Tuesday, August 13, 2013

Bone Marrow Cells Used in Bladder Regeneration


A new approach to bladder regeneration is capitalizing on the potential of two distinct cell populations harvested from a patient's healthy bone marrow, a new study reports.

The Northwestern Medicine® research, which will be published February 18 in the Proceedings of the National Academy of Sciences by lead author Arun K. Sharma, research assistant professor in urology at Northwestern University Feinberg School of Medicine and colleagues, is an alternative to contemporary tissue-engineering strategies. The bone marrow cells are being used to recreate the organ's smooth muscle, vasculature, and nerve tissue.

"We are manipulating a person's own disease-free cells for bladder tissue reformation," said Sharma, a member of the Institute for BioNanotechnology in Medicine and the Ann & Robert H. Lurie Children's Hospital of Chicago Research Center. "We have used the spina bifida patient population as a proof of concept model because those patients typically have bladder dysfunction. However, this regeneration approach could be used for people suffering from a variety of bladder issues where the bone marrow microenvironment is deemed normal."

In end-stage neurogenic bladder disease -- an illness often associated with spinal cord diseases like spina bifida -- the nerves which carry messages between the bladder and the brain do not work properly, causing an inability to pass urine. The most common surgical option, augmentation cystoplasty, involves placing a "patch" derived from an individual's bowel over a part of the diseased organ in order to increase its size. The current "gold standard," the procedure remains problematic because the bowel tissue introduces long-term complications like the development of electrolyte imbalance and bladder cancer.

Because Sharma's procedure does not use bowel tissue, it offers the benefits of augmentation without the association of long-term risks. His technique combines stem and progenitor cells from a patient's bone marrow with a synthetic scaffold created in the lab of Guillermo Ameer, ScD, professor of biomedical engineering at McCormick School of Engineering and Applied Science and of surgery at Feinberg. The scaffold takes the place of the traditional patch.

"We decided to use material that has the ability to be tailored to simulate mechanical properties of the bladder," said Sharma, director of pediatric urological regenerative medicine at Lurie Children's. "Using the elastomer created by Dr. Ameer and the bone marrow stem and progenitor cells, I believe that we have developed a technique that can potentially be used in lieu of current bladder augmentation procedures. However, further study is needed."

Follow-up to landmark spina bifida study could influence future treatment


HOUSTON — Almost 10 years ago, the Management of Myelomeningocele (MOMS) study began comparing two approaches to treatment for a serious form of spina bifida: prenatal surgery versus the standard postnatal repair.

This breakthrough study, funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and published by the New England Journal of Medicine in 2011, found that children whose spina bifida defects were repaired surgically before birth were more likely to walk without the assistance of orthotics or devices.  NICHD is one of the Institutes of the National Institutes of Health.

Now, a follow-up study, also funded by NICHD and informally known as MOMS2, is being conducted to determine whether prenatal repair done in the original study influenced the adaptive behavior of these children, now 5 to 9 years of age, compared with those who underwent postnatal repair.

One of the effects in question is the brain development of these children. Jenifer Juranek, Ph.D., a neuroimaging expert with the Texas Fetal Center and the Children’s Learning Institute at The University of Texas Health Science Center at Houston (UTHealth), is performing high-resolution magnetic resonance imaging (MRI) brain sequences on 177 of the children from the original study to investigate if those who underwent prenatal surgery experienced greater structural modification in their brains than those infants who underwent postnatal surgery.

The follow-up brain imaging protocol was set up by Juranek at each of the three original MOMS study sites: Vanderbilt University in Nashville, Tenn., The Children's Hospital of Philadelphia, and the University of California at San Francisco. Each follow-up image will be analyzed and quantified by Juranek for such key development indicators as brain volume, matter integrity, synaptic pruning (i.e., when excess connections between cells are eliminated) and myelination, which enables nerve cells to transmit information faster and allows for more complex brain processes.

“Researchers have demonstrated that many neurodevelopmental disorders like spina bifida may be linked to poorly-timed cellular events during brain development. These events lead to specific structural and functional brain development,” said Juranek. “With this follow-up study, researchers can evaluate the impact different intervention strategies have on brain structure, function and behavior.”

The results of the MOMS2 study could influence future surgical procedures for babies diagnosed with myelomeningocele, says KuoJen Tsao, M.D., associate professor of pediatric surgery at UTHealth Medical School and a co-director of the Texas Fetal Center.

“The MOMS study gave us data that goes two or three years out from surgery, but we know there is a lot of development beyond that,” said Tsao. “We know there are certain short-term outcomes, but there may be some long-term neurological effects we don’t know about. What’s most exciting about the MOMS2 study is they are going to follow these patients at school age.”

