Collaboration creates largest bank of autism research data to date

A US data partnership between the National Database for Autism Research (NDAR) and the Autism Genetic Resource Exchange (AGRE) positions NDAR as possibly the largest repository to date of genetic, phenotypic, clinical, and medical imaging data related to research on autism spectrum disorders (ASD).

Thomas R. Insel, director of the National Institute of Mental Health, said: “The collaboration between AGRE and NDAR exemplifies the efforts of government and stakeholders to work together for a common cause. NDAR continues to be a leader in the effort to standardise and share ASD data with the research community, and serves as a model to all research communities.”

As a result of the partnership, approved NDAR users will have access to data from more than 35,000 autism research participants. NDAR’s mission is to facilitate data sharing and scientific collaboration on a broad scale, providing a shared common platform for autism researchers to accelerate scientific discovery. Built around the concept of federated repositories, NDAR integrates and standardises data, tools, and computational techniques across multiple public and private autism databases.

Through NDAR, researchers can access results from these different sources at the same time, using the rich data set to conduct independent analyses, supplement their own research data, or evaluate the data supporting published journal articles, among many other uses.

Databases previously federated with NDAR include Autism Speaks' Autism Tissue Program, the Kennedy Krieger Institute's Interactive Autism Network (IAN), and the NIH Pediatric MRI Data Repository. AGRE currently houses a clinical dataset with detailed medical, developmental, morphological, demographic, and behavioural information from people with ASD and their families.

International team makes cells crawl

Cell biologists at Johns Hopkins have identified key steps in how certain mole cules alter a cell’s skeletal shape and drive the cell’s movement. Results of their research, published in the December 13 issue of Science Signaling, have implications for understanding what triggers the metastatic spread of cancer cells and wound-healing.

“Essentially we are figuring out how cells crawl,” says Takanari Inoue, assistant professor of Cell Biology and member of the Center for Cell Dynamics in the Johns Hopkins University School of Medicine’s Institute for Basic Biomedical Sciences. “With work like ours, scientists can reveal what happens when cells move when they aren’t supposed to.”

Their new discovery highlights the role of the cell’s skeleton, or cytoskeleton, in situations where “shape shifting” can rapidly change a cell’s motion and function in response to differing environmental conditions.

When cell’s such as fibroblasts, which gather to heal wounds, move from one place to another, its cytoskeleton forms ripple-like waves, or ruffles, across its surface that move towards the front of the cell and down, helping pull the cell across a surface. Researchers have shown that these ruffles form when a small molecule, PIP2, appears on the inside surface of the membrane at the front edge of a cell. Until now, however, they have been unable to recreate cell ruffles simply by directing PIP2 to the cell’s front edge. Manipulations have instead led the cytoskeleton to form completely different structures on the inside of the cell, which researchers call ‘comets’ on the basis that they look like stars shooting across the sky, In their experiments, Inoue and his group tried to create ruffles by sending an enzyme in to the cell membrane to convert another small molecule into PIP2. Using cytoskeleton building blocks marked to glow, the team saw that this approach caused the cytoskeleton to form comets, not ruffles as predicted.

The team then tried to make ruffles by increasing PIP2 at the membrane, rather than changing the quantities of any other molecules. Using molecular tricks that hid existing PIP2 then revealed it, the researchers effectively increased the amount of available PIP2 at the membrane. This time they saw ruffles. Inoue said: “Now that we’ve figured out this part of how cells make ruffles, we hope to continue teasing apart the mechanism of cell movement to someday understand metastasis. It will be interesting to manipulate other molecules at the cell surface to see what other types of cytoskeletal conformations we can control.”

Prostate cancer breakthrough

After a 20-year quest to find a genetic driver for prostate cancer, researchers have identified a rare, inherited mutation linked to a 10 or 20 times higher risk of developing the disease.

A report on the discovery, published in the January 12, 2012 issue of the New England Journal of Medicine, was led by investigators at the Johns Hopkins University School of Medicine and the University of Michigan Health System.

While accounting for only a small fraction of all prostate cancer cases, the discovery may provide important clues about how this common cancer develops and help to identify a subset of men who might benefit from additional, or earlier, screening. This year, an estimated 240,000 men in the United States will be diagnosed with prostate cancer.

For this study, the researchers sequenced the DNA of more than 200 genes in a human chromosome region known as 17q21-22, which in a previous study, Cooney identified as a region of interest.

