A new test for consciousness in ‘comatose’ patients

The Coma Science Group (CRCyclotron, University of Liège /Liège University Hospital), led by Dr Steven Laureys, has developed, along with its partners in London, Ontario, (Canada) and Cambridge (England), a portable test which will permit a simpler and less expensive diagnosis of ‘vegetative’ patients who still have consciousness, despite the fact that they do not have the means to express it. The researchers’ conclusions are published in The Lancet.

The desire to develop this simple test of consciousness, at the patient’s bedside, follows on from previous research carried out by the Coma Science Group. Professor Laureys and his colleagues had in effect already demonstrated, in 2009, that 40% of so-called ‘vegetative’ patients had been badly diagnosed and that in reality they retained a certain degree of consciousness. Following on from this study Laureys’ team at the University Hospital of Liège, on the recommendation of the Federal Health Service, was able to prescribe the compulsory use of a specially designed scale of consciousness (the coma recovery scale), now used in every coma specialist centre in Belgium.

In 2010 the Coma Science Group researchers and their colleagues at Cambridge (England) made another fundamental breakthrough in showing that it was possible to communicate with ‘vegetative’ patients through the means of scanners whose technology was based on functional magnetic resonance imaging (fMRI). Classically, the clinical evaluation of coma always proceeded via a muscular response to a stimulus. This study showed that, thanks to fMRI, a doctor could detect traces of consciousness and even communicate with so-called ‘vegetative patients due to the fact that they mentally responded in an appropriate manner to a task suggested by the evaluator. Scientifically revolutionary, using functional magnetic resonance imaging in the evaluation of comas is nevertheless very expensive, and not every hospital is equipped with or has access to it.

The new test described in The Lancet should change this situation. “As doctors, we as a rule ask the patient to respond to a simple command, such as ‘pinch my hand,’ to assure us that the patient is conscious. When we obtain a response, everything is fine, but if we cannot detect a response that does not necessarily mean to say that the patient is unconscious. Sometimes he or she cannot move because injuries have affected the nerves, the spinal cord or the brain,” explains Dr Laureys. “With our new test, we also ask patients to move their hand or their foot, but we no longer have confidence in the muscular response. We measure the activity of the motor cortex directly using electroencephalography (EEG), a cheaper method which is widespread throughout the hospital centres.”

“That means that this portable test can be carried out in every health care centre and even at home!” states Camille Chatelle, a neuropsychologist and one of the new study’s co-authors. doi: 10.1016/S0140-6736(11)61224-5

Children with autism have more brain cells

Children with autism have more brain cells and heavier brains compared to typically developing children, according to researchers. Published in the Journal of the American Medical Association on 9 November 2011, the small, preliminary study provides direct evidence for possible prenatal causes of autism.

“Earlier studies of head circumference and early brain overgrowth have pointed us in this direction, but there have been few quantitative neuroanatomical studies due to the lack of post-mortem tissue from children with autism,” said Thomas R. Insel, MD, director of the US National Institute of Mental Health (NIMH), part of US NIH. “These new results, along with an earlier study reporting altered wiring of the prefrontal cortex, focus our attention on this critical area of the brain in autism.”

The prefrontal cortex is involved in various higher order functions such as language and communication, social behaviour, mood, and attention. Children who have autism tend to show deficits in such functions.

Eric Courchesne, Ph.D., of the University of San Diego School of Medicine Autism Center of Excellence, and colleagues conducted direct counts of brain cells in specific regions of the prefrontal cortex in postmortem brains of seven boys who had autism and six typically developing males, ranging in age from 2-16 years. Most participants had died in accidents, but the researchers did not base their selection on causes of death.

To assist in this task, the researchers used a computerized tissue analysis system developed by co-investigator and NIMH grantee Peter Mouton, PhD, of the University of South Florida, Tampa, and colleagues.

