Week Ending FRIDAY May 22, 2009---------------------------News Archive
Twins Born After Fertility Treatment Have a Higher Risk of Problems at Birth and in the First Three Years of Life
Twins born as a result of assisted reproductive technology (ART) are more likely to be admitted to neonatal intensive care and to be hospitalised in their first three years of life than spontaneously conceived twins, according to new research published online (Wednesday 20 May) in Europe’s leading reproductive medicine journal Human Reproduction.
It is known already that ART twins are at higher risk of problems such as low birth weight and premature delivery than singletons around the time of their birth, but, to a large extent, these risks exist as part of the problems associated with multiple births in general. Up to now there has been conflicting evidence about whether assisted reproduction itself is responsible for adding to the number of problems seen in ART twins.
To answer this question, researchers in Australia and the UK looked at perinatal outcomes and hospital admissions for all twin children born in Western Australia between 1994 and 2000, whether as a result of ART or spontaneous conception.
Twins that arise as a result of ART usually do so because two (or sometimes more) separate embryos are implanted in the woman’s womb. They are non-identical and each has its own placenta. However, twins that arise as a result of spontaneous conception can either be non-identical because two eggs have been fertilised at the same time, or identical because one fertilised egg has divided to make two embryos. Identical twins share a placenta in about two-thirds of all cases, and this is associated with an increased risk of death and other complications. In order to ensure that, as far as possible, they were comparing like for like, the researchers matched the ART twins with spontaneously conceived, non-identical twins of different sexes (referred to in the study as “unlike sex spontaneously conceived twins”, or “ULS SC twins”).
Michèle Hansen, a researcher and PhD student at the Telethon Institute for Child Health Research in Western Australia, said: “We found that twins conceived following ART treatment had a greater risk of adverse perinatal outcome, including preterm birth, low birthweight and death, compared with spontaneously conceived twins of unlike sex. ART twins had more than double the risk of perinatal death compared to ULS SC twins, although the risk was similar to that of all SC twins, including identical twins.
“ART twins stayed longer in hospital than ULS SC twins at the time of their birth: an average of 12 days compared with eight days. ART twins were four times more likely to be admitted to neo-natal intensive care than ULS SC twins, and were more likely to be admitted to hospital during the first three years of their life. After adjusting for confounding factors such as year of birth, maternal age, parity and so on, ART twins still had a nearly two-thirds higher risk of being admitted to neo-natal intensive care, and a higher risk of being admitted to hospital in their first three years of life, although this was only statistically significant in their second year, when their risk was nearly two-thirds higher.”
Ms Hansen continued: “Couples undergoing fertility treatment should be aware that, in addition to the known increased perinatal risks associated with a twin birth, ART twins are more likely than spontaneously conceived twins to be admitted to neonatal intensive care and to be hospitalised in their first three years of life.
“We don't know the reason for the increased risks of adverse perinatal outcome and hospitalisation and preliminary analysis of specific diagnoses does not provide any answers. The underlying causes of parental infertility and/or components of the ART procedure may be increasing the risks of adverse outcome, and increased concern about children born after a long period of infertility may also be contributing to their increased risk of hospitalisation. Estimates of the cost of an ART twin delivery should take into account these increased risks, and, in order to reduce the problems associated with twin births, clinicians and couples should consider the benefits of opting for single embryo transfer.”
A second study, also published online today in Human Reproduction, provides reassuring evidence on the outcome of children born after embryos were frozen and stored, before being thawed and transferred to the womb . The results are good news as an increasing number of children, estimated to be 25% of ART babies worldwide, are now born after freezing or vitrification (a process similar to freezing that prevents the formation of ice crystals).
The study, led by Dr Ulla-Britt Wennerholm, an obstetrician at the Institute for Clinical Sciences, Sahlgrenska Academy (Goteborg, Sweden), reviewed the evidence from 21 controlled studies that reported on prenatal or child outcomes after freezing or vitrification.
She found that embryos that had been frozen shortly after they started to divide (early stage cleavage embryos) had a better, or at least as good, obstetric outcome (measured as preterm birth and low birth weight) as children born from fresh cycles of IVF (in vitro fertilisation) or ICSI (intracytoplasmic sperm injection). There were comparable malformation rates between the fresh and frozen cycles. There were limited data available for freezing of blastocysts (embryos that have developed for about five days) and for vitrification of early cleavage stage embryos, blastocysts and eggs.
“Slow freezing of embryos has been used for 25 years and data concerning infant outcome seem reassuring with even higher birthweights and lower rates of preterm and low birthweights than children born after fresh IVF/ICSI. For the newly introduced technique of vitrification of blastocysts and oocytes, very limited data have been reported on obstetric and neonatal outcomes. This emphasises the urgent need for properly controlled follow-up studies of neonatal outcomes and a careful assessment of evidence currently available before these techniques are added to daily routines. In addition, long-term follow-up studies are needed for all cryopreservation techniques,” concluded Dr Wennerholm.
Gene Therapy Could Expand Stem Cells' Promise
Once placed into a patient's body, stem cells intended to treat or cure a disease could end up wreaking havoc simply because they are no longer under the control of the clinician
But gene therapy has the potential to solve this problem, according to a perspective article from physician-scientists at NewYork-Presbyterian Hospital/Weill Cornell Medical Center published in a recent issue of the journal Cell Stem Cell. The paper details strategies for genetically modifying stem cells prior to transplantation in order to ensure their safety.
"Stem cell therapy offers enormous potential to treat and even cure serious diseases. But wayward stem cells can turn into a runaway train without a conductor. This is an issue that can be dealt with and we have the technology to do that in the form of gene therapy," says senior author Dr. Ronald G. Crystal, chief of the Division of Pulmonary and Critical Care Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, and the Bruce Webster Professor of Internal Medicine and Professor of Genetic Medicine at Weill Cornell Medical College.