Starting with samples from 94 families, each of which had multiple cases among close relatives, four families were found to have the same mutation in the HOXB13 gene, which plays an important role in the development of the prostate during the foetal stage and its function later in life. The mutation was carried by all 18 men with prostate cancer in these four families.

They then looked for the same gene mutation among 5,100 men who had been treated for prostate cancer. The mutation was found in 1.4% of the men. It turned out that those men were much more likely to have at least one first-degree relative who had also been diagnosed. The researchers also looked for the mutation in a control group of 1,400 men without prostate cancer, and only one of those men carried the mutation. In addition, the researchers studied men who were specifically enrolled in studies of early-onset or familial prostate cancer.

One of the study’s senior authors, Kathleen Cooney, professor of internal medicine and urology at the U-M Medical School, said: “We found that the mutation was significantly more common in men with a family history and early diagnosis, compared with men diagnosed after age 55, without a family history. The difference was 3.1% versus 0.62%.”

The researchers say with further study, it may be possible to develop a genetic test for inherited prostate cancer. The next step, they say, is to develop a mouse model with the mutation to see if it causes prostate cancer.

Link between pre-natal HIV exposure and language delay in children

Children exposed to HIV before birth are at risk for language impairments, according to a study by researchers at the US National Institutes of Health and other institutions.

Moreover, children exposed to HIV before birth may benefit from routine screening for language impairment, even if they don't have any obvious signs of a language problem, the researchers said.

The researchers found that 35% of school-age children born to women with an HIV infection during pregnancy have difficulty understanding spoken words and expressing themselves verbally. On a standard series of tests of language ability, children exposed to HIV before birth scored, on average, within the lowest 21% of all children who have taken the test.

George K. Siberry of the Pediatric, Adolescent and Maternal AIDS Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), said: “Our results show that children exposed to HIV have more than twice the chance of having a language impairment than do children in the general population.”

The study could not determine if the high rates of language impairment in the HIV-exposed children can be attributed to HIV exposure or to other unidentified factors, such as their family status, maternal substance use, environment, or social or economic background.

The 468 children in the study were 7 to 16 years old. A total of 306 were HIVinfected, while the remaining 162 were exposed to HIV during pregnancy but did not become HIV-infected. In addition to evaluating the children’s language ability, the researchers analysed their medical records, tested their hearing and evaluated their general cognitive development. Results showed that 11% suffered from primary language impairment, implying no hearing or cognitive impairment was to blame.

Acute lung injury linked to long-lasting depression

Critically ill patients who recover from a potentially deadly syndrome known as acute lung injury frequently emerge with new long-lasting depressive symptoms as well as new physical impairments that make them unable to perform many daily tasks, Johns Hopkins research suggests.

Results of the new study, published in the American Journal of Respiratory and Critical Care Medicine, also suggest that the depressive symptoms frequently precede the new physical impairments, not the other way around. The research team also said the findings may be applicable to patients with other types of disease or injury who spend time in hospital intensive care units hooked up to ventilators that breathe for them.

“When people are discharged from the ICU, we tend, understandably, to focus on their physical health, but our data tells us we need to focus on their mental health, too,” says study leader O. Joseph Bienvenu, an associate professor of psychiatry and behavioural sciences at the Johns Hopkins University School of Medicine. “Depression can make recovery much more difficult. Identifying depressive symptoms early – and treating them – could make a real difference in how patients fare physically in the long term.”

Researchers assessed 186 survivors of acute lung injury at three, six, 12 and 24 months after they became ill, and surveyed their levels of depression as well as their ability to independently perform important tasks of daily life, such as using the telephone, shopping and preparing food. They found that 40% of patients developed depressive symptoms in the first two years after discharge and that 66% experienced new physical impairments. The average age of patients in the study was 49 years.

It is unclear, say the researchers, whether it is the acute lung injury syndrome, or the time spent in ICU, which is causing the new problems. Standard ICU care for patients with acute lung injury often includes deep sedation, which has been linked with depressive symptoms, and bed rest, which is known to cause physical impairment.

Patients’ lungs typically recover relatively quickly from acute lung injury, a syndrome often caused by pneumonia, but also by other infections or trauma, in which the body’s inflammatory response gets out of control, causing fluid to flood into the lungs. An estimated 190,000 Americans suffer from acute lung injury each year and almost 40% die while in hospital.