The researchers found that children with autism had 67% more neurons in the prefrontal cortex and heavier brains for their age compared to typically developing children. Since these neurons are produced before birth, the study’s findings suggest that faulty prenatal cell birth or maintenance may be involved in the development of autism. Another possible factor that may contribute to the neuronal excess is a reduction in apoptosis, or programmed cell death, which normally occurs during the third trimester and early postnatal life.

Though small, this preliminary study examined all relevant postmortem tissue available at the time. The relative scarcity of tissue from very young children may limit future research as well, but efforts to include a larger number of samples are needed to confirm these findings and to identify patterns of age-related changes in autism.

Researchers discover how breast cancer spreads to the lungs

The spread of breast cancer is responsible for more than 90% of breast cancer deaths. Now, the process by which it metastasizes has been unravelled by researchers at Johns Hopkins. Reporting in two papers, the researchers have discovered the switch that enables breast cancer cells to travel to and be received in the lungs.

The results appear in two separate papers, one in the 12 September 2011 issue of the Proceedings of the National Academy of Science Early Edition and the other in the 22 August 2011 issue of Oncogene.

“Metastasis transforms breast cancer from a local, curable disease, to one that is systemic and lethal,” says Gregg L. Semenza, MD, PhD, the C. Michael Armstrong Professor of Medicine, director of the Vascular Program in the Institute for Cell Engineering and a member of the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins. “Metastasis was long thought a late event in cancer progression, but we have now shown metastasis to be an early event that is dependent on HIF-1.”

Discovered by Dr Semenza’s team nearly 20 years ago, the HIF-1 protein controls genes that enable cells to survive in low oxygen, like cells in solid tumours. More recently, others have found that in patients with breast cancer, an increase in HIF-1 activity correlates with increase in metastasis and decreased survival.

To uncover the role of HIF-1 in breast cancer metastasis to the lungs, the research team first looked at the lung, which is prepared for the arrival of metastatic cells by enzymes that are produced by the breast cancer cells. Using human breast cancer cells, the research team examined the genes that encode these enzymes and found regions where HIF-1 could bind to the DNA. Since HIF-1 is active in low oxygen, the team genetically engineered and reduced the amount of HIF-1 the cells could make, then examined how active the enzyme-producing genes were in cells grown in normal or low oxygen levels. They found that the cells were unable to produce these enzymes without HIF-1.

The team next implanted some of these same human breast cancer cells – some that made normal amounts of HIF-1 and some that made reduced amounts – into mice and examined the lungs after 45 days. Compared with breast cancer cells that made normal amounts of HIF-1, those making less HIF-1 resulted in smaller tumours and fewer changes in the lung, leading them to conclude that HIF- 1 is critical for lung metastasis.

In order for breast cancer cells to spread to lungs, they must leave the breast, enter blood vessels that lead to the lungs, and exit those same vessels. “Blood vessels are pretty tight, a cell has to work pretty hard to get through the vessel wall,” says Dr Semenza. “Since HIF-1 triggers the lung to prepare for arriving breast cancer cells, we wondered if HIF-1 also is involved in getting cells into and out of blood vessels.”

Dr Semenza’s team used breast cancer cells grown in low oxygen to examine the activity of 88 genes known to play a role in metastasis. Looking for genes that are turned on in response to low oxygen they found one called angiopoietin-like 4 and one called L1 cell adhesion molecule, known as ANGPTL4 and L1CAM for short. Further examination of the DNA around these genes revealed regions where HIF-1 could bind, and removing HIF-1 from cells rendered them unable to turn on the two genes.