Stem cells have the capacity to differentiate into any of the different tissues making up the human body, thus holding the promise of treating or curing diseases such as multiple sclerosis or spinal-cord injury by replacing diseased cells with healthy cells.
But unlike other therapies such as chemotherapy, antibiotics or aspirin, stem cells have no expiration date, and that poses a real problem.
"Almost all therapeutics we use have a half life. They only last a certain amount of time," Dr. Crystal says. "Stem cells are the opposite. Once the future stem cell therapist does the therapy, stem cells have the innate potential to produce more cells."
The challenge takes on even more urgency with recent developments, including a federal administration now more open to exploring the potential of stem cells, the recent FDA approval of a human trial involving embryonic stem cells, as well as the reported case of a young boy who developed a brain tumor four years after receiving a stem-cell treatment for a rare genetic disorder.
As evidenced by this boy's experience, one of the biggest potential problems with stem cell therapy is the development of tumors.
But there are other problems as well.
Stem cells directed to become beating heart cells might mistakenly end up in the brain. Or insulin-producing beta cells which can't stop means the body can no longer regulate insulin levels.
"You've totally lost control," Dr. Crystal says. "What do you do?"
The best chance of circumventing these issues is genetic modification of the stem cells prior to actually transplanting them, Dr. Crystal says. Theoretically, this is similar to how gene therapy is used to treat cancer, but with important improvements.
"Instead of gene therapy being done in the patient, as is the case in cancer, it's being done in the cells in a laboratory before doctors use them for therapy so that they still have control of these cells," Dr. Crystal explains.
Therapists would rig certain genes to respond to a "remote control" signal. For instance, giving a certain drug could prompt a "suicide" gene to kill a budding tumor.
But gene therapy also needs to be carefully done and, ideally, two independent gene-manipulation systems would be used to ensure that stem cells remain firmly in control of clinicians.
BPA, Chemical Used to Make Plastics, Found to Leach from Polycarbonate Drinking Bottles Into Humans
A new study from Harvard School of Public Health (HSPH) researchers found that participants who drank for a week from polycarbonate bottles, the popular, hard-plastic drinking bottles and baby bottles, showed a two-thirds increase in their urine of the chemical bisphenol A (BPA)
Exposure to BPA, used in the manufacture of polycarbonate and other plastics, has been shown to interfere with reproductive development in animals and has been linked with cardiovascular disease and diabetes in humans. The study is the first to show that drinking from polycarbonate bottles increased the level of urinary BPA, and thus suggests that drinking containers made with BPA release the chemical into the liquid that people drink in sufficient amounts to increase the level of BPA excreted in human urine.
The study appears on the website of the journal Environmental Health Perspectives and is freely available at http://www.ehponline.org/members/2009/0900604/0900604.pdf.
In addition to polycarbonate bottles, which are refillable and a popular container among students, campers and others and are also used as baby bottles, BPA is also found in dentistry composites and sealants and in the lining of aluminum food and beverage cans. (In bottles, polycarbonate can be identified by the recycling number 7.) Numerous studies have shown that it acts as an endocrine-disruptor in animals, including early onset of sexual maturation, altered development and tissue organization of the mammary gland and decreased sperm production in offspring. It may be most harmful in the stages of early development.
"We found that drinking cold liquids from polycarbonate bottles for just one week increased urinary BPA levels by more than two-thirds. If you heat those bottles, as is the case with baby bottles, we would expect the levels to be considerably higher. This would be of concern since infants may be particularly susceptible to BPA's endocrine-disrupting potential," said Karin B. Michels, associate professor of epidemiology at HSPH and Harvard Medical School and senior author of the study.
The researchers, led by first author Jenny Carwile, a doctoral student in the department of epidemiology at HSPH, and Michels, recruited Harvard College students for the study in April 2008. The 77 participants began the study with a seven-day "washout" phase in which they drank all cold beverages from stainless steel bottles in order to minimize BPA exposure. Participants provided urine samples during the washout period. They were then given two polycarbonate bottles and asked to drink all cold beverages from the bottles during the next week; urine samples were also provided during that time.
The results showed that the participants' urinary BPA concentrations increased 69% after drinking from the polycarbonate bottles. (The study authors noted that BPA concentrations in the college population were similar to those reported for the U.S. general population.) Previous studies had found that BPA could leach from polycarbonate bottles into their contents; this study is the first to show a corresponding increase in urinary BPA concentrations in humans.
One of the study's strengths, the authors note, is that the students drank from the bottles in a normal use setting. Additionally, the students did not wash their bottles in dishwashers nor put hot liquids in them; heating has been shown to increase the leaching of BPA from polycarbonate, so BPA levels might have been higher had students drunk hot liquids from the bottles.
Canada banned the use of BPA in polycarbonate baby bottles in 2008 and some polycarbonate bottle manufacturers have voluntarily eliminated BPA from their products. With increasing evidence of the potential harmful effects of BPA in humans, the authors believe further research is needed on the effect of BPA on infants and on reproductive disorders and on breast cancer in adults.
"This study is coming at an important time because many states are deciding whether to ban the use of BPA in baby bottles and sippy cups. While previous studies have demonstrated that BPA is linked to adverse health effects, this study fills in a missing piece of the puzzle-whether or not polycarbonate plastic bottles are an important contributor to the amount of BPA in the body," said Carwile.
The study was supported by the Harvard University Center for the Environment and the National Institute of Environmental Health Sciences Biological Analysis Core, Department of Environmental Health, HSPH. Carwile was also supported by the Training Program in Environmental Epidemiology.
Back to Basics: Scientists Discover a Fundamental Mechanism for Cell Organization
Scientists have discovered that cells use a very simple phase transition - similar to water vapor condensing into dew - to assemble and localize subcellular structures that are involved in formation of the embryo.
