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Week Ending FRIDAY June 26, 2009---------------------------News Archive / Return to News Alerts


Environmental Cues - Reproductive Timing and Longevity
Implications for improving human health and lengthening lifespan

When humans and animals delay reproduction because food or other resources are scarce, they may live longer to increase the impact of their reproduction, according to a new study by University of Minnesota - published in the June 25 issue of PLoS (Public Library of Science) One.

The discovery might explain why starvation can lead to longer life. It potentially has important implications for improving human health and lengthening lifespan.

The basic idea is that individuals use environmental cues to predict population declines, causing them to delay reproduction until the decline has occurred, and when each subsequent offspring will make a bigger contribution to the gene pool. Likewise, if bad times turn to good times and the population is on the verge of a boom, reproducing sooner rather than later will help their genes thrive.

“If the population is decreasing, future kids make a bigger splash in the gene pool than current kids,” explains Will Ratcliff, a College of Biological Sciences graduate student who came up with the idea for the study. “So, if there are tradeoffs between current and future reproduction, delaying reproduction can be a good idea, even if it reduces the number of kids you have during your lifetime.”

Fluctuations in testosterone levels provide an example of how the environment and organisms interact to guide reproduction, explains R. Ford Denison, adjunct professor in the College of Biological Sciences and Ratcliff’s adviser. Testosterone suppresses the immune system. So when environmental conditions trigger high levels, reproduction is high but longevity drops.

Environmental factors also control the age of menarche. In African countries with chronic food shortages, girls experience menarche (first menstrual period) much later than in the United States, where rich diets trigger early menarche. Food scarcity is a signal that the population is likely to decline, so reproduction is delayed; while an abundance of rich food signals an increase, causing reproductive age to drop.

“Our hypothesis may explain hormesis, the mysterious health benefits of low doses of toxins – including those made in broccoli to defend themselves from insects,” says Denison. “When their usual foods are scarce, organisms turn to plants containing chemicals that can suppress reproduction and consequently increase longevity. These toxins may be abundant in ‘famine foods’ that are eaten only when meat and fruit are not available” Denison said.

Graduate student Peter Hawthorne and professor Michael Travisano also co-authored the paper. All four co-authors are in the College of Biological Sciences’ department of ecology, evolution and behavior.

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Stem Cells Determine Their Daughters’ Fate
From roundworm to human, most cells in an animal’s body ultimately come from stem cells

When one of these versatile, unspecialized cells divides, the resulting “daughter” cell receives instructions to differentiate into a specific cell type. In some cases this signal comes from other cells. But now, for the first time, researchers at the Carnegie Institution’s Department of Embryology have found a type of stem cell that directly determines the fate of its daughters.

The finding, reported in the January 25, 2009 online edition of the journal Science, could transform our basic understanding of stem cells by demonstrating that some tissues maintain themselves throughout life. It could also prove valuable in the fight against some cancers.

“We found that stem cells can participate actively in determining what type of cell their daughters will become right at the moment of stem cell division,” said Embryology director and study co-author Allan Spradling. “This suggests that tissue stem cells might not just be a source of new cells, but could actually be the ‘brains’ of the tissue—the cells that figure out what type of new cell is needed at any given moment.”

Because they truly can become any cell in the body, “embryonic” stem cells tend to receive a lot of attention. Yet “adult” stem cells remain in fully developed organisms, where they replace specific cell types lost to age or disease. Spradling and postdoctoral researcher Benjamin Ohlstein performed the study using intestinal stem cells (ISCs), a type of adult stem cell in the fruit fly Drosophila melanogaster that they discovered only a year ago.

These cells directly use the “Notch” signaling pathway, a system well-known to biologists, to replenish one of two cell types in the fruit fly’s gut. The fate of any given daughter appears to depend on a protein, called Delta, which sits on the surface of the ISC and activates the Notch pathway in its daughters.

“Delta and the Notch receptor protein are both attached to the surface of cells, and don’t float around freely, so we always have to assume that the Delta signal comes from nearby cells,” Ohlstein said. “But the ISC is literally about as nearby as you can get.”

Most daughters receive a strong Delta signal from the ISC and become enterocytes (ECs)—cells that line the inside of the gut and absorb nutrients. But when the Delta signal is weak, the daughters will become hormone-generating enteroendocrine cells. For every 15-20 ECs it creates, a given ISC will also produce two enteroendocrine cells, usually in matched pairs at the same time.

Spradling and Ohlstein tracked the whereabouts of Delta, Notch, and several other related proteins using fluorescent marker molecules. They found that most ISCs have large amounts of Delta protein. This made it relatively easy to single out ISCs during the experiments—usually a significant challenge with stem cells—and to track where Delta molecules moved over time.

Delta seems to control not just what types of new cells are made, but also puts the brakes on excessive cell division. In several experiments where Delta or other Notch signaling genes were disabled or blocked, the daughter cells continued to divide, eventually producing tumors.

“Each individual stem cell seems to have a great degree of independence from the rest of the animal’s body,” Spradling explained. “On one hand, the ISCs can respond quickly to the needs of the gut lining as it loses cells. On the other hand, they seem rather vulnerable to losing control of cell division.”

It remains to be proven whether ISCs require a specific microenvironment created by neighboring cells, known as a niche, as other types of stem cells in Drosophila and mammals do. Understanding such a niche could have huge implications for the study of certain kinds of cancer, including those of the brain and intestine.

Future studies of ISCs might also reveal how the mammalian intestine responds to nutrition, stress, and illness. Like the fruit fly gut, mammalian intestines also contain large numbers of dispersed stem cells.

“Our hope is that the distinctive molecular properties of Drosophila ISCs we discovered will now allow mammalian intestinal stem cells to be definitively identified and better studied,” Spradling added.


“Scrawny” Gene Keeps Stem Cells Healthy
Stem cells are the body’s primal cells, retaining the youthful ability to develop into more specialized types of cells over many cycles of cell division. How do they do it?

Scientists at the Carnegie Institution have identified a gene, named scrawny, that appears to be a key factor in keeping a variety of stem cells in their undifferentiated state. Understanding how stem cells maintain their potency has implications both for our knowledge of basic biology and also for medical applications. The results are published in the January 9, 2009 print edition of Science.

“Our tissues and indeed our very lives depend on the continuous functioning of stem cells,” says Allan C. Spradling, director of the Carnegie Institution’s Department of Embryology. “Yet we know little about the genes and molecular pathways that keep stem cells from turning into regular tissue cells—a process known as differentiation.”

In the study, Spradling, with colleagues Michael Buszczak and Shelley Paterno, determined that the fruit fly gene scrawny (so named because of the appearance of mutant adult flies) modifies a specific chromosomal protein, histone H2B, used by cells to package DNA into chromosomes. By controlling the proteins that wrap the genes, scrawny can silence genes that would otherwise cause a generalized cell to differentiate into a specific type of cell, such as a skin or intestinal cell.

The researchers observed the effects of scrawny on every major type of stem cell found in fruit flies. In the experiments, mutant flies without functioning copies of the scrawny prematurely lost their stem cells in reproductive tissue, skin, and intestinal tissue.

Stem cells function as a repair system for the body. They maintain healthy tissues and organs by producing new cells to replenish dying cells and rebuild damaged tissues. “Losing stem cells represents the cellular equivalent of eating the seed corn,” says Spradling.

While the scrawny gene has so far only been identified in fruit flies, very similar genes that may carry out the same function are known to be present in all multicellular organisms, including humans. The results of this study are an important step forward in stem cell research. “This new understanding of the role played by scrawny may make it easier to expand stem cell populations in culture, and to direct stem cell differentiation in desired directions,” says Spradling.

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Stem Cell Surprise for Tissue Regeneration
Scientists working at the Carnegie Institution’s Department of Embryology, with colleagues, have overturned previous research that identified critical genes for making muscle stem cells

It turns out that the genes that make muscle stem cells in the embryo are surprisingly not needed in adult muscle stem cells to regenerate muscles after injury. The finding challenges the current course of research into muscular dystrophy, muscle injury, and regenerative medicine, which uses stem cells for healing tissues, and it favours using age-matched stem cells for therapy. The study is published in the June 25 advance on-line edition of Nature.