When breast cancer cells turn on ANGPTL4, it helps them travel through blood vessel walls, the team found by injecting these cells either with normal or “knocked-down” levels of ANGPTL4 into mice and examining their lungs. Cells lacking HIF-1 and containing extra ANGPTL4 were better able to invade the lungs than cells without extra ANGPTL4; the researchers concluded that ANGPTL4 promotes cell exit from blood vessels. And they found the same to be true for L1CAM. Blocking HIF-1

Lastly, a few years ago Dr Semenza’s team found that digitalis/digoxin, commonly used to treat irregular heartbeats, can block HIF-1 production and can stop liver and prostate cancer cells from growing. To see if digitalis could do the same with metastatic breast cancer, the researchers transplanted human breast cancer cells into mice. After two weeks they gave the mice daily injections of digitalis or saline. They found both fewer and smaller lung metastases in mice treated with digitalis.

“This is really exciting,” says Dr Semenza. “The therapeutic range for digoxin is well established, and our findings warrant clinical trials to determine if these doses are enough to sufficiently block HIF-1 and slow breast cancer growth and metastasis.”

Study shows simple steps can reduce catheter-related infections

By following a few basic rules for handling central venous catheters, nurses and doctors at a group of children’s hospitals have, in three years, prevented nearly a thousand infections and saved more than a hundred children’s lives and millions of dollars, according to a study by investigators at Johns Hopkins Children's Center and elsewhere.

The results of the program, spearheaded by the US National Association of Children's Hospitals and Related Institutions (NACHRI) and led by Marlene Miller, MD, MSc, director of Pediatric Quality and Safety at Johns Hopkins, are published online in the November 2011 issue of Pediatrics.

The research involved 29 pediatric intensive-care units (PICUs) and examined whether and how low-tech steps involving proper daily care and maintenance of central lines might reduce infection rates.

Researchers found that proper daily care of the central line (or central venous catheter) slashed the number of infections by more than half (56%) over three years.

Because central lines also provide quick direct access into a patient's bloodstream in emergencies, children in the PICU often have them for weeks or months. Inserted incorrectly or mishandled after insertion, the central line can become a gateway for bacteria or other germs to enter the patient's bloodstream, causing invasive disease and organ damage in these already vulnerable patients.

Because the catheter is often accessed multiple times a day after insertion, proper handling is critical, the investigators say. Basic precautions, such as daily assessment of the actual need for a central line and prompt removal if no longer needed; regularly changing the dressing covering the central line; changing the tubes and caps attached to it; cleaning the line before and after each use; and hand washing before handling the line can go a long way to keep bacteria and other bugs at bay.

The results, the investigators say, are impressive because they showed sustained and continuous reduction in infections over a long period of time and across PICUs with varying staffing, sizes and protocols.

“The drastic reduction in infections sustained over time and across many different hospitals shows that proper catheter care, when practiced rigorously and systematically, can be a game-changer in the battle against catheter-related infections,” says Miller, the study’s lead investigator and vice president for quality transformation at NACHRI.

In an 18-month-long sub-study, researchers examined two more steps: additional scrubbing of the device’s cap with antiseptic solution before each access and placing antiseptic-soaked sponges at the catheter insertion site. Neither strategy reduced infection rates further, they found.

Scientists discover link among spectrum of childhood diseases

An international collaboration of scientists has identified a genetic mutation that causes a rare childhood disease characterised predominantly by inflammation and fat loss. The research suggests that the disorder, named chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), actually represents a spectrum of diseases that have been described in the literature under a variety of names. More importantly, since no effective treatment for this disease currently exists, the findings may have uncovered a possible target for future treatments.

The collaboration began when NIAMS rheumatologist Raphaela GoldbachMansky, M.D., started seeking the cause of inflammatory skin lesions, fat loss and fevers in two of her young patients. At a scientific meeting, she learned about recent publications by two other research groups – one led by dermatologists Antonio Torrelo, M.D., from the Boy Jesus Hospital, Madrid, and Amy Paller, M.D., from Northwestern University, Chicago, and the other led by Abraham Zlotogorski, M.D., from the Hadassah-Hebrew University Medical Center, Jerusalem – describing similar conditions. She immediately located the publications’ authors and emailed them that same night.