The discovery, which was made during the 2008 Physiology course at the Marine Biological Laboratory (MBL), is reported in the May 21 early online edition of Science by Clifford P. Brangwynne and Anthony A. Hyman of the Max Planck Institute for Molecular Cell Biology and Genetics in Dresden, Germany, and their colleagues, including Frank Jülicher of the Max Planck Institute for the Physics of Complex Systems, also in Dresden.
Working with the worm C. elegans, the scientists found that subcellular structures called P granules, which are thought to specify the “germ cells” that ultimately give rise to sperm or eggs, are liquid droplets that transition between a dissolved or condensed state. In newly fertilized one-cell embryos, the P granules are dissolving throughout the cell, like water droplets at high temperature. But prior to the first cell division, the P granules rapidly condense at one end of the cell, as if the temperature were suddenly lowered there. The progenitor germ cell subsequently forms where the P granules have condensed.
“This kind of phase transition could potentially be working for many other subcellular structures similar to P granules,” Brangwynne says. P granules are ribonucleoprotein assemblies (RNPs), and a given cell may contain dozens of different types of RNPs.
“It is interesting to think about this in the context of evolution and the origin of life,” he says. What we have found is that, in some cases, simple physical-chemical mechanisms, such as a classic phase transition, give rise to subcellular structure…This is likely the kind of thing that happened in the so-called primordial soup; but it's not surprising that even highly evolved cells continue to take advantage of such mechanisms.”
The insight emerged when Brangwynne, a biophysicist who was a teaching assistant in the MBL Physiology course, watched a movie of P granules fusing that had been made by a student in the course, David Courson of the University of Chicago. “We were looking at that and thinking, man, that looks exactly like two liquid droplets fusing,” Brangwynne says. They began making measurements of liquid-type behaviors in P granules, and made the first estimates of P granule viscosity and surface tension. By the end of the course they were “90 percent sure” that P granules are liquid droplets that localize in the cell by controlled dissolution and condensation, a concept that Brangwynne further confirmed after he returned to Dresden.
Brangwynne credits the discovery to the “dynamic nature” of the MBL Physiology course, where scientists from different fields (biology, physics, computer science) work intensively together on major research questions in cell biology. In addition to Courson, the other co-authors of the Science paper who were in the Physiology course are Hyman, and Jülicher, who were Physiology faculty members, and Jöbin Gharakhani, who was a teaching assistant. The paper also credits Physiology course co-director Tim Mitchison for valuable discussions.
“There are so many molecules in the cell, and we are coming out of the age of cataloguing them all, which was critical, to find out who the players are,” Brangwynne says. “Now we are putting it all together. What are the principles that come out of these complex interactions (between molecules)? In the end, it may be relatively simple principles that help us understand what is really happening.”
THURSDAY May 21, 2009---------------------------News Archive
Smoking in Pregnancy Likely to Produce Children Who Smoke
Children of mothers who smoked during pregnancy and their early childhood years may be predisposed to take up smoking as teens and young adults, compounding the physical damage they sustained from the smoke exposure
"It is well-known that maternal smoking influences a developing fetus in myriad ways, contributing to low birth weight, premature birth and a host of other health problems after birth," said Roni Grad, M.D., associate professor of clinical pediatrics at the University of Arizona College of Medicine. "Previous studies have suggested that maternal smoking during pregnancy may increase the risk of the offspring becoming regular smokers as adults, but the impact of postnatal cigarette smoke exposure was hard to differentiate from prenatal exposure."
The study results will be presented on Tuesday, May 19, at the American Thoracic Society's 105th International Conference in San Diego.
To determine the impact of maternal smoking during pregnancy and early childhood, the on the smoking behavior of the offspring as young adults, the researchers used data from the Tucson Children's Respiratory Study. Maternal smoking during pregnancy, at nine days, 1.5 months and 1.5 years was used to assess smoke exposure during pregnancy and the early life of the child. Maternal smoking was further assessed at ages six, nine and eleven years to evaluate smoke exposure during the school age years of the child. The smoking behavior of the offspring was then assessed at ages 16 and 22 years.
The researchers found that maternal smoking during pregnancy and the early childhood years was associated with the offspring being regular smokers at the age of 22, independent of whether the mother smoked during the school age years of the child. Furthermore, of all of the offspring who had ever smoked, offspring of mothers who smoked during pregnancy and early life were less likely to quit than those of mothers who had never smoked or who had taken up the habit only when the child reaches the school age years. Finally, the impact of early maternal smoking was independent of the effect of paternal smoking and also the effect of exposure to peer smoking during the offspring's adolescence. The greatest impact on the smoking behavior of the offspring as young adults was linked to .
"Smoking during pregnancy by mothers who stopped smoking by the time the child reached the school age years is a risk factor for smoking in their offspring during early adulthood," said Dr. Grad. "The data suggest that a biological effect is in play, and that eliminating maternal smoking during pregnancy and the preschool years of the child will reduce the risk of her children becoming regular smokers in adulthood. In children of mothers who did smoke during this critical period, it is important to prevent experimentation with tobacco during the adolescent years."
Ghrelin Hormone Increases Appetite AND Abdominal Fat
The ghrelin hormone not only stimulates the brain giving rise to an increase in appetite, but also favours the accumulation of lipids in visceral fatty tissue, located in the abdominal zone and considered to be the most harmful
The Metabolic Research Laboratory of the University Hospital of Navarra, Spain, published their conclusions recently in the International Journal of Obesity.
Ghrelin is a hormone produced in the stomach which tells the brain that the body has to be fed. Thus, the level of ghrelin increases before eating and decreases after. It is known to be important in the development of obesity, explained Ms Amaia Rodríguez Murueta-Goyena, doctor in biology and main researcher on the study.
