Light shed on sight

Nearly 100 years after World War I neurologist, Gordon Holmes, first mapped the blind spots caused by missile wounds to the brains of soldiers, Perelman School of Medicine researchers at the University of Pennsylvania have perfected his map using modern-day technology. Their results create a map of vision in the brain based upon an individual's brain structure, even for people who cannot see. Among other things, this could help guide efforts to restore vision using a neural prosthesis that stimulates the surface of the brain.

Scientists frequently use a brain imaging technique called functional MRI (fMRI) to measure the seemingly unique activation map of vision on an individual’s brain. This fMRI test requires staring at a flashing screen for many minutes while brain activity is measured, which is an impossibility for people blinded by eye disease. The Penn team has solved this problem by collecting traditional fMRI measures of brain activity from 25 people with normal vision. They then found a common mathematical description of the relationship between visual function and brain anatomy, thereby identifying a precise statistical relationship between the structure of the folds of the brain and the representation of the visual world.

Co-lead author Noah Benson, post-doctoral researcher in Psychology and Neurology at Perelman said: “At first, it seems like the visual area of the brain has a different shape and size in every person. Building upon prior studies of regularities in brain anatomy, we found that these individual differences go away when examined with our mathematical template.”

Senior author Geoffrey Aguirre, assistant professor of Neurology, said: “By measuring brain anatomy and applying an algorithm, we can now accurately predict how the visual world for an individual should be arranged on the surface of the brain. We are already using this advance to study how vision loss changes the organisation of the brain.”

doi: 10.1016/j.cub.2012.09.014

Computer programme to prevent DVTs

Researchers at Johns Hopkins have devised a computerised checklist system to prevent potentially deadly blood clots in hospitalised trauma patients. According to the team, the programme, which help physicians identify and use the best methods of prevention, has been proven to dramatically reduce the number of dangerous venous thromboembolisms (VTEs) in patients.

The programme requires doctors to enter their patients’ medical orders. Then, the automated checklist recommends evidencebased best treatments for each patient’s needs, which usually involves the regular administration of low-dose blood thinners, or the use of compression devices to keep blood flowing in the legs. The researchers say this new system worked far better than previous methods, which included handing out laminated cards outlining best practices, or lectures on the topic.

The research team found a nearly twofold improvement in prophylaxis orders among patients who had no contraindications to receiving low-dose blood thinners. Blood thinners are often not ordered in patients with bleeding risk, as they can exacerbate bleeding.
While the rate of pulmonary emboli, or PE events, stayed steady throughout the study period, the researchers found the rate of DVT (deep vein thrombosis) in legs dropped nearly 90%, from 2.26% of trauma patients to 0.25% of trauma patients.

Elliott R. Haut, MD, an associate professor of surgery at the Johns Hopkins University School of Medicine, and leader of the study, said: “VTE hits all segments of the population. All hospitalised patients are at risk for this complication and a huge number of these deadly clots are preventable if we give patients the right prophylaxis. We tried education alone for years and still only 40 to 60% of patients were getting optimal treatment.”

More than 600,000 people get a VTE each year in the United States and one in six die as a result, more than the number who die annually from breast cancer, AIDS or in car crashes. In 2008, the US Surgeon General made a call to action to prevent DVT and PE. The Agency for Healthcare Research and Quality (AHRQ) has called appropriate prophylaxis the number one patient safety initiative needed to prevent in-hospital death.

Trauma patients are at a particularly high risk of developing DVT or PE, as risk factors for VTE include major surgery and extreme injury, especially to the spinal cord.

doi: 10.1001/archsurg.2012.2024

Under anaesthetic, or just asleep?

A study by researchers at the Perelman School of Medicine at the University of Pennsylvania has demonstrated in an animal model that a commonly used inhaled anaesthetic drug, isoflurane, works by directly causing sleeppromoting neurons in the brain to activate, thereby hijacking our natural sleep circuitry. The findings are the latest work by investigators at the Center for Anesthesia Research at Penn who are exploring how anaesthetics interact within the central nervous system to cause a state of unconsciousness.