Based on the clinical presentation and, particularly, the unusual skin lesions seen in the children, the researchers suspected that the children must have the same disease. Subsequent analyses – involving biopsies, blood tests and genetic testing – confirmed their suspicions. All but one child had at least one mutation in a gene called PSMB8, which had been recently identified in three adult patients with a disease called joint contractures, muscle atrophy and panniculitis-associated lipodystrophy (JMP).

PSMB8 is one of more than 20 components involved in making a cellular structure called a proteasome, which recycles proteins from cells that are stressed or dying.

“When the proteasome doesn’t function, there is a buildup of protein waste products in the cells – much like if your trash wasn’t picked up each week, it would accumulate in your driveway,” said Dr. Goldbach-Mansky.

The one patient without the mutation had a blood profile that was identical to the ones who did, and showed the same accumulation of waste products in the cells seen in children with the genetic mutation. Blood tests also showed high levels of an inflammatory chemical called interferon gamma-induced protein 10 (IP-10) that is stimulated by interferons. The chemical is produced in response to some infections, and the group suspects that it also may be produced in the cellular stress response.

The discovery, which is described in Arthritis & Rheumatism, unifies several different diseases into one spectrum of proteasome-associated autoinflammatory syndromes, said Dr Goldbach-Mansky. She hopes that these findings will enable doctors to identify more children who fit into this spectrum of difficult-to-treat disorders so that they can develop a better understanding of the disorders and their treatment.

US Foundation for the NIH launches study to develop diabetes diagnostic tools

The US Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium has launched a multi-year clinical study to improve tools for measuring the function of insulin-producing beta cells in people with type 2 diabetes mellitus. Researchers hope the initiative will lead to improved techniques for tracking progression of the disease and pave the way for more effective treatments.

Utilising a collaborative approach, the FNIH Biomarkers Consortium has brought together diabetes experts from the US National Institutes of Health, US FDA, leading academic institutions, the pharmaceutical industry, and non-profit sector to develop the project. Participating and funding organisations include: Amylin Pharmaceuticals, Eli Lilly, Johnson & Johnson Pharmaceutical Research and Development, Juvenile Diabetes Research Foundation, Merck, Sharp & Dohme, Novartis Institutes for BioMedical Research, Pfizer, Sanofi-Aventis, and Takeda Global Research & Development Center.

“Today, diabetes researchers are working without the benefit of agreedupon standards for gauging beta cell function,” said Myrlene Staten, Senior Advisor at the National Institute of Diabetes and Digestive and Kidney Diseases and co-chair of the steering committee with oversight of the project. “We anticipate this initiative will give researchers practical tools that can be used to measure beta cell function over time and stimulate research to maintain and improve that function.”

The project, “Diabetes Drug Development: Identification and Validation of Markers that Predict Long- Term Beta Cell Function and Mass,” managed by the Metabolic Disorders Steering Committee (MDSC) of the FNIH Biomarkers Consortium, is a threeyear, US$5.1 million clinical study to standardise tests for measuring beta cell function in the clinical setting. It also aims to improve methods for the early prediction of the long-term response to an intervention and for identification of patients at risk for rapid beta cell function deterioration, thereby enabling future clinical studies that examine diabetes progression.

“One of the next frontiers of diabetes therapeutics is to change the progression rate of beta cell failure,” said Dr David Fryburg, project team leader, Principal Consultant, ROI BioPharma, and Chief Medical Officer, Selventa.

Functional MR tomography measures foetal brain development for first time

A team of researchers at the MedUni’s Clinical Department of Neuroradiology and Musculoskeletal Radiology has demonstrated for the first time ever that there are foetal brain developments that can be measured using functional magnetic resonance tomography in the womb. This means, says study leader Veronika Schöpf, that pathological changes to brain development will be detectable earlier than they are currently - and appropriate measures can be taken in good time.