New malaria vaccine identified

A new candidate malaria vaccine, with the potential to neutralise all strains of the most deadly species of malaria parasite, has been developed by a team led by scientists at the University of Oxford. The results of this new vaccine independently confirm the utility of a key discovery reported last month from scientists at the Wellcome Trust Sanger Institute, who identified a target within the parasite as a potential ‘Achilles’ heel’ that could hold significant promise for vaccine development.

According to the World Malaria Report 2010, malaria killed an estimated 781,000 people in 2009, mainly young children and pregnant women. It is caused by parasites that are injected into the bloodstream by infected mosquitoes. The most deadly form, Plasmodium falciparum, is responsible for nine out of ten deaths from malaria. Vaccinating against malaria is likely to be the most cost-effective way of protecting populations against disease. However, no licensed vaccine is currently available. Another vaccine is achieving promising but incomplete levels of protection in clinical trials in Africa.

In early November, research published in the journal Nature showed that the P. falciparum parasite relies on a single receptor, known as ‘basigin’, on the surface of red blood cells, to which it attaches a protein – the antigen RH5 – to ‘unlock’ the doorway in to the red blood cell. Once there, it grows and replicates, causing potentially life-threatening disease.

Dr Gavin Wright from the Wellcome Trust Sanger Institute, a co-author on both studies, said: “Our initial finding was unexpected and completely changed the way in which we view how the malaria parasite invades red blood cells. It provided a target for potential new vaccines.”

Dr Sandy Douglas, a Wellcome Trust Clinical Research Training Fellow from the University of Oxford and first author on the new study, adds: “We have created a vaccine that confirms the recent discovery relating to the biology of RH5, given it can generate an immune response capable of neutralising many – and potentially all – strains of the P. falciparum parasite. This is an important step towards developing a much-needed vaccine against one of the world’s major killers.”

The antigens of the malaria parasite are often genetically very diverse as they evolve to avoid recognition by antibodies. However, the RH5 antigen appears to have little genetic diversity. The researchers believe that this is because even people who have been naturally and repeatedly exposed to malaria have low or undetectable levels of antibodies that target this particular antigen; these very low levels of antibody would be insufficient to kill the parasites, and hence would not exert a selective pressure for the antigen to evolve variability. According to the study authors, the next step is to begin safety tests with the vaccine, with the intention of launching clinical trials in patients in the next two to three years.

France invests US$1.18mn in research of antibiotic-resistant, infected burns

Pherecydes Pharma, a biotechnology company specialising in the research and development of lytic bacteriophages for both therapeutic and diagnostic purposes, has announced that it has received funding of EUR900,000 (US$1.18mn) from France’s General Directorate for Armaments to part-finance the PACOBURNS project. This project aims to explore the possibility of using bacteriophages to combat antibiotic-resistant bacterial infections, especially skin infections.

The funds invested by the DGA fall within the framework of its RAPID program, which supports dual innovation by small and medium-sized companies, through providing financial assistance for projects that have great technological and commercial potential, are innovative in terms of industrial research, and have both military and civilian applications.

Using relevant animal models, PACOBURNS will evaluate the therapeutic efficacy, safety and pharmacodynamics of treating open burn wounds with two cocktails of bacteriophages: the first designed for infections caused by escherichia coli type bacteria; and the second for infections caused by pseudomonas aeruginosa species. Trials on humans are scheduled to begin earlymid 2013.

The project is targeting a market where antibiotics are becoming less effective. Resistance to antibiotics has become a major public health problem; at least 25,000 people die in Europe each year as a result of antibiotic-resistant infections.

In the current state of pharmaceutical research, no new antibiotic is likely to reach the market over the next eight to ten years.

PACOBURNS will enable Pherecydes Pharma to speed up the development of its leading therapeutic products, in particular through facilitating clinical trials. The company’s future plans include extending the topical application of its cocktails to other skin pathologies (such as varicose ulcers), testing new products administered by aerosol, and lastly testing new products administered internally.

New technology dissolves blood clots after stroke

Johns Hopkins neurologists report success with a new means of getting rid of potentially lethal blood clots in the brain safely, without cutting through brain tissue, or removing large pieces of skull. The minimally- invasive treatment, they report, increased the number of patients with intracerebral haemorrhage (ICH) who could function independently by 10 to 15% six months following the procedure.