Previous studies have shown that two genes Pax3 and Pax7, are essential for making the embryonic and neonatal muscle stem cells in the mouse. Lead researcher Christoph Lepper, a predoctoral fellow in Carnegie’s Chen-Ming Fan’s lab and a Johns Hopkins student, for the first time looked at these two genes in promoting stem cells at varying stages of muscle growth in live mice after birth.

As Christoph explained: “The paired-box genes, Pax3 and Pax7 are involved in the development of the skeletal muscles. It is well established that both genes are needed to produce muscle stem cells in the embryo. A previous student, Alice Chen, studied how these genes are turned on in embryonic muscle stem cells (also published in Nature)."

"I thought that if they are so important in the embryo, they must be important for adult muscle stem cells. Using genetic tricks, I was able to suppress both genes in the adult muscle stem cells. I was totally surprised to find that the muscle stem cells are normal without them.”

The researchers then looked at whether the same was true upon injury, after which the repair process requires muscle stem cells to make new muscles. For this, they injured the leg muscles between the knee and ankle. They were again surprised that these muscle stem cells, without the two key embryonic muscle stem cell genes, could generate muscles as well as normal muscle stem cells. They even performed a second round of injury and found that the stem cells were still active.

The scientists then wondered when these genes become unnecessary for muscle stem cells to regenerate muscles. It turned out that these embryonic genes are important to muscle stem cell creation up to the first three weeks after birth.

What makes the muscle stem cells different after three weeks? The scientist believe that these two embryonic muscle stem cell genes also tell the stem cells to become quiet as the organism matures.

After that time is reached, they “hand over” their jobs to a different set of genes. The researchers suggest that since the adult muscle stem cells are only activated when injury occurs (by trauma or exercise), they use a new set of genes from those used during embryonic development, which proceeds without injury. The scientists are eager to find these adult muscle stem cell genes.

“We are just beginning to learn the basics of stem cell biology, and there are many surprises,” remarked Allan Spradling, director of Carnegie’s Department of Embryology. “This work illustrates the importance of carrying out basic research using animal models before rushing into the clinic with half-baked therapies.”

The research was funded by the Carnegie Institution, NIH, and the Riley Children’s Foundation.

THURSDAY June 25, 2009---------------------------News Archive / Return to News Alerts

Human Placenta Abundant Source of Hematopoietic Cells
Investigators at Children's Hospital Oakland Research Institute, Oakland, California found a way to obtain large numbers of hematopoietic stem cell from human term placentas

Their results appear in the July 2009 issue of Experimental Biology and Medicine, describing in detaile a practical way to obtain hematopoietic stem cells from placenta in numbers that are several-fold higher than could be obtained from cord blood.

The research team consisted of Dr. Vladimir Serikov, MD, PhD, D.Sci, Assistant Staff Scientist, Catherin Hounshell, research associate, Sandra Larkin, research associate, Mr. William Green, student, Dr. Hurokazy Ikeda, MD, Visiting Scientist, Dr. Mark Walters, Medical Director of Children's Hospital Oakland Hematology and Oncology Programs, and Dr. Frans Kuypers, Senior Scientist.

The team performed studies of human term placentas, human cord blood, and immunodeficient mice. Dr. Serikov said that the human term placenta is a hematopoietic organ. A fact shown by his team more then a year ago. This year's finding were confirmed by UCSF scientists headed by Dr. S. Fisher.

In his report, Dr. Serikov demonstrated that human placentas could provide abundant amounts of CD34+ CD133+ colony-forming cells, as well as other primitive hematopoietic progenitors, suitable for transplantation in humans.

Hematopoietic stem cells maintain their differentiation capacity, and stromal stem cells (that support long-term culture of hematopoietic cells). Live hematopoietic cells can similarly be obtained from whole cryopreserved placentas.

Cells derived from placental tissue differentiated into all blood lineages in vitro. Animal experiments further demonstrated successful engraftment of placenta-derived HSC in immunodeficient mice.

Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine said "the outstanding importance of these results for practical hematology is determined by the fact that the total number of stem cells that can be harvested from cord blood limits the efficacy of this stem cell source for transplants only to small children."

The novel findings of the Children's Hospital reseach demonstrates that placentas may provide a source of autologous stem cells sufficient for reconstitution of hematopoiesis in adult patients.

The methods used to obtain hematopoietic cells from placentas, developed by Dr. Serikov and Dr. Kuypers, can augument umbilical cord blood-based therapy in replacing bone marrow transplantation, and will dramatically change the whole field of transplantology."

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Child Psychologists Discuss How Parents of Preemies Sometimes Develop PTSD
Cocooned in tubes and wires, too fragile to be held, small, sick newborns fight for life in neonatal intensive care units. Though many go home healthy, the babies' harrowing starts leave indelible marks on their parents

To learn exactly how parents are affected, Richard Shaw, MD, a child psychiatrist at Lucile Packard Children's Hospital and an associate professor at the Stanford University School of Medicine, is studying post-traumatic stress disorder among moms and dads whose infants stayed in a NICU. (His latest paper on the subject was published in the March-April issue of the journal Psychosomatics.) He recently sat down for a Q&A session on the topic.

Question: How could PTSD interfere with a parent's ability to be a good caregiver?
Shaw: Parents with PTSD tend to be highly anxious and prone to overinterpret mild distress in their children as indicating possible serious illness. They may constantly expect their child to become ill, recreating the feelings of anxiety and distress they experienced at the time of their child's birth. They may repeatedly bring their children to the doctor - often unnecessarily - and, in so doing, foster a pattern in which their child manifests physical symptoms as a way to express emotion.

Parents may also develop symptoms of what has been termed the "vulnerable child syndrome." In this syndrome, parents with a history of having a medically fragile infant become overprotective, limiting their child's independence, because they want to make up for their child's trauma. This may result in children becoming oppositional and defiant as they get older.

Q: What were the most important aspects of your recent findings?
Shaw: We found very high rates of symptoms of traumatic stress in parents of NICU infants in the first few weeks after birth. The parents' symptoms may include nightmares about their child's birth and hospital stay, intrusive memories, a tendency to be jumpy or on edge, sleep difficulties and attempts to avoid reminders of the trauma. In our sample of parents, mothers tended to be more symptomatic, possibly because they are more likely to be at the bedside, and are therefore more likely to experience the traumatic aspects of their child's medical problems.

Q: Did any of your findings surprise you?
Shaw: We were surprised to find that fathers had a delayed reaction in terms of their trauma response. By four months, maternal trauma symptoms had diminished, but fathers' symptoms had increased, and in fact exceeded those of the mothers. It appeared that fathers tend to keep their emotional reactions in check for the first few months, perhaps to allow full support to be given to the mothers. However, by four months, when the mothers are recovering, the fathers go through a very difficult period. Awareness of this phenomenon is essential to ensure that the fathers' needs are not overlooked or neglected.

Q: In your research, the severity of the infants' illness did not correlate to parents' stress levels. Why not?
Shaw: In trauma research in general, the severity of the response tends to depend more on the characteristics of the victim, and less on the circumstances of the trauma. Some individuals seem to be quite resilient and less likely to develop symptoms of PTSD. Others, especially those with prior history of trauma exposure, or those with poor coping abilities, are more vulnerable. These factors appear to be more important than the severity of the child's illness.

Q: What follow-up care should we provide for parents after an infant's NICU stay ends?
Shaw: Parents should be carefully evaluated and offered appropriate psychological support. They should be educated about warning signs in themselves - insomnia, nightmares, irritability, etc. - and involved in hospital-based parent support groups. They also benefit greatly from advice from other parents who have gone through similar NICU experiences. Packard Children's, for example, has a Parent Mentor Program to provide support of this nature. In addition, to advance research in this area, we have recently submitted a grant to study the usefulness of brief, supportive psychotherapy for NICU parents.