However, researchers at University Hospital of Navarra have also discovered that, besides stimulating the hypothalamus to generate appetite, ghrelin also acts on the tabula rasa cortex. They observed how this hormone favours the accumulation of lipids in visceral fatty tissues by causing the over-expression of the fatty genes that take part in the retention of lipids, explained Ms Rodríguez.
It is precisely this accumulated abdomenal fat that is deemed to be most harmful, as visceral obesity is related to higher blood pressure and/or type 2 diabetes. Abdominal fat is in direct contact with the liver, leading to the formation of liver fat and increasing the risk of developing a resistance to insulin. Consequent to its association with hypertension, high levels of triglycerides, resistance to insulin and hypercholesterolemia, visceral fat promotes metabolic syndrome, the researcher pointed out.
Ghrelin can show itself in acylated - octanoic acid present - or deacylated forms, according to Ms Rodriguez. Previously it was thought that only the acylated form was active in the process of weight increase, but many studies now point to both hormones being biologically functional.
Future development of pharmaceutical drugs
The discovery of the twin actions of ghrelin opens the door to future treatment for obesity. The full function of a hormone must be known in order to design effective pharmaceuticals.
Ms Rodríguez points out that the acylated-form of ghrelin in the blood increases amongst obese persons, particularly those suffering from diabetes. Obese persons with diabetes have a greater tendency to accumulate visceral fat than obese persons with normal glycemic levels.
Research Team Finds Important Role for Junk DNA
Scientists have called it "junk DNA."
Scientists are beginning to find, however, that much of this so-called junk plays important roles in the regulation of gene activity. No one yet knows how extensive that role may be.
They have long been perplexed by these extensive strands of genetic material that dominate the genome but seem to lack specific functions. Why would nature force the genome to carry so much excess baggage?
Now researchers from Princeton University and Indiana University who have been studying the genome of a pond organism have found that junk DNA may not be so junky after all. They have discovered that DNA sequences from regions of what had been viewed as the "dispensable genome" are actually performing functions that are central for the organism. They have concluded that the genes spur an almost acrobatic rearrangement of the entire genome that is necessary for the organism to grow.
It all happens very quickly. Genes called transposons in the single-celled pond-dwelling organism Oxytricha produce cell proteins known as transposases. During development, the transposons appear to first influence hundreds of thousands of DNA pieces to regroup. Then, when no longer needed, the organism cleverly erases the transposases from its genetic material, paring its genome to a slim 5 percent of its original load.
In order to prove that the transposons have this reassembly function, the scientists disabled several thousand of these genes in some Oxytricha. The organisms with the altered DNA, they found, failed to develop properly.
Other authors from Princeton's Department of Ecology and Evolutionary Biology include: postdoctoral fellows Mariusz Nowacki and Brian Higgins; 2006 alumna Genevieve Maquilan; and graduate student Estienne Swart. Former Princeton postdoctoral fellow Thomas Doak, now of Indiana University, also contributed to the study.
Landweber and other members of her team are researching the origin and evolution of genes and genome rearrangement, with particular focus on Oxytricha because it undergoes massive genome reorganization during development.
In her lab, Landweber studies the evolutionary origin of novel genetic systems such as Oxytricha's. By combining molecular, evolutionary, theoretical and synthetic biology, Landweber and colleagues last year discovered an RNA (ribonucleic acid)-guided mechanism underlying its complex genome rearrangements.
"Last year, we found the instruction book for how to put this genome back together again - the instruction set comes in the form of RNA that is passed briefly from parent to offspring and these maternal RNAs provide templates for the rearrangement process," Landweber said. "Now we've been studying the actual machinery involved in the process of cutting and splicing tremendous amounts of DNA. Transposons are very good at that."
The term "junk DNA" was originally coined to refer to a region of DNA that contained no genetic information.
Instead, scientists now sometimes refer to these regions as "selfish DNA" if they make no specific contribution to the reproductive success of the host organism. Like a computer virus that copies itself ad nauseum, selfish DNA replicates and passes from parent to offspring for the sole benefit of the DNA itself.
The present study suggests that some selfish DNA transposons can instead confer an important role to their hosts, thereby establishing themselves as long-term residents of the genome.
Area of Brain that Makes You a 'People Person' - Or Not
Cambridge University researchers have discovered that whether someone is a ‘people-person’ may depend on the structure of their brain: the greater the concentration of brain tissue in certain parts of the brain, the more likely they are to be a warm, sentimental person
Why is it that some of us really enjoy the company of others while some people are detached and independent? In an effort to explore these questions, Maël Lebreton and colleagues from the Cambridge Department of Psychiatry, in collaboration with Oulu University, Finland, examined the relationship between personality and brain structure in 41 male volunteers.
The volunteers underwent a brain scan using Magnetic Resonance Imaging (MRI). They also completed a questionnaire that asked them to rate themselves on items such as 'I make a warm personal connection with most people', or 'I like to please other people as much as I can'. The answers to the questionnaire provide an overall measure of emotional warmth and sociability called social reward dependence.
The researchers then analysed the relationship between social reward dependence and the concentration of grey matter (brain-cell containing tissue) in different brain regions. They found that the greater the concentration of tissue in the orbitofrontal cortex (the outer strip of the brain just above the eyes), and in the ventral striatum (a deep structure in the centre of the brain), the higher they tended to score on the social reward dependence measure. The research is published in the European Journal of Neuroscience.
Dr Graham Murray, who is funded by the Medical Research Council and who led the research, said: "Sociability and emotional warmth are very complex features of our personality. This research helps us understand at a biological level why people differ in the degrees to which we express those traits." But he cautioned, "As this research is only correlational and cross-sectional, it cannot prove that brain structure determines personality. It could even be that your personality, through experience, helps in part to determine your brain structure."
Interestingly, the orbitofrontal cortex and ventral striatum have previously been shown to be important for the brain's processing of much simpler rewards like sweet tastes or sexual stimuli.