The study, coordinated by Johns Hopkins and the surgical review centres at the University of Cincinnati and the University of Chicago, involved 93 patients who had been diagnosed with ICH, a particularly lethal, or debilitating, form of stroke considered surgically untreatable under most circumstances.

ICH is a bleed in the brain that causes a clot to form, often caused by uncontrolled high blood pressure. The clot builds up pressure and leaches inflammatory chemicals that can cause irreversible brain damage, often leading to death, or extreme disability. The standard of care for ICH patients is general supportive care, usually in an ICU, where essentially clots are given a chance to dissolve; only 10% undergo the more invasive and risky craniotomy surgery. Roughly 50% of people who suffer an intracerebral haemorrhage die from it.

Although in the United States just 15% of stroke patients have ICH, that translates to roughly 30,000 to 50,000 individuals – more often than not, Asians, Hispanics, African-Americans, the elderly and those who lack access to medical care. The more common form of stroke is ischemic stroke, which occurs when an artery supplying blood to the brain is blocked.

Surgeons performed the procedure by drilling a dime-sized hole in each patient’s skull close to the clot location. Using a CT scan system, they guided the catheter directly into the clot, through which they administered small doses of clot-busting drug t-PA into the clot for a couple of days, shrinking the clots by roughly 20% per day. Those patients who underwent supportive therapy saw their clots shrink by about 5% per day.

Not only was the minimally-invasive surgery free of the potentially dangerous side-effects associated with craniotomy, but it was also found to be as safe as supportive therapy, which can involve intense blood pressure control, artificial ventilation, drugs to control swelling and watchful waiting for the clot to dissipate on its own. Additionally, the new procedure doesn’t need specialised equipment, say the study authors.

Gastric bypass can help diabetes patients achieve remission

Weight loss surgery is not a cure for type 2 diabetes, but it can improve blood sugar control, according to a new study published in the British Journal of Surgery. Whereas some previous studies have claimed that up to 80% of diabetes patients have been cured following gastric bypass surgery, researchers at Imperial College London found that only 41% of patients achieve remission using more stringent criteria.

Recently the American Diabetes Association defined complete remission of diabetes as returning to normal measures of glucose metabolism without taking diabetes medication at least one year after surgery.

Dr Carel le Roux, from the Department of Medicine at Imperial College London, who led the study, said: “Using the new criteria, we don’t get such eye-catching figures as some that have been quoted in recent years, but it’s clear that weight loss surgery, particularly gastric bypass, has a significant beneficial effect on glucose control… Stomach surgery may not mean that patients can stop taking diabetes medication, but surgery and medication together achieve better results than either treatment on its own.”

Of three weight loss surgeries studied, gastric bypass was found to be the most successful. Sleeve gastrectomy, which involves surgically removing a portion of the stomach, and gastric banding, in which a band is placed around part of the stomach, achieved remission rates of 26% and 7% respectively.

Middle East Health will look at this in more detail in the next issue – May-June 2012

Pregnancy and placenta disorders responsible for majority of stillbirths

Half of all stillbirths result from pregnancy disorders and conditions affecting the placenta, according to results reported by a National Institutes of Health network.

The NIH network researchers also found that most stillbirths could not be accounted for by pregnancy history and other maternal characteristics at the time of mothers finding out they were pregnant. However, some characteristics were associated with an increase in risk for stillbirth, such as a previous stillbirth, being a firsttime mother, a history of miscarriage, gestational diabetes, AB blood type, drug addiction, smoking three months before getting pregnant and maternal obesity.

Researchers in the NIH network study conducted a comprehensive medical evaluation after each stillbirth, consisting of an autopsy of the foetus, examination of the placenta, a test to check for abnormalities in the baby’s chromosomes, as well as other tests and a review of the medical records, to identify the cause of death. A probable cause of death was identifiable in 61% of cases and a probable, or possible, cause of death in 76%. Earlier studies, which typically were limited to analysing medical records, could only identify a cause of death in about 50% of cases.

The study authors noted that fewer than 50% of stillbirths in the United States undergo an autopsy exam due to various factors, including reluctance by the family and physician, and concerns about cost.

