Monday, May 4, 2009

Medical Technology: 'SmartShunt' To Regulate Pressure In The Brain

Medical Technology: 'SmartShunt' To Regulate Pressure In The Brain

ScienceDaily (Apr. 19, 2009) — ETH Zurich researchers have simulated the motion of the cerebrospinal fluid in the human brain. They are using the results to develop a self-regulating system to treat hydrocephalus.

Cerebrospinal fluid is a colorless liquid surrounding the brain and the spinal cord and filling the cavities in the brain. It protects the brain from impact and vibrations, carries nutrients to it and harmful substances away from it, and acts as one of the brain’s communication routes. If too much of this fluid is produced or too little flows away, excessive pressure builds up in the head and hydrocephalus occurs.

The liquid flows into the abdomen

As a rule nowadays, hydrocephalus is treated by using a “shunt”: this involves implanting into the patient a thin tube that carries excess cerebrospinal fluid from the head into the abdomen via a pressure relief valve. However, this process often drains away too much or too little fluid. Most valves can no longer be adjusted after implantation. Although some valves have this option, the patient must visit the doctor for adjustments to be made.

ETH Zurich researchers led by Dimos Poulikakos, Professor of Thermodynamics, and Vartan Kurtcuoglu, Director of the Biofluidics group in the Laboratory for Thermodynamics in Emerging Technologies, want to go one step further. They are working on a “SmartShunt”, a self-regulating pressure relief device. To achieve their aim they must understand exactly how the cerebrospinal fluid flows within the skull. For this, they simulated the motion of the fluid in three dimensions on a computer. Initial results were published in the February issue of the Journal of Biomechanical Engineering. Its title page shows a graphic image of the results, the research group having already made the title page in the January issue with a publication on aortic aneurysms (see the Literature references).

A brain scan is the first step

The cerebrospinal fluid fills the space between the skull and the brain, called the sub-arachnoid space, in which it pulses in a cycle controlled indirectly by the heart. With each heartbeat, the heart pumps blood through the brain, causing the blood vessels to expand and the space available for the cerebrospinal fluid to decrease correspondingly. The blood flows away again before the next heartbeat, and the space for the cerebrospinal fluid increases.

The publication came into being in collaboration with Peter Bösiger, Professor at the Institute of Biomedical Technology of ETH Zurich. His group scanned the sub-arachnoid space of a healthy 25-year-old man by magnetic resonance imaging (MRI). They also used a special MRI technique to measure the velocity of the fluid in three planes to provide the boundary conditions for the calculations.

The scientists built a computer model based on the results of the measurements. They used a series of partial differential equations to describe the motion of the cerebrospinal fluid. At the same time, they had to take into account the fact that the sub-arachnoid space is criss-crossed by a sort of fine, networklike bar of tissues that retard the movement of the fluid. Instead of computing with the single bar, they represented the sub-arachnoid space in their model as a uniform porous medium similar to a sponge.

Valve for self-regulation

Based on the results, the researchers in the multi-disciplinary “SmartShunt” Project are now developing the basis for a shunt to control the outflow of cerebrospinal fluid automatically in accordance with the patient’s specific needs. The goal is a valve that controls the pressure in the patient’s head in real time, saving him or her regular visits to the doctor.

Dimos Poulikakos says, “We attach importance to the fact that definitereal medical problems are addressed in the continuation of basic research.” The researchers work in close collaboration with the medical staff of the University Hospital Zurich and with other ETH Zurich institutes. The Swiss National Science Foundation is funding the interdisciplinary project to the tune of approximately CHF 850,000. Poulikakos plans to start developing the actual product together with the industry in about three year’s time.

Knowledge of the cerebrospinal fluid motion will also be useful for other medical applications. The liquid plays a part in Alzheimer’s disease, in multiple sclerosis and in meningitis. In addition, drugs that cannot cross the blood-brain barrier can be injected into the cerebrospinal fluid, from where they reach the brain. In other cases, for example regarding painkillers, injection into the cerebrospinal fluid can allow the dose to be decreased to reduce side-effects.

Smurf Genes Help Cells Find the Path Ahead

Smurf Genes Help Cells Find the Path Ahead
April 16, 2009
Howard Hughes Medical Institute

Two critical genes that serve as beacons and give cells a much needed sense of direction in the chaotic days of early development have been identified by researchers at the University of Toronto.