“Despite more than 160 years of continuous use in humans, we still do not understand how anaesthetic drugs work to produce the state of general anaesthesia,” said study author Max B. Kelz, assistant professor of Anesthesiology and Critical Care. “We show in this new work that a commonly used inhaled anaesthetic drug directly causes sleep-promoting neurons to fire. We believe that this result is not simply a coincidence. Rather, our view is that many general anaesthetics work to cause unconsciousness in part by commandeering the brain’s natural sleep circuitry, which initiates our nightly journey into unconsciousness.”

In the new study, Kelz and colleagues focused on a particular part of the brain, deep within the hypothalamus, which is known to increase in activity as one drifts off to sleep. Through a combination of direct electrical recording and other methods, they found that isoflurane boosts activity in this sleep-promoting brain area in mice. As further evidence of a connection, animals lacking the function of those neurons exhibited acute partial resistant to entering states of anaesthesia.

Being an anaesthesiologist himself, Kenz had long wondered just how accurate this notion of putting his patients to sleep really was. He said: “The development of anaesthetic drugs has been hailed as one of humankind's greatest discoveries in the last thousand years. Anaesthetics are annually given to over 230 million patients worldwide. Yet as a society, and even within the anaesthesia community, we seem to have lost our curiosity for how and why they work.”

Clever medical tape for newborns

While commercial medical tapes are great at keeping medical devices attached to the skin, they can cause damage once it's time to remove them – especially to newborns and elderly who have fragile skin. However, a new quick-release tape designed by Brigham and Women's Hospital (BWH) offers the strong adhesion properties of commercial medical tape, but without the ouch factor upon removal.

BWH’s Jeffrey Karp, senior study author in collaboration with The Institute for Pediatric Innovation, said: “Current adhesive tapes that contain backing and adhesive layers are tailored to fracture at the adhesive-skin interface. With adults the adhesive fails leaving small remnants of adhesive on the skin while with fragile neonate skin, the fracture is more likely to occur in the skin causing significant damage. Our approach transitions the fracture zone away from the skin to the adhesive-backing interface thus completely preventing any harm during removal.”

The approach incorporates an anisotropic adhesive interface between the backing and adhesive layers. The anisotropic properties of this middle layer means that it has different physical properties dependent on direction. The researchers employed laser etching and a release liner to create the anisotropic interface resulting in a medical tape with high shear strength (for strong adhesion) and low peel force (for safe, quick removal). Once the backing is peeled off, any remaining adhesive left on the skin can safely be rolled off with a finger.

Lead study author Bryan Laulicht said: “This is one of the biggest problems faced in the neonate units, where the patients are helpless and repeatedly wrapped in medical tapes designed for adult skin.”

There are more than 1.5 million injuries each year in the United States caused by medical tape removal. Such injuries in babies and the elderly can range from skin irritation to permanent scarring.

Sensor detects early stage disease

Scientists have developed a prototype ultra-sensitive sensor that would enable doctors to detect the early stages of diseases and viruses with the naked eye, according to research from Imperial College London. According to their results, their visual sensor technology is ten times more sensitive than the current gold standard methods for measuring the specific biomarkers that indicate the onset of diseases such as prostate cancer and infection by viruses, including HIV. For instance, the sensor was able to detect minute levels of a biomarker called p24, which indicates HIV infection, in samples where patients had low viral loads. These low levels of p24 could not be diagnosed using existing tests such as the Enzymelinked Immunosorbent Assay (ELISA) test and the gold standard nucleic acid based test.

The researchers say their sensor would benefit countries where sophisticated detection equipment is scarce, enabling cheaper and simpler detection and treatments for patients. Professor Molly Stevens, from the Departments of Materials and Bioengineering at Imperial College London, said: “It is vital that patients get periodically tested in order to assess the success of retroviral therapies and check for new cases of infection. Unfortunately, the existing gold standard detection methods can be too expensive to be implemented in parts of the world where resources are scarce. Our approach affords for improved sensitivity, does not require sophisticated instrumentation and it is ten times cheaper, which could allow more tests to be performed for better screening of many diseases.”

The researchers also tested samples for the biomarker called Prostate Specific Antigen (PSA), which is an early indicator for Prostate Cancer. The team say the sensor can also be reconfigured for other viruses and diseases where the specific biomarker is known.