Dr Murray explained: "It's interesting that the degree to which we find social interaction rewarding relates to the structure of our brains in regions that are important for very simple biological drives such as food, sweet liquids and sex. Perhaps this gives us a clue to how complex features like sentimentality and affection evolved from structures that in lower animals originally were only important for basic biological survival processes."
The research could also lead to new insights into psychiatric disorders where difficulties in social interaction are prominent, such as autism or schizophrenia.
"Patients with certain psychiatric conditions often experience difficulties in feeling emotional closeness, and this can have a big impact on their life. It could be that the cause of these difficulties is at least partly due to brain structural features of those disorders," said Dr Murray.
Why Do People with Down Syndrome Have Less Cancer?
Research in mice and human stem cells suggests new therapeutic targets
Most cancers are rare in people with Down syndrome, whose overall cancer mortality is below 10 percent of that in the general population. Since they have an extra copy of chromosome 21, it's been proposed that people with Down syndrome may be getting an extra dose of one or more cancer-protective genes. The late cancer researcher Judah Folkman, MD, founder of the Vascular Biology Program at Children's Hospital Boston, popularized the notion that they might be benefiting from a gene that blocks angiogenesis, the development of blood vessels essential for cancer's growth, since their incidence of other angiogenesis-related diseases like macular degeneration is also lower. A study from Children's confirms this idea in mice and human cells and identifies specific new therapeutic targets for treating cancer.
Publishing online May 20 in the journal Nature, cancer researcher Sandra Ryeom, PhD, and colleagues from Children's Vascular Biology Program show that a single extra copy of Dscr1 (one of the 231 genes on chromosome 21 affected by trisomy, with three copies rather than two) is sufficient to significantly suppress angiogenesis and tumor growth in mice, as well as angiogenesis in human cells. The team also found its protein, DSCR1, to be elevated in tissues from people with Down syndrome and in a mouse model of the disease.
Further study confirmed that DSCR1 acts by suppressing signaling by the angiogenesis-promoting protein vascular endothelial growth factor (VEGF). In a mouse model of Down syndrome, endothelial cells (which make up blood vessel walls) showed a decreased growth response to VEGF when they had an extra copy of Dscr1. An extra copy of another chromosome 21 gene, Dyrk1A, also appeared to decrease cells' response to VEGF.
Finally, Ryeom and colleagues showed that these extra genes suppress VEGF signaling via a specific signaling pathway inside endothelial cells -- the calcineurin pathway. Until now, Ryeom says, little has been known about the internal pathways VEGF activates once it binds to cellular receptors; most existing anti-VEGF drugs work by simply binding to VEGF (like Avastin) or blocking its ability to bind to its cellular receptors.
"We're now moving further downstream by going inside the cell," Ryeom says. "When we targeted calcineurin, we suppressed the ability of endothelial cells to grow and form vessels. While it's likely not the only pathway that's involved, if you take it out, VEGF is only half as effective."
Ryeom and her group next validated the mouse findings in human cells. In collaboration with George Daley, MD, PhD, and colleagues in the Stem Cell program at Children's, she worked with induced pluripotent stem cells (iPS cells) created from skin cells from a patient with Down syndrome - one of 10 disease-specific lines recently developed in Daley's lab.
Knowing that iPS cells tend to induce tumors known as teratomas when inserted into mice, Ryeom guessed that teratomas grown from iPS cells with an extra chromosome 21 would have far fewer blood vessels than teratomas from iPS cells with the normal number of chromosomes. She was right: blood vessels budded in the Down teratomas, but never fully formed.
"The studies in the iPS cells helped validate and confirm that the suppression of angiogenesis that we saw in mouse models also holds true in humans," says Ryeom. "It suggests that these two genes might point to a viable cancer therapy."
Ryeom's group has identified which part of the DSCR1 protein blocks calcineurin and is testing to see whether that fragment can be delivered specifically to endothelial cells, to prevent them from forming new blood vessels, without affecting calcineurin pathways in other cells and causing side effects. "Immunosuppressive drugs also target calcineurin in T-cells," Ryeom notes. "We think that Dscr1 blocks calcineurin specifically in endothelial cells, without affecting T-cells, but we need to check."
Folkman's interest in why patients with Down syndrome have such a reduced risk for cancer focused on endostatin, an anti-angiogenic compound made by the body. Discovered in the Folkman lab, endostatin is a fragment of collagen 18 - whose gene is also on chromosome 21. People with Down syndrome reportedly have almost doubled levels of endostatin because of the extra copy of the gene.
"I think there may be four or five genes on chromosome 21 that are necessary for angiogenesis suppression," says Ryeom. "In huge databases of cancer patients with solid tumors, there are very few with Down syndrome. This suggests that protection from chromosome 21 genes is pretty complete."
WEDNESDAY May 20, 2009---------------------------News Archive
Excessive Cola Consumption Can Lead to Super-Sized Muscle Problems Warn Doctors
Doctors have issued a warning about excessive cola consumption after noticing an increase in the number of patients suffering from muscle problems, according to the June issue of IJCP, the International Journal of Clinical Practice
"We are consuming more soft drinks than ever before and a number of health issues have already been identified including tooth problems, bone demineralisation and the development of metabolic syndrome and diabetes" says Dr Moses Elisaf from the Department of Internal Medicine at the University of Ioannina, Greece. "Evidence is increasing to suggest that excessive cola consumption can also lead to hypokalaemia, in which the blood potassium levels fall, causing an adverse effect on vital muscle functions."
A research review carried out by Dr Elisaf and his colleagues has shown that symptoms can range from mild weakness to profound paralysis. Luckily all the patients studied made a rapid and full recovery after they stopped drinking cola and took oral or intravenous potassium.
The case studies looked at patients whose consumption ranged from two to nine litres of cola a day.
They included two pregnant women who were admitted with low potassium levels.