The new findings, from the laboratory of Jeffrey L. Wrana, a Howard Hughes Medical Institute international research scholar, were published April 17, 2009, in the journal Cell, and help explain how a cell determines its sense of space. A better understanding of this phenomenon, called planar cell polarity, may also help scientists learn how improper cellular orientation can lead to spina bifida, polycystic kidney disease, and metastatic cancer. Each of these illnesses involves cells that don’t have a proper sense of direction, so they cannot tell which way they are going.

In a developing embryo, cells need to be in the right position at the right time. To get to their proper destination, cells must understand the difference between top and bottom, forward and backward. If this orientation is off just a little, development can be disrupted or derailed. In spina bifida, for example, cells can fail to recognize front from back, leading to improper formation of the spine.

In the past decade, Wrana has helped identify the importance of two Smurf genes (Smurf stands for Smad ubiquitination regulatory factor) in helping cells move and distinguish top from bottom. Cells rely on cues from their neighbors to sense this kind of orientation, and Wrana has been trying to understand how the Smurf genes facilitate the process. Until now, he didn’t know Smurf proteins had anything to with orienting cells in the backward/forward direction, as well.

“Our results were unexpected, but also exciting because they suggest the Smurf genes are coordinating different types of cell polarity,” says Wrana, who also works at Mount Sinai Hospital in Toronto.

As part of his study, Wrana and his team genetically engineered mouse embryos so they did not have functional copies of both Smurf genes, but the embryos failed to develop properly and died before birth. When Wrana examined the embryos, he observed that they had an atypical shape—they were short and wide instead of long and thin. In addition, he saw that the neural tube—the precursor to the spinal cord—had failed to close into its proper tubular shape. This type of developmental anomaly is similar to what happens in human babies who are born with spina bifida. The findings surprised Wrana because he did not expect that the changes in top/bottom polarity would be vital in this aspect of embryo development.

Instead, these characteristics suggested that the Smurf genes were related to an important network of genes called the Wnt signaling pathway. When this pathway goes awry in early development—which can happen for a variety of reasons—a number of defects can arise, including those Wrana saw in his Smurf-deficient mice. Researchers had known that Wnt signaling helps establish planar cell polarity, so Wrana investigated whether Smurfs were involved, too.

His first stop was the inner ear of the embryonic mouse. The inner ear contains hair cells, which vibrate in response to sound. To do their job, hair cells must line up neatly in a hexagonal pattern, like paving stones on a cobblestone street—a pattern made possible by planar cell polarity. But in the Smurf-deficient mice, the hair cells looked like they were laid by a drunken mason. “In the normal embryos, the hair cells were all pointing the same way in a beautiful array,” Wrana says. “But in the mutants they were disorganized and rotated and pointing the wrong way.”

This disruption suggested the Smurf genes were critical for planar cell polarity. To strengthen his case, Wrana used advanced proteomics techniques to map the interactions of proteins in a cell. Those analyses showed that the proteins made by the Smurf genes interacted with two proteins, called Prickle and Disheveled, that are also linked to planar cell polarity.

In healthy cells that know front from back, Prickle accumulates on one side of the cell, and Disheveled on the other side. This lopsidedness appears critical for planar cell polarity. Wrana found that the Smurf genes actually create this lopsidedness by destroying Prickle on one side of the cell. We believe that through this destruction of Prickle, cells establish an asymmetrical distribution of proteins, and that’s how the cells become polarized properly,” Wrana says.

Wrana is now investigating what role Smurf genes play in other tissues, such as the trachea and kidneys, where planar cell polarity is known to be important. He also wants to study their role in diseases. For example, “there are lots of hints that planar cell polarity is important in cancer,” he says. Other researchers have found that cancer cells often have an excess of the proteins made by the Smurf genes. “We think the elevated expression of Smurfs interferes with the polarity of the cells,” he says. “Within the tumor, the cells become disorganized and display aberrant behaviors, which may help them escape and metastasize.”

Do Pesticides Make Birth Defects Crop Up?

Do Pesticides Make Birth Defects Crop Up?
High Pesticide Levels in Spring and Summer May Be Linked to an Increase in Birth Defects, Study Says
By Salynn Boyles
WebMD Health News
Reviewed by Louise Chang, MD

March 27, 2009 -- New research shows that babies conceived in the spring and early summer have a higher risk for a wide range of birth defects, including Down syndrome, cleft palate, and spina bifida.

The reported increase in birth defects was modest, but it coincided with a similar spike in groundwater pesticide levels during the spring-early summer planting season.

These findings suggest that pesticide exposure may influence birth outcomes nationwide, researchers say.