The sensor works by analysing serum, derived from blood, in a disposable container. If the result is positive for p24 or PSA, there is a reaction that generates irregular clumps of nanoparticles, which give off a distinctive blue hue in the solution inside the container. If the results are negative, the nanoparticles separate into ball-like shapes, creating a reddish hue. Both reactions can be easily seen by the naked eye.

Dr Roberto de la Rica, co-author of the study from the Department of Materials at Imperial College London, adds: “We have developed a test that we hope will enable previously undetectable HIV infections and indicators of cancer to be picked up, which would mean people could be treated sooner. We also believe that this test could be significantly cheaper to administer, which could pave the way for more widespread use of HIV testing in poorer parts of the world.”

The next stage of the research will see the team approaching not-for-profit global health organisations, which could provide strategic direction and funding for manufacturing and distributing the sensor to low income countries.

doi: 10.1038/nnano.2012.186

House dust triggers asthma

A bacterial protein in common house dust may worsen allergic responses to indoor allergens, according to research conducted by the National Institutes of Health and Duke University. The finding is the first to document the presence of the protein flagellin in house dust, bolstering the link between allergic asthma and the environment.

Study author Donald Cook said: “Most people with asthma have allergic asthma, resulting largely from allergic responses to inhaled substances. Although flagellin is not an allergen, it can boost allergic responses to true allergens.”

After inhaling house dust, mice that were able to respond to flagellin displayed all of the common symptoms of allergic asthma, including more mucous production, airway obstruction, and airway inflammation. However, mice lacking a gene that detects the presence of flagellin had reduced levels of these symptoms.

“More work will be required to confirm our conclusions, but it's possible that cleaning can reduce the amount of house dust in general, and flagellated bacteria in particular, to reduce the incidence of allergic asthma,” Cook said.

In addition to the mouse study, the research team also determined that people with asthma have higher levels of antibodies against flagellin in their blood than do non-asthmatic subjects, which provides more evidence of a link between environmental factors and allergic asthma in humans.

doi: 10.1038/nm.2920

Linguists have stronger brain power

At the Swedish Armed Forces Interpreter Academy, young recruits learn a new language at a very fast pace. By measuring their brains before and after the language training, a group of researchers have had an almost unique opportunity to observe what happens to the brain when we learn a new language in a short period of time. At the Swedish Armed Forces Interpreter Academy in the city of Uppsala, young people with a flair for languages go from having no knowledge of a language such as Arabic, Russian or Dari to speaking it fluently in the space of 13 months. From morning to evening, weekdays and weekends, the recruits study at a pace unlike on any other language course.

As a control group, the researchers used medicine and cognitive science students at Umeå University – students who also study hard, but not languages. Both groups were given MRI scans before and after a three-month period of intensive study. While the brain structure of the control group remained unchanged, specific parts of the brain of the language students grew. The parts that developed in size were the hippocampus, a deep-lying brain structure that is involved in learning new material and spatial navigation, and three areas in the cerebral cortex.

Johan Mårtensson, a researcher in psychology at Lund University, Sweden, said: “We were surprised that different parts of the brain developed to different degrees depending on how well the students performed and how much effort they had had to put in to keep up with the course.”

Students with greater growth in the hippocampus and areas of the cerebral cortex related to language learning (superior temporal gyrus) had better language skills than the other students. In students who had to put more effort into their learning, greater growth was seen in an area of the motor region of the cerebral cortex (middle frontal gyrus). The areas of the brain in which the changes take place are thus linked to how easy one finds it to learn a language and development varies according to performance.

Previous research from other groups has indicated that Alzheimer’s disease has a later onset in bilingual or multilingual groups. “Even if we cannot compare three months of intensive language study with a lifetime of being bilingual, there is a lot to suggest that learning languages is a good way to keep the brain in shape”, said Johan Mårtensson.

doi: 10.1016/j.neuroimage.2012.06.043

Researchers study new treatment for depression

Australian researchers at Monash Alfred Psychiatry Research Centre (MAPrc) are studying the potential of using Magnetic Seizure Therapy (MST) as an alternative treatment for depression, the results of which could directly benefit the 30% of patients suffering from depression who don’t respond to traditional treatment.