Genetic Finding that Could Lead to Therapy for Neuroblastoma
Researchers have identified a genetic glitch that could lead to development of neuroblastoma, a deadly form of cancer that typically strikes children under 2

Two University of Florida scientists are part of the multicenter team of researchers that made the discovery, which could pave the way for better treatments that target the disease, according to findings published Wednesday in the journal Nature.

"What makes our study so important is that although neuroblastoma accounts for 7 percent of childhood cancers, it is responsible for 15 percent of deaths in children with cancer," said Wendy London, Ph.D., a research associate professor of epidemiology, biostatistics and health policy research at the UF College of Medicine and a member of the UF Shands Cancer Center. "This paper adds yet another gene in the pathway that could lead to tumorigenesis (tumor formation) of neuroblastoma."

Neuroblastoma forms in developing nerve cells, with tumors most often found on a child's adrenal gland. It's the most common form of cancer in babies and the third most common childhood cancer, according to the American Cancer Society.

Led by John J. Maris, M.D., director of the Cancer Center at The Children's Hospital of Philadelphia, researchers performed what's known as a genome-wide association study to uncover errors in DNA that could be associated with neuroblastoma.

To do this, researchers analyzed the genetic makeup of 846 patients with neuroblastoma, whose samples were derived from the Children's Oncology Group Neuroblastoma Tumor Bank, and 803 healthy patients in a control group.

On the basis of their initial findings, the researchers performed a second validation analysis, pinpointing that a glitch called a "copy number variation" in a single chromosome is associated with neuroblastoma. Copy number variation has to do with the gain, loss or duplication of snippets of DNA.

"This is part of series of papers that creates the bigger picture, an understanding of the genetic mechanisms that lead to neuroblastoma," said London, the principal investigator for the Children's Oncology Group Statistics and Data Center at UF. "We are searching for genetic targets to treat with therapy."

The researchers reported additional genetic links in Nature Genetics in May. The team discovered that on the gene called BARD1, six single-nucleotide polymorphisms — variations in tiny pieces of DNA — were also associated with neuroblastoma.

"Only two years ago we had very little idea of what causes neuroblastoma," said Maris, who led both studies. "Now we have unlocked a lot of the mystery of why neuroblastoma arises in some children and not in others."

Although neuroblastoma is one of the more common childhood cancers, it is relatively rare overall when compared with more common adult cancers, which has proved to be a challenge for researchers trying to uncover its causes, said Peter Zage, M.D., Ph.D., an assistant professor of pediatrics at the Children's Cancer Hospital at the University of Texas M.D. Anderson Cancer Center.

"Dr. Maris' group has been able to collect a relatively large number of cases for a neuroblastoma study and so has been able to identify these genetic variations and specific genes to provide us with some new avenues for therapy that we probably would not have been able to identify looking at the smaller cohorts of patients we each see at our individual institutions. In that sense, it's certainly an amazing leap forward in our understanding of the disease."

The discovery does hold promise for developing treatments, but London cautions that these potential "targeted therapies" won't work on all neuroblastoma patients. Not all neuroblastoma patients have this particular genetic anomaly, and not all children with this anomaly will develop neuroblastoma. Development of neuroblastoma is complicated and can occur because of multiple reasons, arising after a complex chain of events, London said.

"What's amazing is there are so many different ways for tumorigenesis to occur," London said. "That's the reason it is so hard to treat and cure cancer, or even to understand why it happens and how it happens."

All the researchers involved in the study are members of the Children's Oncology Group, the only National Institutes of Health/National Cancer Institute pediatric cancer cooperative group. The group performs clinical trials, collects specimens and performs statistical analysis related to pediatric cancers. UF is one of three institutions with a COG Statistics and Data Center, where study design, data collection and statistical analysis for COG research occurs.

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New Way that Cells Fix Damage to DNA
A team of researchers at The Scripps Research Institute and other institutions has discovered a new way by which DNA repairs itself, a process that is critical to the protection of the genome, and integral to prevention of cancer development

Scientists who study the repair of the DNA bases, which make up the information in the human genome, had known of only one type of method that cells use to fix a specific kind of damage to their DNA, but in the June 11, 2009 issue of Nature, the team found a novel way—one that combines elements from the known mechanisms and an unrelated second method that was previously not known to play a role in this type of DNA repair.

"We found a connection between the known DNA repair processes that people did not know was there," says Professor John Tainer, a member of the Skaggs Institute for Chemical Biology at Scripps Research, who led the study with Geoffrey P. Margison of the University of Manchester (United Kingdom) and Anthony E. Pegg of the Pennsylvania State University College of Medicine. "This changes the game, and gives us something important to look for in cancers that are resistant to chemotherapy."

This new mechanism is controlled by alkyltransferase-like proteins (ATLs), whose structure and function had been unknown and which had been identified only in bacteria and yeast. In addition to describing the function of ATLs, in the new study the scientists showed that ATLs exist in a multicellular organism, the sea anemone, which suggests this protein or its cousins in terms of repair activity also exist in other species, including humans.

Known Strategies for DNA Repair
Damage occurs to a cell's DNA on a continuing basis from outside sources, such as radiation and UV light, and from activities that go on day by day inside the cell. Most of this damage consists of damage to the DNA bases adenine, cytosine, guanine, and thymine. These bases pair up together inside the DNA double helix—adenine and thymine join together, and guanine and cytosine link to each other and their sequence forms the information in the human genome.

These bases can be chemically modified in a number of ways, including by alkylation, in which an alkyl group (or "adduct") is transferred onto a guanine base. When this happens, one of the hydrogen bonds holding guanine and cytosine together is removed, increasing the chances that thymine will be inserted across from guanine during DNA replication. If DNA is replicated with this "transition" error, a mutated gene results, so the information is changed. This can lead to harmful results, like cell death or cancer.

As shown in the reported work, this kind of damage occurs, for example, when chemicals derived from cigarette smoke stick to guanine, or when chemotherapy agents put an alkyl adduct onto guanine.

But that is where DNA repair mechanisms come in, which is good in the case of chemicals from cigarettes, but not so desirable when they repair genetic damage purposely induced by chemotherapy drugs intended to kill cancer cells.

The DNA repair process that removes such toxic "lesions" is known as base repair, and uses a protein called AGT (O6-alkylguanine DNA-alkytransferase) to remove the alkyl group before DNA replicates. The protein essentially sticks a chemical finger inside the DNA to flip the damaged guanine out from the DNA helix structure so that its adduct is exposed and can be transferred from the guanine to a part of its protein structure. The guanine is now repaired and can rejoin cytosine with three hydrogen bonds linking them.

AGT is believed to act alone, but there is another, unrelated repair process—nucleotide excision repair (NER)—that uses lots of proteins in its pathway. This repair occurs when bulky adducts stuck to bases distort the sleek shape of the DNA helix. Then a whole group of proteins come in and remove a patch of bases that includes the adduct, and DNA polymerase follows and fills in the patch while adding the correct base back.

A New Way
Before the new study, ATLs were believed to be involved in DNA damage responses, because they protected cells from DNA alkylation damage in lab experiments, but no one understood how they worked or what they did. In the new study, the team describes ATLs' role.

The scientists undertook a series of structural, genetic, and biochemistry experiments on the protein and determined its structure, both alone and with a guanine that had a methyl adduct and another with a smoking-derived adduct stuck on it. They found that the ATL structure looks like AGT. It, too, had a chemical finger that can rotate a damaged guanine base out from the DNA helix, but it doesn't remove the adduct like AGT does. Instead, ATL binds tightly to the damaged guanine and bends the DNA in a way that is more pronounced than what AGT does for repair.

"Base flipping by ATL is like a switch that activates the NER pathway, which then removes the alkyl adduct from the guanine," says first author Julie Tubbs, a research associate at Scripps Research. "So we believe that ATL is conceptually acting like a bridge, connecting the two DNA repair pathways—base and NER—together. This is a surprisingly general mechanism to channel specific base damage into the general NER pathway."