“There appears to be a season of conception in which the risk of having a child with a birth defect is higher,” Indiana University School of Medicine neonatology professor Paul D. Winchester, MD, tells WebMD.

“This study does not prove that pesticides cause birth defects, but we set out to show that they did not and we were not reassured.”
Pesticide Levels Measured in Water

In earlier studies, researchers have reported increases in birth defects, pregnancy complications, and miscarriages in babies born to farm workers with high levels of exposure to agricultural pesticides.

But the study is one of the first to suggest that indirect exposure to agricultural chemical may influence birth outcomes.

Winchester and colleagues compared data on pesticide levels in surface water between 1996 and 2002 to data on birth defects at the national level during the same period.

The researchers used the U.S. Geological Survey’s National Water Quality Assessment (NAWQA), which includes samples from 186 streams across the United States, representing 50% of the drinking water consumed in the country.

Statistics on birth defects were reported to the CDC by individual states.

The NAWQA analysis confirmed that concentrations of widely used pesticides in ground water were highest in the months of April through July during the period examined.

During this same period, women who conceived in these months were about 3% more likely to deliver a baby with a birth defect than women who conceived in other months, Winchester says.

“That doesn’t sound like much, but at a population level it could mean thousands of additional birth defects,” he says.
Prospective Study Under Way

Winchester adds that inconsistent recording of birth defects from state to state during the time the data were collected probably resulted in an underestimation of birth defects.

During this time, 13 states and the District of Columbia had only passive birth defects surveillance programs.

March of Dimes medical Director Alan R. Fleischman, MD, tells WebMD that even with the limitations, the study raises important questions about the impact of environmental chemical exposures on birth outcomes.

“There is a limit to what you can imply from this type of study,” he says. “But it does focus attention on an important issue.”

Fleischman chairs the advisory committee for the National Children’s Study, the largest prospective study ever in the U.S. to examine the effect of environmental influences on children’s health.

Researchers are now recruiting women for the trial. The goal is to follow 100,000 children nationwide from conception to age 21.

“We will certainly be measuring exposure to environmental chemicals before conception and during pregnancy,” he says. “This is not easy to do, but it is important to better understand the relationship between chemical exposures and birth outcomes.”
pregnancy week-by-week newslet

Panel: Avoid Epilepsy Drug in Pregnancy

Panel: Avoid Epilepsy Drug in Pregnancy
New Guidelines Urge Pregnant Women to Avoid Taking Valproate Because of Risk of Birth Defects
By Charlene Laino
WebMD Health News
Reviewed by Louise Chang, MD

April 27, 2009 (Seattle) -- Women with epilepsy should avoid taking the drug valproate (Depakote) during pregnancy if possible, according to new guidelines developed by the American Academy of Neurology (AAN) and the American Epilepsy Society.

"There is good evidence that valproate, whether used by itself or in combination with other medications, increases the risk of major birth defects, including cleft palate and spinal bifida," says guideline co-author Gary S. Gronseth, MD, vice chairman of neurology at the University of Kansas Medical Center in Kansas City.

Additionally, taking valproate during pregnancy has been linked to lower IQs in children, he tells WebMD.

The guidelines come on the heels of a study showing that women with epilepsy who took valproate during pregnancy gave birth to children whose IQ at age 3 averaged up to 9 points lower than the scores of children exposed to other epilepsy drugs.

In response to the guidelines, a spokesperson for Abbott, which makes valproate, said the drug may be the only effective medication for some women, but doctors and patients should discuss risks and benefits of treatment.

Pregnant women may also want to avoid taking the seizure drugs phenytoin (Dilantin) and phenobarbital, as they too have been linked to lower IQs in children, Gronseth says.
Epilepsy and Pregnancy

Gronseth and other panel members stress that pregnancy is safe for most women with epilepsy.

"Overall, what we found was very reassuring to woman with epilepsy planning to become pregnant," says lead guideline author Cynthia Harden, MD, director of the epilepsy division at the University of Miami's Miller School of Medicine.

"Contrary to previous dogma, women with epilepsy are not at a substantially increased risk of having a cesarean section, late pregnancy bleeding, or premature contractions or premature labor and delivery," she says.

Also, if a woman is seizure-free for nine months to one year before she becomes pregnant, it's likely that she will not have any seizures during the pregnancy -- even if she switches medications, Harden tells WebMD.

About 500,000 women of childbearing age in the U.S. have some form of epilepsy, which is characterized by brief disturbances of electrical activity in the brain, according to Harden. Three to five out of every 1,000 births are to women with epilepsy.