In the study, 16 foetuses between the 20th and 36th weeks of pregnancy were measured. Measurements were taken of the brain’s resting state networks. These networks remain in a state of readiness at rest and their activity increases after appropriate stimulation. The examinations are completely stress-free for the mothers and extend “normal” MRI scans by just a few minutes.

“We have been able to demonstrate, for the first time ever, that the resting state networks are formed in utero and that these can be imaged and measured using functional imaging,” explains Schöpf, who is part of the working group led by Daniela Prayer, Head of the Department of Neuroradiology and Musculoskeletal Radiology and head of the centre for pre-natal magnetic resonance imaging at the MedUni Vienna.

This discovery means that, in future, the developmental progress of brain activity in the foetus can be measured and other findings and prognoses made regarding possible malfunctioning processes. As a result, functional defects, such as of the optic nerves or motor system, can be detected while the foetus is still in the womb – an achievement that was previously impossible – so that parents can be offered more informed advice and counselling, for example.

Scientists develop novel tool for MI quantification

A team of scientists from INEB-Instituto de Engenharia Biomédica, has developed an original tool to quantify the size of heart ischemia in pre-clinical animal models. The MIQuant, acronym for myocardial infarct (MI) quantification is user-friendly semi-automated software and is made freely available online to contribute towards the standardization and simplification of infarct size assessment. This innovation takes advantage of earlier methods of planimetry for assessment of MI size and promises more accurate and faster evaluation of new heart regeneration therapies.

Team leader Perpétua Pinto-do-Ó, PhD, of INEB explains: “This development is a great illustration of where communication between different scientific languages can lead us. Sometimes biologists, physicians and engineers waste the opportunity for novel improvements due to the difficulties to translate their problems and questions. It took us time, but we found here just the right platform to smoothen our differences which resulted in an application that will be useful not only to our lab but to the whole of the experimental cardiovascular community.”

Diana S. Nascimento, PhD, first author of the paper published 30 September 2011 in PLoS ONE online, summoned up: “At the time we were implementing from scratch our work in the cardiac system and it was after establishing a mouse model of myocardial infarction that we were confronted with the huge amount of time and variability on the infarct analysis. We just had to take some action.”

Therefore, the team started two years ago – in collaboration with Pedro Quelhas, PhD, INEB-FEUP – designing a tool to address the main constrains found while developing research on the role of stem/progenitors cells have on cardiac regeneration and repair: the laborious time-consuming and highly variable methods available for the assessment of infarct size measurements in a mouse model of myocardial infarction. The purpose has been to automate the process just enough to promote standardisation. From the discussion within this multidisciplinary project it was evident that a semiautomated method allowing for some kind of intervening by the biologist was more likely to be accepted in the area. However, the engineers in the team do not exclude future developments towards the full automation.

“Basically, any laboratory that works in experimental cardiovascular therapies using small rodents as models can make use of the MIQuant software. In this way we expect to contribute towards the standardisation of infarct size assessment across studies and, therefore, to systematisation of the evaluation of cardiac regenerative potential in emerging therapies,” said Pinto-do-Ó. doi: 10.1371/journal.pone.0025045

New algorithm could cut routine MR scan time by 66%

Magnetic resonance imaging (MRI) devices can scan the inside of the body in intricate detail, allowing clinicians to spot even the earliest signs of cancer or other abnormalities. But they can be a long and uncomfortable experience for patients, requiring them to lie still in the machine for up to 45 minutes. Now this scan time could be cut to just 15 minutes, thanks to an algorithm developed at MIT’s Research Laboratory of Electronics in the US.

Dwight Nishimura, the director of the Magnetic Resonance Systems Research Laboratory at Stanford University, says the research group has done some very interesting algorithmic work. “This work is potentially of high significance because it applies to routine clinical MRI, among other applications,” he says. “Ultimately, their approach might enable a substantial reduction in examination time.”