Before the new study, scientists also didn't know if ATLs functioned outside of single celled organisms. In the new study, however, the scientists discovered ATLs in two types of ancient organisms, archaeal bacteria and in sea anemone, suggesting this new bridging pathway may be general to most cells and organisms.

"What's especially important about these newly discovered ATLs is that we now know that ATLs exist in all domains of life, so it is very likely that ATL was common to the evolutionary branches before complex eukaryotes [single-celled or multicellular organisms whose cells contain a distinct membrane-bound nucleus]," Tainer says. "This suggests higher eukaryotes, including mammals and humans, will either have an ATL or have lost or replaced it with a protein of analogous function."

If ATLs are found in humans, Tainer sees that either inhibiting or bolstering their function could aid cancer therapy. Inhibiting DNA repair would help chemotherapy effectively destroy cancer cells. Augmenting ATL function could help protect sensitive tissue, such as bone marrow, that is easily destroyed during cancer treatment.

"There are all kinds of exciting ideas to emerge from this research," says Tainer. "For one thing, we now know what to look for when we see resistance to some chemotherapies."

WEDNESDAY June 24, 2009---------------------------News Archive / Return to News Alerts


Weed Killer Kills Embryonic, Placental and Umbilical Cord Cells
Used in yards, farms and parks throughout the world, Roundup has long been a top-selling weed killer. But now researchers have found that one of Roundup’s inert ingredients can kill human cells, particularly embryonic, placental and umbilical cord cells

The new findings intensify a debate about so-called “inerts” — the solvents, preservatives, surfactants and other substances that manufacturers add to pesticides. Nearly 4,000 inert ingredients are approved for use by the U.S. Environmental Protection Agency.

Glyphosate, Roundup’s active ingredient, is the most widely used herbicide in the United States. About 100 million pounds are applied to U.S. farms and lawns every year, according to the EPA.

Until now, most health studies have focused on the safety of glyphosate, rather than the mixture of ingredients found in Roundup. But in the new study, scientists found that Roundup’s inert ingredients amplified the toxic effect on human cells—even at concentrations much more diluted than those used on farms and lawns.

One specific inert ingredient, polyethoxylated tallowamine, or POEA, was more deadly to human embryonic, placental and umbilical cord cells than the herbicide itself – a finding the researchers call “astonishing.”

“This clearly confirms that the [inert ingredients] in Roundup formulations are not inert,” wrote the study authors from France’s University of Caen. “Moreover, the proprietary mixtures available on the market could cause cell damage and even death [at the] residual levels” found on Roundup-treated crops, such as soybeans, alfalfa and corn, or lawns and gardens.

The research team suspects that Roundup might cause pregnancy problems by interfering with hormone production, possibly leading to abnormal fetal development, low birth weights or miscarriages.

Monsanto, Roundup’s manufacturer, contends that the methods used in the study don’t reflect realistic conditions and that their product, which has been sold since the 1970s, is safe when used as directed. Hundreds of studies over the past 35 years have addressed the safety of glyphosate.

“Roundup has one of the most extensive human health safety and environmental data packages of any pesticide that's out there,” said Monsanto spokesman John Combest. “It's used in public parks, it's used to protect schools. There's been a great deal of study on Roundup, and we're very proud of its performance.”

The EPA considers glyphosate to have low toxicity when used at the recommended doses.

“Risk estimates for glyphosate were well below the level of concern,” said EPA spokesman Dale Kemery. The EPA classifies glyphosate as a Group E chemical, which means there is strong evidence that it does not cause cancer in humans.

In addition, the EPA and the U.S. Department of Agriculture both recognize POEA as an inert ingredient. Derived from animal fat, POEA is allowed in products certified organic by the USDA. The EPA has concluded that it is not dangerous to public health or the environment.

The French team, led by Gilles-Eric Seralini, a University of Caen molecular biologist, said its results highlight the need for health agencies to reconsider the safety of Roundup.

“The authorizations for using these Roundup herbicides must now clearly be revised since their toxic effects depend on, and are multiplied by, other compounds used in the mixtures,” Seralini’s team wrote.

Controversy about the safety of the weed killer recently erupted in Argentina, one of the world’s largest exporters of soy.

Last month, an environmental group petitioned Argentina’s Supreme Court, seeking a temporary ban on glyphosate use after an Argentine scientist and local activists reported a high incidence of birth defects and cancers in people living near crop-spraying areas. Scientists there also linked genetic malformations in amphibians to glysophate. In addition, last year in Sweden, a scientific team found that exposure is a risk factor for people developing non-Hodgkin lymphoma.

Inert ingredients are often less scrutinized than active pest-killing ingredients. Since specific herbicide formulations are protected as trade secrets, manufacturers aren’t required to publicly disclose them. Although Monsanto is the largest manufacturer of glyphosate-based herbicides, several other manufacturers sell similar herbicides with different inert ingredients.

The term “inert ingredient” is often misleading, according to Caroline Cox, research director of the Center for Environmental Health, an Oakland-based environmental organization. Federal law classifies all pesticide ingredients that don’t harm pests as “inert,” she said. Inert compounds, therefore, aren’t necessarily biologically or toxicologically harmless – they simply don’t kill insects or weeds.

Kemery said the EPA takes into account the inert ingredients and how the product is used, whenever a pesticide is approved for use. The aim, he said, is to ensure that “if the product is used according to labeled directions, both people’s health and the environment will not be harmed.” One label requirement for Roundup is that it should not be used in or near freshwater to protect amphibians and other wildlife.

But some inert ingredients have been found to potentially affect human health. Many amplify the effects of active ingredients by helping them penetrate clothing, protective equipment and cell membranes, or by increasing their toxicity. For example, a Croatian team recently found that an herbicide formulation containing atrazine caused DNA damage, which can lead to cancer, while atrazine alone did not.

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ADHD Genes Found Playing Roles in Neurodevelopment
Missing DNA segments may suggest future drug targets

Pediatric researchers have identified hundreds of gene variations that occur more frequently in children with attention-deficit hyperactivity disorder (ADHD) than in children without ADHD. Many of those genes were already known to be important for learning, behavior, brain function and neurodevelopment, but had not been previously associated with ADHD.

"Because the gene alterations we found are involved in the development of the nervous system, they may eventually guide researchers to better targets in designing early intervention for children with ADHD," said lead author Josephine Elia, M.D., a psychiatrist and ADHD expert at The Children's Hospital of Philadelphia.

The study appeared online today in the journal Molecular Psychiatry.

Unlike changes to single DNA bases, called SNPs or "snips," the alterations examined in the current study are broader changes in structure. Called copy number variations (CNVs), they are missing or repeated stretches of DNA. CNVs have recently been found to play significant roles in many diseases, including autism and schizophrenia Everyone has CNVs in their DNA, but not all of the variations occur in locations that affect the function of a gene. The current study is the first to investigate the role of CNVs in ADHD.

Individually, each CNV may be rare, but taken together, a combination of changes in crucial regions may interact to raise an individual's risk for a specific disease. "When we began this study in 2003, we expected to find a handful of genes that predispose a child to ADHD," said study co-leader Peter S. White, Ph.D., a molecular geneticist and director of the Center for Biomedical Informatics at Children's Hospital. "Instead, there may be hundreds of genes involved, only some of which are changed in each person. But if those genes act on similar pathways, you may end up with a similar result—ADHD. This may also help to explain why children with ADHD often present clinically with slightly different symptoms."

ADHD is the most common neuropsychiatric disorder in children, affecting an estimated 1 in 20 children worldwide. It may include hyperactive behavior, impulsivity and inattentive symptoms, with impaired skills in planning, organizing, and maintaining focus. Its cause is unknown, but it is known from family studies to be strongly influenced by genetics.

Drawing on DNA samples from the Children's Hospital pediatric network, the researchers analyzed genomes from 335 ADHD patients and their families, compared to more than 2,000 unrelated healthy children. The team used highly automated gene-analyzing technology at the Center for Applied Genomics at Children's Hospital, directed by Hakon Hakonarson, M.D., Ph.D., a co-leader of this study.