The researchers determined that pregnancy or birth-related complications contributed to the largest proportion of stillbirths (29%). Such complications can include preterm labour, premature rupture of membranes that hold the amniotic fluid and abruption of the placenta, in which the placenta separates from the uterus wall. Other causes identified were abnormalities of the placenta (24%), genetic conditions or birth defects (14%), infection (13%), problems with the umbilical cord (10%), maternal high blood pressure (9%) and other medical conditions affecting the mother (8%).

The researchers confirmed findings by other studies that African-American women were at greater risk for stillbirth compared with white women and Hispanic women, and showed that about 22% of the excess risk for African Americans was associated with maternal factors present at the time the women learned they were pregnant.

A stillbirth is the death of a baby at or after the 20th week of pregnancy. Stillbirth occurs in 1 out of 160 pregnancies in the United States. Since 2003, the stillbirth rate has remained at about 26,000 stillbirths each year.

Findings shed new light on hair senses

Neuroscientists at the Johns Hopkins University School of Medicine have discovered how the sense of touch is wired in the skin and nervous system, opening new doors for understanding how the brain collects and processes information from hairy skin.

David Ginty, professor of neuroscience at Johns Hopkins, said: “You can deflect a single hair on your arm and feel it, but how can you tell the difference between a raindrop, a light breeze or a poke of a stick? Touch is not yes or no; it’s very rich, and now we’re starting to understand how all those inputs are processed.”

In trying to understand how touchresponsive nerve cells develop, Ginty and his colleagues built new tools that enabled them to look at individual nerve cells. First, they genetically engineered mice to make a fluorescent protein in one type of nerve cell – called the C-type lowthreshold mechanosensory receptor, or CLTMR – which stretches from the spinal cord to the skin. Using the fluorescent protein, the team found that each CLTMR cell branched to send projections to as many as 30 different hair follicles.

Mice have three different types of hair: thick, long guard hair that accounts for about 1% of total hairs; a shorter hair called the awl/auchene that constitutes about 23% of body hair; and a fine hair called the zigzag that makes up 76% of body hair.

According to the researchers’ findings, which were published by Cell (December 22, 2011), about 80% of the C-LTMR cell endings associate with zigzag hair follicles, the rest with the awl/auchene and none with the guard hair follicles.

The researchers then similarly marked two other types of touch nerve cells and found that, not only is each hair type associated with a specific set of nerve endings, but that they are evenly spaced and patterned throughout the skin.

Then, using a different dying technique which stained the other end of the nerve cell in the spinal cord, they found that the nerves connecting each patch of skin containing one guard hair and other associated smaller hairs, line up in columns in the spinal cord. Neighbouring columns correspond to neighbouring patches of skin. They estimate that there are about 3,000 to 5,000 columns in the spinal cord, with each column accounting for 100 to 150 hair follicles.

Ginty believes that the organisation of the columns is key to how various inputs are processed and messaged to the brain, and that many of the same structures are shared in humans.

Younger patients more likely to live longer after heart transplant

Heart transplant patients who receive new organs before the age of 55 and get them at hospitals that perform at least nine heart transplants a year are significantly more likely than other people to survive at least 10 years after their operations, new Johns Hopkins research suggests.

Examining data from the more than 22,000 American adults who got new hearts between 1987 and 1999, researchers found that roughly half were still alive a decade after being transplanted and further analysis identified factors that appear to predict at least 10 years of life after the operations.

“There are 2,000 to 2,500 heart transplants a year in the U.S. and many people die waiting,” says Arman Kilic, MD, a surgical resident at The Johns Hopkins Hospital and leader of the study published in The Annals of Thoracic Surgery. “We have to be very smart about how to allocate scarce organs, and our research suggests we can predict which patients will live longer with a new heart.”

Kilic and his colleagues used information collected by the United Network of Organ Sharing (UNOS) and compared the 9,404 heart transplant recipients who survived for 10 or more years with the 10,373 who did not. Some 3,000 were lost to follow-up.

The researchers found that patients 55 and younger had a 24% greater chance of 10-year survival than older patients; those treated at hospitals performing nine or more heart transplants a year had a 31% greater chance of 10-year survival than those at lower volume centres; and white patients were 35% more likely to survive a decade than minority patients.

Kilic says that nearly half of heart transplant recipients in the study were over 55 and there is debate over how old is too old to undergo the surgery. “After the age of 55, we see the biggest difference in long-term survival,” he says. “The chance of surviving for 10 years drops precipitously.”


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