The guidelines were prompted by a thorough review of more than 50 articles published over the last 10 years. They were presented here at the AAN's annual meeting and simultaneously published online in the journal Neurology.

Other recommendations include:

* If possible, women with epilepsy should avoid taking more than one epilepsy drug at a time during pregnancy, as doing so raises the risk of birth defects compared with taking only one medication.
* Pregnant women with epilepsy should have their blood tested regularly. "Pregnancy has been shown to lower the levels of anti-epileptic drugs in the blood, which may put women at risk of seizures. Checking these levels and adjusting the medication doses should help to keep the pregnant woman seizure-free," Harden says.
* Women planning to become pregnant should take at least 400 micrograms of folic acid a day, as supplementation has been shown to be "possibly effective" in preventing major birth defects. That's the same amount of folic acid already recommended by the CDC to prevent neural tube defects, especially spina bifida.
* Smoking during pregnancy may increase substantially the risk of premature contractions and premature labor and delivery during pregnancy.
Epilepsy Drugs and Breastfeeding

The epilepsy drugs primidone (Mysoline) and levetiracetam (Keppra) were detected in breast milk at various levels "that may be clinically important," while valproate, phenobarbital, phenytoin, and carbamazepine ( Tegretol) were not, the panel says.

"We didn't find much evidence one way or another that any of the drugs caused adverse effects in babies who were breastfed, but this information can help women and their doctors to make decisions about breastfeeding," Harden says.

Women should not stop taking any drug without consulting their physician, Harden stresses.

She suggests that women with epilepsy have a discussion with their doctor about seizure medications at least six months before becoming pregnant.

Valproate is an "excellent drug," and for some women, it may be the only medication that effectively controls their seizures, Gronseth says. "Women and their doctors have to weigh the potential risk of birth defects against the potential risk of uncontrolled seizures."
Valproate Also Used to Treat Migraines

"Luckily, it's not that hard to avoid valproate during pregnancy," as there are now more than a dozen seizure drugs available, says AAN spokesman Joseph Sirven, MD, professor of neurology at the Mayo Clinic in Phoenix.

Sirven points out that many more people, including pregnant women, take valproate to relieve migraine headaches.

"Lower doses are used than for epilepsy, so the drug may not pose the same problems [as when used to treat seizures]," he tells WebMD.

Nonetheless, women who have been prescribed valproate for any reason "should have a frank discussion with their doctors if they are planning to become pregnant," Sirven says.

Folic acid may raise cancer risk in offspring

Folic acid may raise cancer risk in offspring
From Monday's Globe and Mail
April 20, 2009 at 9:09 AM EDT

Canadian researchers have discovered that folic acid consumed during pregnancy can alter the gene function of offspring, potentially affecting their susceptibility to disease.

The finding is part of a growing - and controversial - body of research that raises serious questions about whether long-term consumption of folate and folic acid may increase the risk of developing certain cancers in some people.

The debate is far from benign. Food manufacturers are required to add folic acid to enriched flour and grain products under federal regulations that came into force in 1998. The premise behind fortification, which was also mandated in the United States, is to ensure that women receive adequate levels of folate in order to reduce the risk of birth defects in their offspring.

A decade later, however, new research and scientific studies have found evidence that increased consumption of folic acid may help trigger the onset of colon and other types of cancer.

Folic acid is the synthetic form of folate, which is a B vitamin that occurs naturally in leafy greens and other fruits and vegetables. It has been shown to significantly reduce the chance of neural tube defects, such as spina bifida, and helps produce and maintain healthy cells and is involved in numerous biological functions.

The new Canadian research, presented yesterday at the annual meeting of the American Association for Cancer Research in Denver, found that folic acid consumption by the mother has effects on her offspring.

The research is part of a burgeoning field of science known as epigenetics, which studies how gene activities are changed or influenced by diet, lifestyle and other environmental factors. Certain genes can become activated or rendered dormant depending on these factors.

In some cases, genes that protect the body against certain types of cancer can be shut off, while genes that promote tumour formation can be turned on. Changes to genes can also trigger mutations, which explains why epigenetics has been gaining so much attention in the scientific community for its potential ability to help explain the mystery of disease risk.

In the new study, led by Karen Sie, a research scientist in the University of Toronto's faculty of medicine, researchers gave two groups of laboratory rats folic acid supplementation. One group received the equivalent of the daily recommended intake for humans, 0.4 milligrams, and the other group received a higher dose, equal to 1 milligram in humans, which is the maximum recommended daily intake for women during pregnancy.