One common risk associated with myelomeningocele is the buildup of fluid inside the skull that leads to brain swelling. This swelling is repaired with shunts inserted into the brain to relieve pressure. The original MOMS study found that prenatal surgery reduced the need for shunts, which may improve long-term brain development.

“Once you put in a shunt you have risks,” said Juranek. “Getting into the center of brain isn’t easy. If you put in a shunt, you are likely to cut through gray and white matter, both of which are responsible for certain brain functions.”

Tsao added, “The important thing about the MOMS2 study is it will answer questions that we are asking now. That’s where Dr. Juranek’s work is very important.”

Other follow-up testing will look at other development factors such as attention, executive function and fine and gross motor skills.

Air pollutants linked to higher risk of birth defects, researchers find

 David Miklos


BY ERIN DIGITALE - Breathing traffic pollution in early pregnancy is linked to a higher risk for certain serious birth defects, according to new research from the Stanford University School of Medicine.
The finding comes from a study examining air quality and birth-defect data for women living in California’s San Joaquin Valley, one of the smoggiest regions of the country. “We found an association between specific traffic-related air pollutants and neural tube defects, which are malformations of the brain and spine,” said the study’s lead author, Amy Padula, PhD, a postdoctoral scholar in pediatrics. The research appears online today in the American Journal of Epidemiology.

“Birth defects affect one in every 33 babies, and about two-thirds of these defects are due to unknown causes,” said the paper’s senior author, Gary Shaw, PhD, professor of neonatal and developmental medicine. “When these babies are born, they bring into a family’s life an amazing number of questions, many of which we can’t answer.”

The scientists studied 806 women who had a pregnancy affected by a birth defect between 1997 and 2006, and 849 women who had healthy babies during the same period. The study examined two types of neural tube defects (spina bifida, a spinal-column malformation, and anencephaly, an underdeveloped or absent brain); cleft lip, with or without cleft palate; cleft palate only; and gastroschisis, in which the infant is born with some of his or her intestines outside the body.

All women studied resided in an area of California known for poor air quality — the San Joaquin Valley — during the first eight weeks of their pregnancies, a window of time when many birth defects develop. The researchers asked each woman for her home address during this period and scored subjects’ exposure to air pollutants using data collected by the Environmental Protection Agency as part of federally mandated air-quality monitoring. The pollutants assessed included carbon monoxide, nitrogen oxide, nitrogen dioxide, particulate matter and ozone, as well as local traffic density.

After controlling for factors such as race/ethnicity, maternal education and multivitamin use, women who breathed the highest levels of carbon monoxide were nearly twice as likely to have a baby with spina bifida or anencephaly as those with the lowest carbon monoxide exposure, the study found. Nitrogen oxide and nitrogen dioxide exposures were also linked to increased risk for these defects; women with the highest nitrogen oxide exposure had nearly three times the risk of having a pregnancy affected by anencephaly than those with the lowest exposure, for example. Further studies are needed to examine the combined effects of multiple pollutants.

The quality of earlier research linking air pollution and birth defects has been hampered by the difficulty of getting reliable data on women’s exposure to pollutants. The new study is the first to assess women’s pollutant exposures in early pregnancy, when birth defects are developing, rather than at birth.

Further studies are needed to confirm the results of the new research and to examine other pollutants, as well as other types of birth defects, the researchers said.

“If these associations are confirmed, this work offers an avenue for a potential intervention for reducing birth defects,” Padula said.

“In addition, for our colleagues who are bench scientists, this work gives them an opportunity to think about what pollution exposures might mean mechanistically,” Shaw said. “It could give them a better understanding of the details of human development.”

Suzan Carmichael
, PhD, associate professor of neonatal and developmental medicine, was another Stanford co-author. Scientists at the University of California-Berkeley and at Sonoma Technology Inc. in Sonoma, Calif., were also involved in the work.

The study was funded by grants from the National Institute for Environmental Health Science (grant ES018173), the U.S. Environmental Protection Agency and the Centers for Disease Control and Prevention.

Information about Stanford’s Department of Pediatrics, which also supported the work, is available at http://pediatrics.stanford.edu.
Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For more information, please visit the Office of Communication & Public Affairs site at http://mednews.stanford.edu/.

Prescriptions for valproate not decreasing despite birth defect-causing concerns


A recent study shows that prescriptions for the antiepileptic drug valproate have not decreased in recent years even though the drug is known to cause severe birth defects and brain damage.
A new study indicates that women without epilepsy are four times as likely to be prescribed this drug as are women with epilepsy.