The first, a 21 year-old woman, was consuming up to three litres of cola a day and complained of fatigue, appetite loss and persistent vomiting. An electrocardiagram also revealed she had a heart blockage, while blood tests showed she had low potassium levels.
The second also had low potassium levels and was suffering from increasing muscular weakness. It turned out she had been drinking up to seven litres of cola a day for the last 10 months.
In a commentary on the paper, Dr Clifford Packer from the Louis Stokes Cleveland VA Medical Centre in Ohio relates the strange case of the ostrich farmer who returned from the Australian outback with muscle weakness. He had been drinking four litres of cola a day for the last three years and drank up to 10 litres a day when he was in the outback, causing a rapid reduction in his potassium levels.
He also relates a puzzling case he saw in his own clinical practice, which was solved when the patient turned up at his office with a two-litre bottle of cola in the basket of his electric scooter. It turned out he routinely drank up to four litres a day. He refused to stop drinking cola, but halved his consumption and the muscle weakness he had been complaining of improved.
In 2007 the worldwide annual consumption of soft drinks reached 552 billion litres, the equivalent of just under 83 litres per person per year, and this is projected to increase to 95 litres per person per year by 2012. However the figure has already reached an average of 212 litres per person per year in the United States.
It appears that hypokalaemia can be caused by excessive consumption of three of the most common ingredients in cola drinks glucose, fructose and caffeine.
"The individual role of each of these ingredients in the pathophysiology of cola-induced hypokalaemia has not been determined and may vary in different patients" says Dr Elisaf. "However in most of the cases we looked at for our review, caffeine intoxication was thought to play the most important role. This has been borne out by case studies that focus on other products that contain high levels of caffeine but no glucose or fructose. "Despite this, caffeine free cola products can also cause hypokalaemia because the fructose they contain can cause diarrhoea."
The authors argue that in an era when portion sizes are becoming bigger and bigger, the excessive consumption of cola products has real public health implications. "Although most patients recover when they stop drinking cola and take potassium supplements, cola-induced chronic hypokalaemia can make them more susceptible to potentially fatal complications, such as an irregular heartbeat" says Dr Elisaf. "In addition, excessive consumption of any kind of cola can lead to a range of health problems including fatigue, loss of productivity and muscular symptoms that vary from mild weakness to profound paralysis. We believe that further studies are needed to establish how much is too much when it comes to the daily consumption of cola drinks."
Dr Packer agrees that the problem needs to be addressed. "Cola drinks need to be added to the physician's checklist of drugs and substances that can cause hypokalaemia" he says. "And the soft drink industry needs to promote safe and moderate use of its products for all age groups, reduce serving sizes and pay heed to the rising call for healthier drinks."
Caltech, UCSF Scientists Determine How Body Differentiates Between a Scorch and a Scratch
You can tell without looking whether you've been stuck by a pin or burnt by a match. But how?
In research that overturns conventional wisdom, a team of scientists from the California Institute of Technology (Caltech) and the University of California, San Francisco (UCSF), have shown that this sensory discrimination begins in the skin at the very earliest stages of neuronal information processing, with different populations of sensory neurons--called nociceptors--responding to different kinds of painful stimuli.
Their findings were published this week in the early online edition of the Proceedings of the National Academy of Sciences (PNAS).
"Conventional wisdom was that the nociceptive neurons in the skin can't tell the difference between heat and mechanical pain, like a pin prick," says David Anderson, Seymour Benzer Professor of Biology, a Howard Hughes Medical Institute (HHMI) Investigator, and one of the paper's lead authors. "The idea was that the skin is a dumb sensor of anything unpleasant, and that higher brain areas disentangle one pain modality from another, to tell you if you've been scorched or scratched."
This conventional wisdom came from recording the electrical responses of nociceptive neurons, where it was shown that these neurons are capable of sensing pretty much every kind of painful stimulus--from pin pricks to heat to cold. But this, Anderson notes, was not sufficient to understand the control of pain-avoidance behavior. "We were asking the cells what the cells can sense, not asking the animal what the cells can sense," he explained.
And so Anderson and coprincipal investigator Allan Basbaum, chair of the Department of Anatomy at UCSF, decided to ask the animal. To do so, they created a genetically engineered mouse in which specific populations of pain-sensing neurons can be selectively destroyed. They were then able to see if the mouse continued to respond to different types of stimuli by pulling its paw away when exposed to a relatively gentle heat source or poked with a nylon fishing line.
What the researchers found was that, when they killed off a certain population of nociceptor neurons, the mice stopped responding to being poked, but still responded to heat. Conversely, when the researchers injected a toxin to destroy a different population of neurons, the mice stopped responding to heat, but their sense of poke remained intact.
"This tells us that the fibers that mediate the response to being poked are neither necessary nor sufficient for a behavioral response to heat," Anderson explains, "and vice versa for the fibers that mediate the response to heat."
In addition, Anderson notes, neither of these two classes of sensory neurons seem to be required for responding to a painful cold stimulus, like dry ice. Research into pinpointing that population of cells is ongoing.
"This tells us that the discernment of different types of painful stimuli doesn't happen only in the brain--it starts in the skin, which is therefore much smarter than we thought," says Anderson. "That's a pretty heretical point of view."
It's also a potentially useful point of view, as Anderson points out. "If doctors want to repair or replace damaged nerve fibers in conditions such as diabetic neuropathy," he explains, "they need to make sure they're replacing the right kind of nerve fibers."
In addition to Anderson, the paper's coauthors include graduate student Daniel Cavanaugh from UCSF, postdoctoral scholar Hyosang Lee and HHMI Research Specialist Liching Lo from Caltech, Shannon Shields from UCSF (now at the Hospital Nacional de Paraplejicos in Toledo, Spain), and Mark Zylka, a former postdoctoral fellow at Caltech now on the faculty at the University of North Carolina, Chapel Hill.