The study team found a similar quantity of CNVs in both groups. However, distinct patterns emerged. Among 222 inherited CNVs found in ADHD families but not in healthy subjects, a significant number were in genes previously identified in other neurodevelopmental disorders, including autism, schizophrenia and Tourette syndrome. The CNVs found in ADHD families also altered genes important in psychological and neurological functions such as learning, behavior, synaptic transmission and nervous system development.

"We took a systems biology approach, grouping genes into groups with common functions," said White. "We found that the sets of genes more likely to be changed in ADHD patients and families affected functions that made sense biologically." For instance, said White, the team found four deletions of DNA in a gene recently linked to restless legs syndrome, a type of sleep disorder common in adults with ADHD.

Another deletion occurred in a gene for a glutamate receptor. Glutamate is a neurotransmitter, a protein that carries signals in the brain. While ADHD medications act on dopamine and serotonin, which are also neurotransmitters, this new finding may suggest an important role for glutamate as well, at least for some ADHD patients.

"As we delve into the genetics of very complex diseases such as ADHD, we find many contributing genes, often differing from one family to another," added White. "Studying the functions of different genes allows us to identify biological pathways that may be involved in this neuropsychiatric disorder."

Some of the biological pathways involved in ADHD may also be common to other neurological conditions, say the researchers. Likewise, there is some overlap among the CNVs found in ADHD that also occur in autism, schizophrenia and other neurological disorders. This overlap was not surprising, said Elia, because ADHD patients frequently also have one of more of these disorders. However, as researchers learn more about specific genes in neurological conditions, the hope is that researchers might in the future personalize treatments to a patient's own genetic profile, to achieve more targeted, specific therapies.

Elia and White stressed that much further work must be done before genetic findings lead to ADHD treatments.


Missing the Happiness Hormone - Serotonin - Causes Impaired Maternal Behavior in Mice
A lack of serotonin, commonly known as the "happiness hormone", in the brain slows the growth of mice after birth and is responsible for impaired maternal behavior later in life

This research was conducted by Dr. Natalia Alenina, Dana Kikic, and Professor Michael Bader of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, Germany. The researchers discovered that the presence of serotonin in the brain is not crucial for the survival of the animals.

Furthermore, they were able to confirm that there are two strictly separate pathways of serotonin production: One gene is responsible for the formation of serotonin in the brain, another gene for the production of the hormone in the body (PNAS, June 23, 2009, Vol. 106, No. 25, pp 10332-10337).

The researchers "switched off" the gene Tph2 in mice to elucidate the function of the gene in the brain. Tph2 produces the enzyme tryptophan hydroxylase (TPH), which is responsible for the formation of serotonin.

After the researchers switched off Tph2, the animals produced almost no serotonin in the brain. Nevertheless, the animals were viable and half of them survived until adulthood. However, they needed more sleep during the day and the regulation of their respiration, body temperature, and blood pressure was altered.

The female mice were able to give birth and produced enough milk to feed their pups, but their impaired maternal behavior led to poor survival of the offspring.

The Tph2 gene was discovered by MDC researchers several years ago together with researchers of the Free University (FU) Berlin and Humboldt University Berlin (HUB).

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Stem Cells From the Placenta
Placental stem cells may soon multiply the number of children who can be cured of blood disorders thanks to a research team at Children’s Hospital & Research Center Oakland

In the 07/09 issue of Experimental Biology and Medicine, Children’s researchers demonstrate that stem cells in human placentas can become blood-manufacturing cells and that they can be harvested. The team was led by principal investigator Frans Kuypers, PhD, senior scientist and Vladimir Serikov, PhD, assistant staff scientist.

"Yes the stem cells are there; yes they are viable; and yes, we can get them out," declared Dr. Kuypers.

These Stem Cells Save the Lives of Kids With Blood Disorders
Stem cells harvested from umbilical cord blood have already cured hundreds of children with bone marrow-related disorders, including sickle cell disease, thalassemia and leukemia. But upstream from that cord river is a whole placenta lake, filled with many times more stem cells. Harvesting them would mean many more children could be helped.

The placenta is the organ inside a pregnant woman that supplies her fetus with oxygen and food. It also collects fetal waste and disposes of it through the maternal kidneys. After birth, the placenta is expelled and discarded. Implanting placental stem cells in special laboratory mice, the team showed these stem cells not only thrived, they “made human blood in the mouse.”

What’s next is demonstrating that placental stem cells, like those found in cord blood, will do the same in a human.

Since 1997, using cord blood stem cells, researchers and clinicians at Children’s Hospital, among the pioneers in this work, have cured more than 100 children with bone marrow-related disorders, including sickle cell disease, thalassemia and leukemia.

This new research could dramatically increase the numbers of children and adults who could be treated and cured with such stem cells.

Stem Cells Don't Know the Difference Between 'Self' & 'Not-Self
The importance of stem cells is that they are relatively immunologically naïve. Their "naïveté" helps them swiftly and safely take up their new job of making blood cells, including white blood cells, one of the immune system's armies. Instead of attacking host cells, the new white blood cells adopt them, becoming part of their host's new immune system. When successfully transplanted, cord blood stem cells take up residence in a patient’s bone marrow, replacing blood-manufacturing cells damaged or destroyed by disease.

“The more stem cells, the bigger the chance of success,” said Dr. Kuypers. “Some day we will be able to serve more kids and adults with this important resource.”

Genetic Match Needed - But Threshold is Lower
Of course, there still needs to be a genetic match between donor stem cells from cord or placental blood, and the cells of the person receiving them, but the threshold is lower, than for bone marrow cells, for example.

Someone ill with sickle cell disease, who needs their blood-making ability restarted, may need to match a bone marrow donor on six markers. But only four of those markers need to match for a good chance at a successful cord blood transplant. Dr. Kuypers is hopeful the same will be proved true of a placental stem cell transplant.

Gathering Placental Stem Cells on a Large Scale is Best Way to Help Kids
Dr. Kuypers believes that harvesting placental stem cells on a large scale is the best and perhaps the only way to feasibly develop their use.

“We’re looking for partnerships with industry to get placenta-derived stem cells in large quantities into the clinic,” said Dr. Kuypers.

That’s why the team also developed a patent-pending process for freezing placentas that allows them to later be defrosted without damaging the stem cells, allowing harvesting of healthy stem cells when they are needed.

This approach makes it possible to gather, ship and store placentas in a systematic way. For example, the placenta of a baby delivered in Fresno could be frozen there and information about the blood entered in a database accessible across the country. Then the placenta could be shipped to a large-scale storage facility in, for instance, Denver.

Once a transplant team, in say, Seattle, searches the database and finds a match, the frozen placenta could be shipped to them, where the stem cell transplant was to be performed. Then the needed stem cells could be extracted from the placenta on site, using a technique developed by Children’s team.

One day, thanks to research at Children’s Hospital Oakland, unneeded placentas like these, and the potentially life-saving stem cells they contain, may give countless sick children another chance at life.

TUESDAY June 23, 2009---------------------------News Archive / Return to News Alerts

Kohl's3Gpx5: Sperm Shouldn't Leave Home Without It
Joel Drevet and colleagues, at Clermont Université, France, have identified a protein that helps protect immature mouse sperm after they have been released into a region of the testis known as the epididymis, which is where they undergo maturation

Although male mice lacking this protein, Gpx5, had normal looking sperm and were equally as efficient as normal male mice at fertilizing female mice, an increased incidence of miscarriages and fetal developmental defects occurred. Especially when normal female mice were mated with Gpx5-deficient males over 1 year old compared with normal male mice of the same age.

Further analysis indicates that Gpx5 acts as an antioxidant in the epididymis, protecting the sperm from oxidative stress.

The authors in an accompanying commentary, along with John Aitken, at the University of Newcastle, Australia, discuss why this data has immense clinical relevance.