Led by Godfrey P. Oakley, Jr. MD, research professor at Emory's Rollins School of Public Health, a research team analyzed data from the National Hospital and Ambulatory Medical Care Surveys from 1996 to 2007 to examine valproate prescriptions for adolescent girls and adult women aged 14-45 years. Findings from the study concluded that 83 percent of valproate prescriptions were written for women without epilepsy, with 74 percent of those prescribed for psychiatric, non-epilepsy diagnoses and the remaining valproate prescriptions used for conditions such as pain, migraine and other non-epilepsy conditions.

"We were surprised to find that there was no decrease in the number of valproate prescriptions prescribed to women of reproductive-age  despite the numerous, less harmful antiepileptic drugs available and the proven evidence of valproate's harmful effects during pregnancy," says Oakley who is also the director of Emory's Center for Spina Bifida Research, Prevention, and Policy.
The complete study is published in the June 3, 2013 edition of the Birth Defects Research Part A—Clinical and Molecular Teratology journal.

"We believe that sharply reducing the use of valproate for reproductive-age women is an important step in preventing birth defects," explains Oakley.

Genes Involved in Birth Defects May Also Lead to Mental Illness


Gene mutations that lead to major birth defects may also cause subtle disruptions in the brain that contribute to psychiatric disorders such as schizophrenia, autism, and bipolar disorder, according to new research by UC San Francisco scientists.

By Jeffrey Norris

Over the past several years, researchers in the laboratory of psychiatrist Benjamin Cheyette, MD, PhD, have shown that mutations in a gene called Dact1 cause cell signaling networks to go awry during embryonic development. Researchers observed that mice with Dact1 mutations were born with a range of severe malformations, including some reminiscent of spina bifida in humans.
This new study was designed to explore whether Dact1 mutations exert more nuanced effects in the brain that may lead to mental illness. In doing so, Cheyette, John Rubenstein, MD, PhD, and colleagues in UCSF’s Nina Ireland Laboratory of Developmental Neurobiology used a genetic technique in adult mice to selectively delete the Dact1 protein only in interneurons, a group of brain cells that regulates activity in the cerebral cortex, including cognitive and sensory processes. Poor function of interneurons has been implicated in a range of psychiatric conditions.

Brain cells called interneurons, which regulate activity in the cerebral cortex, were
shown by UCSF researchers to form more complex branching patterns in normal
mice (left) in comparison to mice in which the gene encoding the protein Dact1
was knocked out (right).
As reported in the June 24 online issue of PLOS ONE, researchers found that the genetically altered interneurons appeared relatively normal and had managed to find their proper position in the brain’s circuitry during development. But the cells had significantly fewer synapses, the sites where communication with neighboring neurons takes place. In additional observations not included in the new paper, the team also noted that the cells’ dendrites – fine extensions that normally form bushy arbors studded with synapses – were poorly developed and sparsely branched.

“When you delete this gene function after initial, early development – just eliminating it in neurons after they’ve formed – they migrate to the right place and their numbers are correct, but their morphology is a little off,” Cheyette said. “And that’s very much in line with the kinds of pathology that people have been able to identify in psychiatric illness.

"Neurological illnesses tend to be focal, with lesions that you can identify or pathology you can see on an imaging study," Cheyette explained. "Psychiatric illnesses? Not so much. The differences are really subtle and hard to see.”

Key Gene's Role in Development of Human Nervous System

The Dact1 protein is part of a fundamental biological system known as the Wnt (pronounced “wint”) signaling pathway. Interactions among proteins in the Wnt pathway orchestrate many processes essential to life in animals as diverse as fruit flies, mice and humans, including the proper development of the immensely complex human nervous system from a single fertilized egg cell.

Benjamin Cheyette, MD, PhD
One way the Wnt pathway manages this task is by maintaining the “polarity” of cells during development, said Cheyette, “a process of sequestering, increasing the concentration of one set of proteins on one side of the cell and a different set of proteins on the other side of the cell.” Polarity is particularly important as precursor cells transform into nerve cells, Cheyette said, because neurons are “the most polarized cells in the body,” with specialized input and output zones that must wind up in the proper spots if the cells are to function normally.
Cheyette said his group is now conducting behavioral experiments with the mice analyzed in the new PLOS ONE paper and with genetically related mouse lines to test whether these mice have behavioral abnormalities in sociability, sensory perception, anxiety or motivation that resemble symptoms in major psychiatric disorders.

John Rubenstein, MD, PhD
He also hopes to collaborate with UCSF colleagues on follow-up experiments to determine whether the activity of neurons lacking Dact1 is impaired in addition to the structural flaws identified in the new study and prior published work from his lab.