Work on the PNAS paper, "Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli," was funded by grants from the National Institutes of Health, the National Alliance for Research on Schizophrenia and Affective Disorders, the Searle Scholars Program, the Whitehall, Klingenstein, Sloan and Rita Allen Foundations, the Christopher and Dana Reeve Foundation, and the Howard Hughes Medical Institute.
International Team Tracks Clues to HIV
Rice University's Andrew Barron and his group, working with labs in Italy, Germany and Greece, have identified specific molecules that could block the means by which the deadly virus spreads by taking away its ability to bind with other proteins
Using computer simulations, researchers tested more than 100 carbon fullerene, or C-60, derivatives initially developed at Rice for other purposes to see if they could be used to inhibit a strain of the virus, HIV-1 PR, by attaching themselves to its binding pocket.
"There are a lot of people doing this kind of research, but it tends to be one group or one pharmaceutical company taking a shotgun approach -- make a molecule and try it out, then make another molecule and try it out," said Barron, Rice's Charles W. Duncan Jr.-Welch Professor of Chemistry and professor of materials science. "This is interesting because we're tackling an important problem in a very rational way."
The groups reported their findings in a paper published on the American Chemical Society's Journal of Chemical Information and Modeling Web site last week.
Their method of modeling ways to attack HIV may not be unique, but their collaboration is. Research groups from five institutions -- two in Greece, one in Germany, one in Italy and Barron's group at Rice -- came together through e-mail contacts and conversations over many months, each working on facets of the problem. "Not all the groups have ever met in person," Barron said. Most remarkable, he said, is that their research to date has been completely unfunded.
Using simulations to narrow down a collection of fullerenes to find the good ones is "the least time-consuming low-cost procedure for efficient, rational drug design," the team wrote.
"A long time ago, people noticed that C-60 fits perfectly into the hydrophobic pocket in HIV, and it has an inhibition effect," Barron said. "It's not particularly strong, but there's potentially a very strong binding effect. The problem is, it's not the perfect unit." The objective was to find an existing fullerene derivative molecule that could be easily modified to become the perfect unit.
Rice got involved, he said, "because we make the molecules and the other guys had a great method for in-silico testing of molecules. They approached us and said, 'Do you think we could use some of these?' Then we started bouncing ideas around.
"We began thinking about a very simple experiment to calculate the binding efficiency of a molecule in the HIV pocket, then calculate that for a series of molecules, decide which one is best, make that molecule in real life and see if it correlates," Barron said. "If it does, then you've got a way to design your ultimate molecule. Our work was the first step in the process."
In fact, through their "in-silico," or computer-based, calculations, they found two good fits among the fullerene derivatives tested and are now working to enhance their binding properties to get that perfect molecule, one that sticks "like Velcro" to the virus and can be fine-tuned for various strains.
"This is just one component of the problem -- we're not going to cure HIV," Barron cautioned. The hope, he said, is to develop a method for the rapid creation of drugs to address various strains of HIV and other diseases.
Authors of the paper with Barron were Manthos Papadopoulos of the National Hellenic Research Foundation, Athens; Serdar Durdagi of the National Hellenic Research Foundation and the Freie Universitat, Berlin; Claudiu Supuran of the University of Florence, Italy; T. Amanda Strom, Nadjmeh Doostdar and Mananjali Kumar of Rice; and Thomas Mavromoustakos of the National Hellenic Research Foundation and the University of Athens.
The impromptu nature of the project intrigued Barron as much as the subject itself. "Here you've got computational people, experimental people, synthesis people, characterization people who've come together naturally as a collaboration and developed this protocol, developed their own methodologies.
"And no one's paid us to collaborate. Serdar Durdagi’s graduate fellowship was funded by the European Union. The fellowships of Rice graduate students Amanda Strom, Nadjmeh Doostdar and Mananjali Kumar were funded, in part, by Rice's Center for Biological and Environmental Nanotechnology. This is purely an academic collaboration." He said the group is working on a second paper and seeking funding to expand the project.
The paper in the Journal of Chemical Information and Modeling.
Gene Signature Helps Predict Breast Cancer Prognosis
Evidence for epigenetic inheritance in wide range of species
For years, genes have been considered the one and only way biological traits could be passed down through generations of organisms.
Increasingly, biologists are finding that non-genetic variation acquired during the life of an organism can sometimes be passed on to offspringa phenomenon known as epigenetic inheritance. An article forthcoming in the July issue of The Quarterly Review of Biology lists over 100 well-documented cases of epigenetic inheritance between generations of organisms, and suggests that non-DNA inheritance happens much more often than scientists previously thought.
Biologists have suspected for years that some kind of epigenetic inheritance occurs at the cellular level. The different kinds of cells in our bodies provide an example. Skin cells and brain cells have different forms and functions, despite having exactly the same DNA. There must be mechanismsother than DNAthat make sure skin cells stay skin cells when they divide.
Only recently, however, have researchers begun to find molecular evidence of non-DNA inheritance between organisms as well as between cells. The main question now is: How often does it happen?
"The analysis of these data shows that epigenetic inheritance is ubiquitous," write Eva Jablonka and Gal Raz, both of Tel-Aviv University in Israel. Their article outlines inherited epigenetic variation in bacteria, protists, fungi, plants, and animals.
These findings "represent the tip of a very large iceberg," the authors say.
For example, Jablonka and Raz cite a study finding that when fruit flies are exposed to certain chemicals, at least 13 generations of their descendants are born with bristly outgrowths on their eyes. Another study found that exposing a pregnant rat to a chemical that alters reproductive hormones leads to generations of sick offspring. Yet another study shows higher rates of heart disease and diabetes in the children and grandchildren of people who were malnourished in adolescence.
In these cases, as well as the rest of the cases Jablonka and Raz cite, the source of the variation in subsequent generations was not DNA. Rather, the new traits were carried on through epigenetic means.