They found that offspring of rats that received the higher dose experienced a much higher degree of changes to genes in the colon and liver shortly after birth. But as the rats aged, there was a significant drop in the changes to genes.

The researchers don't yet know which specific gene functions were changed. It could be that the high degree of changes noted shortly after birth could silence genes designed to suppress tumours. But the changes could also activate genes that help protect against cancer.

Regardless, the discovery that folic acid can turn genes on or off could help in the quest to determine whether the supplement does contribute to increased risk of cancer in some people.

"The concern is with the high dose that people are getting nowadays," Ms. Sie said.

Despite the new findings, there are still strong defenders of folic acid fortification.

"We know ... folic acid is needed to prevent neural tube defects," said Gideon Koren, director of the Motherisk program at Toronto's Hospital for Sick Children. "As we talk now, 40 per cent of women in Canada do not have enough folic acid to protect the baby from spina bifida and other malformations."

Dr. Koren said Canada's fortification program is one of the key elements needed to reduce the incidence of neural tube defects, and that considering changes because of results from studies that primarily involve rats could be dangerous.

However, others say it's becoming harder to ignore the growing debate about folic acid. Despite its clear benefits when taken by pregnant women, the move to fortify food with folic acid means a major portion of the population is consuming a higher level of the supplement than they would otherwise.

Now, concern is growing that parts of the population that may be susceptible to colon cancer and other diseases could be put at greater risk due to their inadvertent exposure to folic acid.

"It's a real dilemma," said Joel Mason, associate professor of medicine and nutrition and director of the Vitamins and Carcinogenesis laboratory at Tufts University in Boston, who specializes in folic acid and folate.

And there are no simple solutions. Putting an end to fortification could put more women at risk of having babies with neural tube defects. But keeping folic acid supplements in the food supply could put certain people at a higher risk of disease.

A significant amount of research is currently being conducted to answer these questions, including studies looking at whether North American folic acid fortification led to changes in the population rates of certain types of cancer.

Dr. Mason said that despite any fears over safety, the research is too preliminary to warrant changes to fortification programs. But government regulators should be paying close attention as new research emerges, he said.

Canadian study finds immigrant women may be at greater risk of having a baby with a birth defect

Canadian study finds immigrant women may be at greater risk of having a baby with a birth defect

Published: Sunday, 19-Apr-2009

Immigrant women are less likely to use folic acid supplements before pregnancy to prevent spina bifida, particularly those who recently immigrated to the country, according to a new study led by a St. Michael's Hospital physician in collaboration with Statistics Canada, Health Canada and the University of Toronto.

The study is the first to provide national estimates of pre-pregnancy folic acid use in Canada.

"Our study's findings report that while about six in 10 Canadian-born mothers take folic-acid supplements in the three-month period before conception, mothers from non-western countries - China, Northern African, Middle Eastern, Caribbean, Latin American or South Pacific countries - are less likely to use the supplements," St. Michael's Hospital's Dr. Joel Ray said. "This information is important for policy makers and health practitioners as we aim to better educate new mothers and prevent neural tube defects in their babies."

Neural tube defects are birth defects of the spinal cord and brain, otherwise known as spina bifida and anencephaly. Research has shown the risk of neural tube defects can be reduced by nearly 50 per cent with folic acid supplements taken just before and soon after conception, or through consumption of food fortified with folic acid. However, an estimated six to 12 in every 10,000 fetuses in Canada still develop neural tube defects.

The study, an analysis of 6,349 new mothers aged 18 to 45 years, examined the relationship between folic acid supplement use in the three months before conception and the mother's maternal country of birth and years of residence in Canada.

Sixty one per cent of Canadian-born women in the study reported using folic acid supplements in the three month period before conception. However, these rates were much lower among women born in the Caribbean or Latin America (41%), Sub-Sahara Africa (44%), Northern Africa or the Middle East (31%), or South Asia (46%). What's more, only 39% of foreign-born women living in Canada less than four years reported using supplements compared to 64% of foreign-born women living in Canada at least 17 years.

"The disparity in pre-conceptual folic acid supplement use may be due to unplanned/unintended pregnancies or lack of awareness of the benefits of folic acid supplements," Ray said. "Immigrant women, especially those from non-Western countries, are least likely to have this information, which can otherwise be easily provided to these women through various communication mediums."

The study's authors suggest immigrant women be provided with a language-specific pamphlet on the benefits of folic acid, or even with free supplements.