heart muscle weakness by boosting cellular calcium content, Shroff said. The heightened calcium improves muscle contraction but also results in more energy consumption in hearts that often are energy-starved to begin with.
In contrast, inhibiting HDAC alters a natural process to make heart muscle more sensitive to the prevailing level of calcium, he said.
“We did not create this process—we are just manipulating what is already there,” Shroff explained. “The physiology to block HDAC is already there, and we just took advantage of that. This perturbation does not require greater mobilization of calcium, so we won’t end up with increased cardiac energy consumption. That’s been the Achilles heel of treatment so far.”
The team’s next step involves examining HAT- and HDAC-driven regulation of cardiac contraction in the whole animal rather than just muscle samples. Then it can better determine the overall significance of the newly discovered process to the intact heart function and its therapeutic potential.
“We want to see how much protein acetylation matters when operating alongside all the other processes in the heart and the body,” Shroff said. “If this process is shown to be significant under these conditions, it will be an exciting finding.”
Published April 11, 2008 in the Journal of Biological Chemistry
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Whose Your Daddy? Fraud Attempted in a Paternity Test
Researchers all over the world carry out paternity tests regularly. Samples are usually collected from mouth and saliva cells to produce the DNA for analysis.
The team of Dr José Antonio Lorente Acosta (director of the Laboratory of Genetic Identification of the University of Granada) carries out such forensic studies commissioned by the court in cases of paternity and for the identification of possible criminals, or to create DNA databases in the case of missing relatives.
The detection of a fraud attempt in a paternity test in 2007 is changing the action protocol of forensic teams in similar cases. The team of Dr Lorente encountered a mystery: "the saliva analysis (epithelial cells from the interior of the mouth) collected from a person undergoing a paternity test, gave an incongruous result - the DNA could not have come from the man who had carried out the test".
Reviewing the case revealed that the usual procedures had been followed: the suspect washed his mouth and afterwards clinicians took samples with a cotton swab. "After repeating the analysis, there was an only one possible conclusion: In the mouth of that man there was DNA from two different persons". After dismissing other possibilities, the question was: how was it possible? "We arranged to meet the person in question, we showed him the result and we explained to him that we suspected that he had manipulated the samples which, as it was a trial under judicial investigation, could bring him serious consequences. Faced wit the evidence, he admitted that, shortly before the sample taking, he put into his mouth some saliva he kept in a little container."