There are four known mechanisms for epigenetic inheritance. According to Jablonka and Raz, the best understood of these is "DNA methylation." Methyls, small chemical groups within cells, latch on to certain areas along the DNA strand. The methyls serve as a kind of switch that renders genes active or inactive.
By turning genes on and off, methyls can have a profound impact on the form and function of cells and organisms, without changing the underlying DNA. If the normal pattern of methyls is alteredby a chemical agent, for examplethat new pattern can be passed to future generations.
The result, as in the case of the pregnant rats, can be dramatic and stick around for generations, despite the fact that underlying DNA remains unchanged.
New evidence for epigenetic inheritance has profound implications for the study of evolution, Jablonka and Raz say.
"Incorporating epigenetic inheritance into evolutionary theory extends the scope of evolutionary thinking and leads to notions of heredity and evolution that incorporate development," they write.
This is a vindication of sorts for 18th century naturalist Jean Baptiste Lamarck. Lamarck, whose writings on evolution predated Charles Darwin's, believed that evolution was driven in part by the inheritance of acquired traits. His classic example was the giraffe. Giraffe ancestors, Lamarck surmised, reached with their necks to munch leaves high in trees. The reaching caused their necks to become slightly longera trait that was passed on to descendants. Generation after generation inherited slightly longer necks, and the result is what we see in giraffes today.
With the advent of Mendelian genetics and the later discovery of DNA, Lamarck's ideas fell out of favor entirely. Research on epigenetics, while yet to uncover anything as dramatic as Lamarck's giraffes, does suggest that acquired traits can be heritable, and that Lamarck was not so wrong after all.
New Stem Cell Lab for Horses Opens at UC Davis Veterinary School
Focused on providing the latest in stem cell therapies for horses, the UC Davis School of Veterinary Medicine today opened its new Regenerative Medicine Laboratory at the William R. Pritchard Veterinary Medical Teaching Hospital
The new laboratory provides a state-of-the art facility for processing, culturing and storing stem cells for use in horses. It is one of only four such university-based veterinary stem cell labs in the nation, providing services to clients and referring veterinarians.
“We are excited to be able to offer this new clinical service to our clients for their horses as a complement to our stem-cell research program,” said Bennie Osburn, dean of the School of Veterinary Medicine. “Stem cell science is leading us into a new era in human and veterinary medicine.”
In recent years, scientists have made significant advances in using stem cells to treat horses suffering from diseases including colic and neuromuscular degeneration, as well as burns and other injuries. Horses have been one of the first species to benefit from veterinary stem cell therapy because they are prone to many of the injuries that can be successfully treated with such therapy.
“The marvelous thing about stem cell therapy is that it holds the promise of a cure,” said Sean Owens, a veterinary professor and director of the new Regenerative Medicine Laboratory. “We can use pharmacological medicine to alleviate the pain associated with orthopedic injuries in horses, but only with biological medicine such as stem cell therapy can we actually repair the damage that has already been done.”
The research-driven laboratory is expected to yield new knowledge that also will benefit other animal species.
The new Regenerative Medicine Laboratory, located on the first floor of the UC Davis William R. Pritchard Veterinary Medical Teaching Hospital, will support the clinical arm of the veterinary stem cell program. Lab personnel will process, culture and store stem cells that have been collected from the hospital’s equine patients to treat injuries.
The laboratory also will provide stem cell collection kits to private veterinarians so that they can harvest stem cells from their equine patients and return the cells to the UC Davis lab for processing or storage. Processed stem cells then will be returned so that the veterinarians can treat their patients. Some horses also will be referred to the teaching hospital for stem cell treatments.
While the costs associated with stem cell processing and treatment will vary from case to case, the fee for processing and expansion of one bone marrow sample will be approximately $1,800. Each sample will be expanded into four therapeutic stem cell doses. One dose will be returned to the submitting veterinarian, while the other three will be stored for future use. The fee for stem cells injections at the Veterinary Medical Teaching Hospital will vary according to the number and frequency of doses administered. For most patients, the fee will be approximately $1,500.
Stem cells and regenerative medicine
Regenerative medicine is the field of human and veterinary medicine that involves creating living, functional tissues to repair or replace tissues or organs that have been damaged by injury, disease, aging or birth defects.
One way to do this is by collecting stem cells, which are unspecialized cells that can be induced in the laboratory to become specialized cell types such as muscle, blood and nerves.
The use of embryonic stem cells has raised much debate in human medicine. It is important to note that the new regenerative medicine program at the UC Davis Veterinary Medical Teaching Hospital does not use embryonic stem cells, but rather stem cells that have been collected from the horse’s own blood or bone marrow.
“The stem cell, with its ability to recreate, repair or revitalize damaged organs or tissues, is rapidly changing all of medicine," said Gregory Ferraro, a veterinary professor and director of UC Davis’ Center for Equine Health. “The application of stem cell science to treating horses is advancing so quickly that within three to five years, the treatments that are currently being provided for orthopedic repair in athletic horses will seem crude in hindsight.”
Veterinary stem cell team
The Center for Equine Health is coordinating a five-year collaborative research study, now in its second year.
The study is being carried out by a team of 11 UC Davis veterinary researchers, who are working to develop methods for collecting, processing, storing and administering stem cells to repair bone, tendon and ligament injuries in horses. These types of injuries are common problems especially for race horses and other performance horses. The team’s early findings indicate that stem cell treatments may reduce the recurrence of certain tendon and ligament injuries and lessen the progression of arthritis associated with traumatic joint diseases in horses.
This veterinary team, under the direction of professor and equine surgeon Larry Galuppo, also has established a working partnership with the UC Davis Health System’s Stem Cell Program in human medicine, directed by Jan Nolta, a medical school professor and one of the nation’s leading stem cell researchers.