Professor Paul Fitzgerald, deputy director of MAPrc and study lead, said depression affects up to one in five Australians during their lifetime. “Electroconvulsive Therapy (ECT) is one of the only established interventions for treatment resistant depression,” he said. “But use of ECT is limited due to the presence of memory-related side effects and associated stigma.”

For this reason, the MAPrc researchers began exploring new treatment options. MST is a brain-stimulation technique that may have similar clinical effects to ECT without the unwanted side effects.

“In MST, a seizure is induced through the use of magnetic stimulation rather than a direct electrical current like ECT. Magnetic fields are able to pass freely into the brain, making it possible to more precisely focus stimulation,” Professor Fitzgerald said. “By avoiding the use of direct electrical currents and inducing a more focal stimulation, it is thought that MST will result in an improvement of depressive symptoms without the memory difficulties seen with ECT.”

The study found that MST resulted in an overall significant reduction in depression symptoms; 40% showed overall improvement and 30% showed some improvement. None of the trial participants complained of cognitive side effects.

Professor Fitzgerald and his team have received funding to carry out a large-scale trial on MST as an alternative treatment for depression.

Diabetes study cut short

An intensive diet and exercise program resulting in weight loss does not reduce cardiovascular events such as heart attack and stroke in people with longstanding type 2 diabetes, according to a study supported by the US National Institutes of Health.

The Look AHEAD (Action for Health in Diabetes) study tested whether a lifestyle intervention resulting in weight loss would reduce rates of heart disease, stroke, and cardiovascular-related deaths in overweight and obese people with type 2 diabetes, a group at increased risk for these events.

Researchers at 16 centres across the United States worked with 5,145 people, with half randomly assigned to receive an intensive lifestyle intervention and the other half to join a general programme of diabetes support and education. Both groups received routine medical care from their own health care providers.

Although the intervention did not reduce cardiovascular events, Look AHEAD has shown other important health benefits of the lifestyle intervention, including decreasing sleep apnoea, reducing the need for diabetes medications, helping to maintain physical mobility and improving quality of life.

Dr Rena Wing, chair of the Look AHEAD study and professor of psychiatry and human behavior at Brown University, said: “Look AHEAD found that people who are obese and have type 2 diabetes can lose weight and maintain their weight loss with a lifestyle intervention. Although the study found weight loss had many positive health benefits for people with type 2 diabetes, the weight loss did not reduce the number of cardiovascular events.”

Participants in the intervention group lost an average of more than 8% of their initial body weight after one year of intervention. They maintained an average weight loss of nearly 5% at four years, an amount of weight loss that experts recommend to improve health. Participants in the diabetes support and education group lost about 1% of their initial weight after one and four years.

In September 2012, the NIH stopped the intervention arm, acting on the recommendation of the study's data and safety monitoring board. At the time, participants had been in the intervention for up to 11 years. Because there was little chance of finding a difference in cardiovascular events between the groups with further intervention, the board recommended stopping the intensive lifestyle intervention, but encouraged the study to continue following all Look AHEAD participants to identify longerterm effects of the intervention.

Diabetes reversed in mice

New research has found that a type of anti-tumour immune cell protects against obesity and the metabolic syndrome that leads to diabetes. Results show that natural killer T-cells (iNKT) – immune cells known to be protective against malignancy – are lost when humans become obese, but can be restored through weight loss. Marie Curie Fellow, Lydia Lynch at Trinity College Dublin, Ireland, made the discovery and has shown that therapies that activate iNKT cells could help manage obesity, diabetes, and metabolic disease.

iNKT cells had been thought to be rare in humans until work by Dr Lydia Lynch and others found they were plentiful in human omental fat and in fat tissue from mice. Dr Lynch said: “Now we have identified a role for these cells in the regulation of body weight and the metabolic state, likely by regulating inflammation in adipose tissue.”

The team also discovered that a lipid called alpha-galactosylceramide (aGC) can lead to a dramatic improvement in metabolism, weight loss, and fatty liver disease, and can reverse diabetes by bolstering cells that have been depleted.