MRI scanners use strong magnetic fields and radio waves to produce images of the body. Rather than taking just one scan of a patient, the machines typically acquire a variety of images of the same body part, each designed to create a contrast between different types of tissue. By comparing multiple images of the same region, and studying how the contrasts vary across the different tissue types, radiologists can detect subtle abnormalities such as a developing tumor. But taking multiple scans of the same region in this way is timeconsuming, meaning patients must spend long periods inside the machine.

In a paper to be published in the journal Magnetic Resonance in Medicine, researchers led by Elfar Adalsteinsson, an associate professor of electrical engineering and computer science and health sciences and technology, and Vivek Goyal, the Esther and Harold E. Edgerton Career Development Associate Professor of Electrical Engineering and Computer Science, detail an algorithm they have developed to dramatically speed up this process. The algorithm uses information gained from the first contrast scan to help it produce the subsequent images. In this way, the scanner does not have to start from scratch each time it produces a different image from the raw data, but already has a basic outline to work from, considerably shortening the time it takes to acquire each later scan.

The algorithm uses the first scan to predict the likely position of the boundaries between different types of tissue in the subsequent contrast scans. “Given the data from one contrast, it gives you a certain likelihood that a particular edge, say the periphery of the brain or the edges that confine different compartments inside the brain, will be in the same place,” Adalsteinsson says.

However, the algorithm cannot impose too much information from the first scan onto the subsequent ones, Goyal says, as this would risk losing the unique tissue features revealed by the different contrasts. “You don’t want to presuppose too much,” he says. “So you don’t assume, for example, that the bright-and-dark pattern from one image will be replicated in the next image, because in fact those kinds of dark and light patterns are often reversed, and can reveal completely different tissue properties.”

New ‘scarless’  surgery removes tumours through natural skull opening

A technique developed by Johns Hopkins surgeons is providing a new route to get to and remove tumours buried at the base of the skull: through the natural hole behind the molars, above the jawbone and beneath the cheekbone.

In a report detailing the novel surgery, published in the October 2011 issue of The Laryngoscope, the surgeons say the procedure, already performed in seven patients, yields faster recovery and fewer complications than traditional approaches. And, because the incisions are made inside the cheek, there are no visible scars.

Kofi Boahene, MD, an assistant professor of facial plastic and reconstructive surgery and otolaryngology–head and neck surgery at the Johns Hopkins University School of Medicine, says the idea for the new approach came to him when a 20-year-old female patient previously treated for a brain tumour developed a new tumour deep in the skull base.

Traditional surgeries to remove skull base tumours require incisions through the face and bone removal, which can sometimes be disfiguring. Additionally, these operations can harm facial nerves, leading to paralysis that affects facial expressions and days or weeks of hospitalisation and recovery. Boahene said he was gazing at a skull model in his office, considering options to spare his patient from another traditional surgery. “I looked at the ‘window” that already exists in the skull, above the jawbone and below the cheekbone and realised this was an access route not previously recognised for this kind of surgery,” he said.

Knowing there was always the option of switching to the traditional approach while trying the new approach, Boahene and his colleagues performed the new procedure on his patient in 2010. The expected surgery time shrunk from six hours to two. Additionally, the patient was able to leave the hospital the next day and return to college, with no visible evidence that she had surgery performed.

The report in The Laryngoscope describes details of the surgeries on three of the seven patients Boahene and his colleagues have thus far treated. Besides benefits for patients, he and his colleagues note, the new procedure is significantly less complicated for surgeons to perform, provides excellent visualisation of the skull base area, and could potentially save healthcare dollars due to patients’ shorter hospital stays.

Not all patients are candidates for this procedure, Boahene cautions. It isn’t an option for those with very large skull base tumours or those with tumours that wrap around blood vessels. For these patients, traditional skull base surgery is still the best choice, he says.

In the future, he and his colleagues plan to try the new procedure using a surgical robot, which could provide even better visualization for surgeons and further reduce chances of complications for patients.

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