Age-related DNA damage to human sperm has been associated with a range of adverse outcomes including decreased fertility, and increased rates of miscarriage and childhood disease. The normal life span of a mouse is 3 years. If one year old mice are showing oxidative stress in their sperm, a correlation with human sperm degeneration may be appropriate.

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Strong Metastasis Inhibitor Identified
It could curb a cancer's deadliness

Researchers at Children's Hospital Boston have isolated a potent inhibitor of tumor metastasis made by tumor cells, one that could potentially be harnessed as a cancer treatment. Their findings were published in the online Early Edition of the Proceedings of the National Academy of Sciences during the week of June 22.

Metastasis—the migration of cancer cells to other parts of the body—is one of the leading causes of death from cancer, and there is no approved therapy for inhibiting or treating metastases. Randoph S. Watnick, PhD, an assistant professor in the Vascular Biology Program at Children's, has been finding that metastatic tumors prepare landing places in distant organs for their metastases, by secreting certain proteins that encourage tumor growth and attract feeder blood vessels. Now, he and his colleagues show that non-metastatic tumors secrete a protein called prosaposin - which inhibits metastasis by causing production of factors that block the growth of blood vessels.

Cells from localized prostate and breast tumors, which didn't metastasize, secreted high levels of prosaposin, they found, while metastatic tumors secreted very little. When the researchers injected mice with tumor cells that were known to be highly metastatic, but to which they had added prosaposin, lung metastases were reduced by 80 percent and lymph node metastases were completely eliminated, and survival time was significantly increased. Conversely, when they suppressed prosaposin expression in tumor cells, they saw more metastases.

When prosaposin was directly injected into mice that had also received an injection of tumor cells, the tumor cells formed virtually no metastases in the lung, or, if they did, formed much smaller colonies. These mice lived at least 30 percent longer than mice not receiving prosaposin.

Watnick and colleagues also demonstrated that prosaposin stimulates activity of the well-known tumor suppressor p53 in the connective tissue (stroma) surrounding the tumor. This in turn stimulated production of thrombospondin-1, a natural inhibitor of blood vessel growth (angiogenesis), both in the tumor stroma and in cells at the distant location.

"Prosaposin, or derivatives that stimulate p53 activity in a similar manner in the tumor stroma, might be an effective way to inhibit the metastatic process in humans," says Watnick.

If this bears out, Watnick envisions treating cancer patients for their primary tumor, and concurrently giving them drugs to prevent metastases or slow their growth. "While we may not be able to keep patients from getting cancer, we can potentially keep them metastasis-free," he says.

Initially, Watnick's scientific interest was focused on metastatic cancer cells; he hoped to use proteomics techniques to isolate different proteins that steered metastases to different parts of the body (explaining, for example, why lung cancer often metastasizes to bone, or prostate cancer to liver). But the late Judah Folkman, MD, founder of the Vascular Biology program at Children's, encouraged him to focus on the metastasis inhibitor -- prosaposin. "You might have a drug right here," he told Watnick.

A patent has been filed by Children's Hospital Boston on the discovery. The hospital's Technology and Innovation Development Office is in active discussions to license prosaposin for commercial development.

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Brain Sees Tools as Temporary Body Parts
Researchers have what they say is the first direct proof of a very old idea: that when we use a tool - even for just a few minutes - it changes the way our brain represents the size of our body

In other words, the tool becomes a part of what is known in psychology as our body schema, according to a report published in the June 23rd issue of Current Biology, a Cell Press publication

"Since the origin of the concept of body schema, the idea of its functional plasticity has always been taken for granted, even if no direct evidence has been provided until now," said Alessandro Farnè of INSERM and the Université Claude Bernard Lyon. "Our series of experiments provides the first, definitive demonstration that this century-old intuition is true."

In the new study, Farnè, Lucilla Cardinali, and their colleagues reasoned that if one incorporates a used tool into the body schema, his or her subsequent bodily movements should differ when compared to those performed before the tool was used.

Indeed, that is exactly what they saw. After using a mechanical grabber that extended their reach, people behaved as though their arm really was longer, they found. What's more, study participants perceived touches delivered on the elbow and middle fingertip of their arm as if they were farther apart after their use of the grabbing tool.

People still went on using their arm successfully following after tool use, but they managed tasks differently. That is, they grasped or pointed to object correctly, but they did not move their hand as quickly and overall took longer to complete the tasks.

It's a phenomenon each of us unconsciously experiences every day, the researchers said. The reason you were able to brush your teeth this morning without necessarily looking at your mouth or arm is because your toothbrush was integrated into your brain's representation of your arm.

The findings help to explain how it is that humans use tools so well.

"We believe this ability of our body representation to functionally adapt to incorporate tools is the fundamental basis of skillful tool use," Cardinali said. "Once the tool is incorporated in the body schema, it can be maneuvered and controlled as if it were a body part itself."

Fly Tumor Suppressor Gene May Provide Insight Into Human Brain Tumors
In the fruit fly's developing brain, stem cells called neuroblasts normally divide to create one self-renewing neuroblast and one cell that has a different fate. But neuroblast growth can sometimes spin out of control and become a brain tumor

Researchers at Duke-NUS Graduate Medical School in Singapore have found a tumor-suppressing protein in the fly's brain, with a counterpart in mammals, that can apparently prevent brain tumors from forming.

"Our data explicitly show that the fruitfly protein PP2A (protein phosphatase 2A) suppresses brain tumor formation and controls the balance of self-renewal and differentiation of neural stem cells," said Hongyan Wang, Ph.D, assistant professor of neuroscience and behavioral disorders, and senior author of a paper published online in the journal Development.

"Given that mechanisms for stem cell division in flies and mammals are likely to be similar, our study on fly PP2A may provide useful insights for certain types of human brain tumors and possibly in a wide variety of cancers," Wang said.

By studying flies that had a PP2A mutation, the researchers learned that flies with missing or abnormally expressed PP2A had ten times the amount of stem cell growth in their larval brains. The flies' neural stem cells did not become neurons (nerve cells) in the brain, the types of cells needed for normal function. Instead, they effectively grew into a tumor mass.

Dr. Wang's previous work had identified a protein kinase called Polo as a tumor suppressor. Because phosphatases like PP2A usually have the opposite biochemical function to kinase, the scientists predicted that PP2A would stop the tumor suppressor Polo and allow for unchecked cell growth. "We were very surprised when we found that PP2A also suppressed tumors," Wang said.

Follow-up experiments showed that PP2A is important for regulating Polo kinase function, and showed that these two critical brain tumor suppressors work together to control neural stem cell divisions.

"Our discovery suggests that PP2A and Polo, both of which are crucial brain tumor-suppressors and cell cycle regulators, can function in the same pathway to regulate stem cell self-renewal and tumor development," Wang said. The research team plans to uncover novel proteins in this pathway by learning which protein functions between PP2A and Polo during the neural stem cell division process.

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A Urine Test for Appendicitis?
Urine marker found though proteomics may indicate which children need surgery

Appendicitis is the most common childhood surgical emergency, but the diagnosis can be challenging, especially in children, often leading to either unnecessary surgery in children without appendicitis, or a ruptured appendix and serious complications when the condition is missed.

Now, emergency medicine physicians and scientists at the Proteomics Center at Children's Hospital Boston demonstrate that a protein detectable in urine might serve as a "biomarker" for appendicitis. Their report was published online June 23 by the Annals of Emergency Medicine.

Despite improvement in imaging technologies, recent figures indicate that 3 to 30 percent of children have unnecessary appendectomies, while 30 to 45 percent of those diagnosed with appendicitis already have a ruptured appendix. Laboratory biomarkers have been identified, but none have proved reliable enough to be clinically useful.

Researchers led by Richard Bachur, MD, acting chief of emergency medicine at Children's Hospital Boston, Hanno Steen, PhD, director of the Proteomics Center, and clinical fellow Alex Kentsis, MD, PhD, decided to take a systematic approach, performing a proteomics study using state-of-the are mass spectrometry (a technique that detects and quantifies proteins in a sample). Their two-part study has identified the most accurate biomarker for acute appendicitis known to date.