Dr Lynch first began this line of investigation in 2007 when her work at St Vincent’s University Hospital, Dublin, focused on the immune systems of obese patients. “We knew that not only did obese patients have more heart attacks and a greater incidence of type 2 diabetes than lean individuals, but they also developed more infections than non-obese individuals,” she said.

Blood samples taken from these patients revealed that both NKT cells and iNKT cells were decreased, and subsequent studies of fat tissue from a group of obese patients who had lost weight following bariatric surgery showed that iNKT cells had increased to normal levels.

The research team put a study group of mice on a high-fat diet and studied the outcome. Dr Lynch said: “Similar to the human subjects we had previously studied, the animals lost their iNKT cells when they became obese. Once we took them off this diet and put them back on a normal standard-fat diet, they lost the weight and their iNKT cells increased.”

In the next experiment, the authors set out to better understand the exact role of the iNKT cells by examining two strains of mice, both of which are deficient in iNKT cells, and a group of control mice, all on a high-fat diet.

Although all the animals grew obese, the iNKT-deficient mice grew 30% fatter than the control animals and developed the mouse equivalent of type 2 diabetes over just six weeks. The mice also had greatly increased triglyceride levels, larger fat cells, and fatty liver disease.

Next, the authors removed iNKT cells from a normal mouse and injected them into obese NKT-deficient mice.

“We actually reversed diabetes, and even though the mice continued to eat a highfat diet, they lost one to two grams of weight (normal mouse weight being 20 to 25 grams) and exhibited a host of features that suggested reduced inflammation, including improved insulin sensitivity, lower triglycerides and leptin, and shrunken adipocytes,” Dr Lynch said.

Finally, in order to demonstrate if the remaining diminished pool of iNKT cells in obesity could be activated to improve metabolism, the scientists tested aGC, a lipid known to activate iNKT cells. They found that administering a single dose of aGC caused a dramatic improvement in metabolism and fatty liver disease, loss of much of the weight gained, and reversal of diabetes in the obese animals.

doi: 10.1016/j.immuni.2012.06.016

Trial looks at stem cells from unrelated donors

A two-year clinical trial by Moffitt Cancer Centre and the Blood and Marrow Transplant Clinical Trials Network compared survival probabilities for patients transplanted with peripheral blood stem cells, or bone marrow stem cells, from unrelated donors.

The goal was to determine whether graft source, (peripheral blood stem cells or bone marrow), affects outcomes in unrelated donor transplants for patients with leukemia or other hematologic malignancies.

Fifty transplant centres in the United States and Canada participated in this phase III study, which randomized 278 patients to receive bone marrow and 273 patients to receive peripheral blood stem cells. According to the trial analyses, there were no observed differences in overall survival, relapse, non-relapse mortality, or acute graft-versus-host disease (GHVD) between the patients receiving peripheral blood stem cells or bone marrow stem cells from unrelated donors.

GVHD is a serious and often deadly post-transplant complication that occurs when the newly transplanted donor cells attack the transplant recipient’s body.

While engraftment was faster in patients receiving peripheral blood stem cells, there was a higher incidence of overall chronic GVHD in these patients (53%) than in those transplanted with bone marrow stem cells (40%). Patients receiving transplants of peripheral blood stem cells from unrelated donors also had a higher incidence of chronic GVHD affecting multiple organs (46%) than patients who received bone marrow stem cells (31%).

Claudio Anasetti, lead author and chair of the Department of Blood and Marrow Transplant at Moffitt Cancer Center, said: “Although peripheral blood stem cells from related donors have demonstrated clinical benefits, our trial demonstrates that when these stem cells originate from unrelated donors, they are not superior to bone marrow stem cells in terms of patient survival, and they increase the risk for chronic GVHD. More effective strategies to prevent GVHD are needed to improve outcomes for all patients receiving unrelated donor transplants.”

About one-third of patients who need a peripheral blood stem cell or bone marrow transplant for treatment of leukaemia or another blood disease are able to secure a related donor. According to the National Marrow Donor Program, for the 70% who cannot find a donor within their family, most will be able to find an unrelated donor. doi: 10.1056/NEJMoa1203517


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