Meanwhile, as-yet-unpublished findings from human genetics research conducted by Cheyette’s group suggest that individuals with autism are significantly more likely than healthy comparison subjects to carry mutations in a Wnt pathway gene called WNT1.

“Just because a gene plays an important role in the embryo doesn’t mean it isn’t also important in the brain later, and might be involved in psychiatric pathology,” said Cheyette. “When these genes are mutated, someone may look fine, develop fine and have no obvious medical problems at birth, but they may also develop autism in childhood or have a psychotic break in adulthood and develop schizophrenia.”

Rubenstein is the Nina Ireland Distinguished Professor in Child Psychiatry.
Additional study authors include postdoctoral scholars Xiaoyong Yang, PhD, Daniel Vogt, PhD, and Amelia Stanco, PhD, and graduate student and first author Annie Arguello. Yang and Stanco are supported by a postdoctoral training grant (T32) led by Judy Ford, PhD, to the UCSF Department of Psychiatry from the National Institute of Mental Health.

Arguello conducted this research while obtaining her PhD in the UCSF doctoral program in Biomedical Sciences (BMS), and was supported by the Initiative to Maximize Student Development Program of the National Institute of General Medicine, as well as by BMS, the UCSF Department of Psychiatry, and the Center for Neurobiology and Psychiatry led by Sam Barondes, MD, Jeanne and Sanford Robertson Endowed Chair in Neurobiology and Psychiatry.

New treatment may work with folic acid to prevent neural tube defects like spina bifida


Researchers at the UCL Institute of Child Health (ICH) are investigating a new treatment that could work alongside folic acid to boost its effectiveness and prevent a greater proportion of neural tube defects – such as spina bifida – in early pregnancy.

A new study published in the journal Brain shows that the new treatment, when tested in mice, reduced the incidence of neural tube defects (NTDs) by 85 per cent. This new approach was also successful in preventing some kinds of NTDs that are currently unresponsive to folic acid.
Researchers at the ICH, which is the research partner of Great Ormond Street Hospital for Children NHS Foundation Trust, believe the findings could make way for future trials in patients, to investigate whether the same level of prevention can be achieved for human NTDs.
NTDs such as spina bifida and anencephaly are still among the most common birth defects worldwide, affecting about 1 in 1,000 pregnancies with much higher rates in some countries.
Folic acid supplements taken in the very early stages of human pregnancy, when an embryo’s central nervous system is still developing, currently prevent a proportion of NTDs (20-80 per cent depending on geographic region). Folic acid works by helping the embryo’s neural tube to close normally, which is an essential step of development (failure of this process results in NTDs). However, a significant number of NTDs are unresponsive to folic acid supplements.
This nucleotide treatment could boost the effects of folic acid and offer expectant mothers an even more reliable safeguard against relatively common defects like spina bifida.
Professor Nicholas Green, Institute of Child Health
One reason why folic acid might not always be effective is that a ‘genetic blockage’ can occur in the way folic acid is handled, or metabolised, in cells. In such cases, even if folic acid is taken early in pregnancy it is blocked from having the desired effect on the embryo. The new treatment being tested at the ICH involves supplementing with ‘nucleotides’, which are needed to make DNA as cells divide in the growing embryo. Nucleotides can bypass the blockage in the way folic acid is handled, ensuring the growth of crucial cells in the embryo.

NTDs are likely to have many possible causes and the ICH team considers that the most effective way to reduce the risk of NTDs is to use a combination of different treatments. In previous studies they found that a particular vitamin, inositol, has a protective effect and this is being tested in a clinical trial.

Similar studies are now proposed for the ‘nucleotide’ treatment, and researchers envisage that a single tablet could eventually be developed for women planning a baby, which would contain folic acid and the new protective compounds.

Commenting on the new research, Nicholas Greene, Professor of Developmental Neurobiology at the ICH, said: “We are still in the early stages of this research, but we hope that these promising results in mice can eventually be replicated with human NTDs. If it is found to be effective, this nucleotide treatment could boost the effects of folic acid and offer expectant mothers an even more reliable safeguard against relatively common defects like spina bifida.”

Professor Greene added: “While we continue our research into this new treatment, it’s important to emphasise that folic acid supplements remain the most effective prevention against NTDs currently available for women who are planning a baby. While we are greatly encouraged by these new findings, I would strongly urge women to continue taking folic acid in its current form until we reach a point where additional supplements might become available.”

The new research has been funded by the Wellcome Trust, Medical Research Council and Newlife Foundation for Disabled Children, who also co-sponsored the establishment of the Newlife Birth Defects Research Centre at the UCL Institute of Child Health.