In the first phase, they examined 12 urine specimens – 6 from patients with appendicitis, taken before and after appendectomy, and 6 from patients without appendicitis – and identified 32 candidate biomarkers, including many proteins associated with immune response and inflammation.

To these 32 they added other candidates found through gene expression studies and other means, yielding a total of 57 potential biomarkers. They then sought to validate these markers in 67 children seen at the hospital for suspected appendicitis over an 18-month period, 25 of whom ultimately had proven appendicitis. The laboratory investigators testing for the markers were not told the patients' clinical status, to ensure unbiased assessment of the test performance.

Seven promising urine biomarkers were identified. The best of them was leucine-rich alpha-2-glycoprotein (LRG), which appears to be a specific marker of local inflammation. It had an "area under the curve" value of 0.97, indicating near-perfect sensitivity (with almost no false-negatives) and near-perfect specificity (almost no false-positives). LRG was strongly elevated in diseased appendices, even when those appendices appeared normal on imaging, and the amount of LRG correlated with the severity of the appendicitis as judged by histologic review of the appendix specimens.

Although mass spectrometry isn't widely available clinically, urine LRG elevations were detected by immunoblotting, suggesting that a rapid clinical test, such as a urine dipstick, could be developed through further research.

Bachur, Steen and Kentsis now seek to develop quantitative LRG urine assays and further validate their findings. "Recent diagnostic advances have focused on advanced radiologic procedures, such as computed tomography and ultrasound, but these resources are not universally available and can delay diagnosis," says Bachur. "Although these advances have improved the diagnosis and decreased complications from appendicitis, CT scans also expose children to radiation that may increase the lifetime risk of cancer."

The researchers note that since their study was limited to children, and that patterns of biomarkers likely vary in older patients, LRG testing would need to be studied in other clinical settings.

Steen, director of the Proteomics Center at Children's, predicts that proteomics will play a major role in discovering diagnostic markers for a variety of pediatric diseases in the future. The hospital made a significant financial investment five years ago to launch the Center.

MONDAY June 22, 2009---------------------------News Archive / Return to News Alerts

3 to 6 Months to Lose Pregnancy Weight is Normal
from the German Institute for Quality and Efficiency in Health Care (IQWiG)

Comparing yourself to the magazine photos of movie stars in bikinis a few weeks after giving birth does not make real-life motherhood for the average woman any easier

Having a baby is a major life change and it can disrupt so many of your usual routines – including what you eat and whether and how you exercise. So what is “normal” for you and your baby in pregnancy? What can you realistically expect after the birth?

There is no standard amount of weight gain that should be expected by every pregnant woman. A small woman who is underweight may need to gain a different amount of weight than a woman who is very overweight before pregnancy begins.

Weight gain differs through pregnancy as well, with more weight being gained in the later parts of pregnancy than in the early months. The woman needs to be able to provide nutrition and support for the baby. Even if you are very overweight, you will still need to gain weight in pregnancy. Much of the weight gain, especially in early pregnancy, is extra fluid (water) to support the extra blood circulation that the placenta and baby needs.

In the 1930s, doctors used to recommend that all women try to restrict their weight gain to about 6.8 kg (or around 15 pounds). By the 1970s, medical advice changed, as doctors realised that restricting weight gain too much in pregnancy could be harmful. The Institute of Medicine (IOM) in the USA issued guidelines that were followed by doctors around the world, including in Germany.

The IOM published revised guidelines in May 2009, taking account of a major review of the evidence about pregnancy weight gain published by the US government’s Agency for Healthcare Research and Quality (AHRQ) in May 2008. The AHRQ researchers concluded that it was not certain that any one specific weight was right for all women.

As there is still no better scientific estimate of how much weight gain is normal, what do the guidelines say?

The first issue to consider is: are you overweight, underweight or within the “normal” weight range? Two approaches are commonly used to determine if people are overweight: The "body mass index" (BMI) and waist measurement. The BMI helps to determine how much you weigh in relation to your height. Waist measurements give you an idea of how fat is distributed in your body.

The BMI is the most common way to try to work out if people are overweight or obese (very overweight). It is a measure of the relationship between weight and height. There are different views on the definition of overweight and obesity. People who have a BMI between 25 and 30 are usually considered to be overweight. Being overweight alone does not always necessarily cause health problems, but it could be a problem if the person already has certain illnesses, such as type 2 diabetes. People who have a BMI over 30 are considered to be obese. Being obese is a greater risk to health than being overweight. You can read more about BMI, weight and health generally here.

The IOM recommendations for BMI and weight gain are:
• If you were underweight before pregnancy (for the IOM, that is a BMI of less than 20): between about 12.5 and 18 kgs extra weight during pregnancy

• If you were normal weight before pregnancy (for the IOM, that is a BMI between 20 and 26): between about 11.5 and 16 kg extra weight during pregnancy

• If you were overweight before pregnancy (for the IOM, that is a BMI between 26 and 29): between about 7 and 11.5 kg extra weight during pregnancy

• If you were obese before pregnancy (for the IOM, that is a BMI of over 29): between 5 and 9 kg extra weight during pregnancy

If you are very young, then more weight gain is probably needed as teenagers may still be growing themselves.

Your weight alone is not a good indicator of how well your baby is doing – or even of your baby’s weight gain. This depends on a lot of factors. It is not really possible to be sure of the baby’s weight before birth. Ultrasound and other tests can give an indication of how the baby is developing.

Can too much (or too little) weight gain cause problems or be a sign of serious problems?
According to AHRQ researchers, women who gain a lot of weight in pregnancy face some increased risks:
caesarean section
macrosomia (the baby being bigger than 4000g or 4500g)
not being able to lose the weight after giving birth

Researchers are still not certain whether or not a lot of weight gain in pregnancy increases the chances that the child will become overweight or obese later on.

Weight loss and undernutrition in pregnancy can harm the growing baby, often because he or she is then born too early (preterm birth) or has a low birthweight.

However, if you gain weight suddenly, or if you are gaining more than half a kilo a week, your doctor or midwife will need to monitor your weight and do additional tests. Very quick and large weight gains (such as 1 kg in a single week) can be a sign of health problems developing in the pregnant women, for example pre-eclampsia.

Pre-eclampsia is a pregnancy-related illness that can become life-threatening for both mother and baby, involving high blood pressure (hypertension) in particular. Pre-eclampsia can limit the baby’s growth and make the mother very ill, including the risk of having fits (convulsions). Higher weight gain puts women at risk of developing “gestational diabetes” – or it can be a sign that they have developed it. This is a condition in pregnancy where a woman who did not have diabetes before starts to have high levels of a type of sugar (glucose) in her blood. This can cause excessive weight gain in her baby.

How can I gain extra weight if I am underweight in pregnancy?
There is no hard and fast rule, and no specific diet that is proven to be particularly helpful. Researchers have looked at whether diet supplements (such as protein supplements) can help increase weight in under-nourished women. But they have not identified any specific supplement that works well. You can speak with your doctor, midwife, dietitian or nutritionist about how to help increase your weight if you need to.

How can I stop gaining too much weight in pregnancy?
Your baby and you both need a balanced diet during pregnancy. If you limit your energy intake too much, both of you could suffer. On the other hand, too much weight gain could also be unhealthy for you both.

One of the possible problems here, especially if you are already overweight, is that you start eating very differently because you are pregnant. You could really enjoy being pregnant and feel like, for these few months, “anything goes”. Or if you are stressed and perhaps struggling a little with all the major changes happening in your body and your life, you could find yourself eating more or differently to make you feel better (often called “emotional eating”). For many women, “emotional eating” can quickly become a way of giving themselves a treat or helping cope with tiredness. A little of that is always fine, but it can quickly develop into a habit that causes problems.

Some of the things that have been tried in research in pregnant women are individual dietary counseling (often with a dietitian or nutritionist), cooking demonstrations and exercise classes. Although these might help individual women, researchers have still not been able to pinpoint anything in particular that has a very high success rate. You can speak with your doctor, midwife, dietitian or nutritionist if you think you might need help, or to find out what options are available in your area.

Is weighing myself regularly a good idea?
This is still not clear. Doctors and midwives will generally weigh you once a month during pregnancy, and they might do this more often if you have signs of problems. Later in the pregnancy, you might have more frequent visits, and you are likely to be weighed then as well.

Weighing yourself could have advantages and disadvantages: researchers are still not sure whether it is helpful. Some research in non-pregnant people has suggested that self-weighing about once a week might help people keep their weight under better control, but this is not certain. Weighing yourself too often could also make you feel worse: we really do not know. At this point, the best that can be said is that weighing yourself up to once a week might not do harm, but there is no reason to stress yourself with frequent weighing.

Does keeping weight gain under control prevent stretch marks and backache?
There is no clear answer to this yet. The AHRQ researchers tried to find out how weight gain affects stretch marks, backache and other common problems for the woman during pregnancy – including whether weight gain affects energy levels. There is, however, surprisingly little research about problems like stretch marks and backache in pregnancy. You will no doubt hear or read many claims about what causes these problems and what might help. These claims are not supported by strong research though.

Whether or not you get stretch marks or backache does not only depend on the weight you gain. Very sudden and major changes in weight can cause more stretch marks, but whether keeping weight down will prevent stretch marks is just not known.

When can I expect to lose the weight after the birth, and is there anything I should do to help get my weight back to normal?
Getting back to roughly where you were before pregnancy is not necessarily going to happen very quickly. For some women, feeding and taking care of a baby are enough to melt away the weight gained during pregnancy: indeed, they really need this stored up energy to help get through those early weeks and months of motherhood.

Most women will not really get close to their pre-pregnancy weight until perhaps six months after the birth. Women who do not lose most of the weight they gained in pregnancy by six months or a year after the baby is born might be more likely to continue to have weight problems in the long term. The problem might get worse in the next pregnancy, too.

The main options for trying to lose weight are a balanced diet or extra exercise. Programmes to help people change their eating and lifestyle habits are often used to try to achieve this. This does not mean starting immediately after the birth. In the research studies, these kind of weight control efforts started a month or two after the birth, or even later. After childbirth, weight loss is complicated by the extra nutritional needs of the mother if the baby is breastfed.

How a Sperm Wags Its Tail
The electric activity that spurs sperm to make a final dash to, then into, a female egg has been measured for the first time

To produce this all-important fertility sprint, sperm tails must switch from an easy, symmetrical beating to a frenetic whiplike lashing. This switching slows down sperm cells but gives them the extra force they need to penetrate an egg's protective coating.

Researchers at Harvard Medical School and Children's Hospital in Boston actually measured the tiny, tiny current in sperm tails that triggers this hyperactivity. The experiments were done with mice, but David Clapham, the Harvard professor of cardiology and neurobiology who supervised the research, says, "I expect that what's true in mice is true in humans. Their genes are very similar to ours."

The key to this seminal stamina is a protein known as CatSper, which both men and mice possess. The protein forms a channel in the middle of the sperm's relatively long tail, allowing electrically charged calcium molecules called cations to flow from body fluids into the sperm. (The name CatSper is short for cation channel in sperm.) These cations cause other fiberlike proteins to contract rapidly and incite the energetic tail whipping.

Although they display normal mating behavior, male mice without CatSper are totally ineffective at impregnating females.

You might guess that knocking out CatSper with a drug would make a great contraceptive. "Yes, it would," agrees Clapham. "It would block the channel that makes males fertile. What's more, it would only be temporary. And, since CatSper is confined to mature sperm, a drug targeted specifically for it would have no side effects."

What you probably wouldn't guess is that such a pill could also work for women. "Sperm swim in the female reproductive tract for at least 15 minutes before they reach an egg." Clapham notes. "Ideally it should be taken just before sex, but it might be made to work after sex."

Such a contraceptive might satisfy the concerns of anti- abortionists, because it would prevent sperm from ever uniting with an egg. Children's Hospital has negotiated a license with a Boston biotech company, Hydra Biosciences, to pursue this approach to pulling the tails of sperm.

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Combined Stem Cell-Gene Therapy Can Cure Human Disease
A study led by researchers at the Salk Institute for Biological Studies, has catapulted the field of regenerative medicine significantly forward, proving in principle that a human genetic disease can be cured using a combination of gene therapy and induced pluripotent stem (iPS) cell technology

The study, published in the May 31, 2009 early online edition of Nature, is a major milestone on the path from the laboratory to the clinic.

"It's been ten years since human stem cells were first cultured in a Petri dish," says the study's leader Juan-Carlos Izpisúa Belmonte, Ph.D., a professor in the Gene Expression Laboratory and director of the Center of Regenerative Medicine in Barcelona (CMRB), Spain. "The hope in the field has always been that we'll be able to correct a disease genetically and then make iPS cells that differentiate into the type of tissue where the disease is manifested and bring it to clinic."

Belmonte's team, working with Salk colleague Inder Verma, Ph.D., a professor in the Laboratory of Genetics, and colleagues at the CMRB, and the CIEMAT in Madrid, Spain, decided to focus on Fanconi anemia (FA), a genetic disorder responsible for a series of hematological abnormalities that impair the body's ability to fight infection, deliver oxygen, and clot blood. Caused by mutations in one of 13 Fanconi anemia (FA) genes, the disease often leads to bone marrow failure, leukemia, and other cancers. Even after receiving bone marrow transplants to correct the hematological problems, patients remain at high risk of developing cancer and other serious health conditions.

After taking hair or skin cells from patients with Fanconi anemia, the investigators corrected the defective gene in the patients' cells using gene therapy techniques pioneered in Verma's laboratory. They then successfully reprogrammed the repaired cells into induced pluripotent stem (iPS) cells using a combination of transcription factors, OCT4, SOX2, KLF4 and cMYC. The resulting FA-iPS cells were indistinguishable from human embryonic stem cells and iPS cells generated from healthy donors.

Since bone marrow failure as a result of the progressive decline in the numbers of functional hematopoietic stem cells is the most prominent feature of Fanconi anemia, the researchers then tested whether patient-specific iPS cells could be used as a source for transplantable hematopoietic stem cells. They found that FA-iPS cells readily differentiated into hematopoietic progenitor cells primed to differentiate into healthy blood cells.

"We haven't cured a human being, but we have cured a cell," Belmonte explains. "In theory we could transplant it into a human and cure the disease."

Although hurdles still loom before that theory can become practice-in particular, preventing the reprogrammed cells from inducing tumors-in coming months Belmonte and Verma will be exploring ways to overcome that and other obstacles. In April 2009, they received a $6.6 million from the California Institute Regenerative Medicine (CIRM) to pursue research aimed at translating basic science into clinical cures.

"If we can demonstrate that a combined iPS-gene therapy approach works in humans, then there is no limit to what we can do," says Verma.

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Growth in German Children Increases Over Past 30 Years
German children are taller than 30 years ago, but the increase in height observed during the last century has become slower

7- to 10-year olds are 1 to 1.5 cm taller than in the 1970s, whereas length at birth only slightly increased between 1984 and 1997, by 0.2 cm. This implies that the rate of growth during childhood has increased. This trend is less marked after puberty. There has also been little change in physical maturation. Thus, the age at menarche in young women has remained constant at about 13 years since the early 1960s.

The correlation between growth and socioeconomic status has been well established. For this reason, body growth is accepted as an important indicator of the socioeconomic conditions of a society. However, the biological mechanism through which this acts is still unknown.

The study appears in the current edition of Deutsches Ärzteblatt International (Dtsch Arztebl Int 2009; 106(23): 377-82), Bettina Gohlke and Joachim Woelfle of the Department of Pediatrics at the University of Bonn summarize the current state of knowledge of changes in height and of the physical development of young people.

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