Ice cream brain freeze holds the answer to headaches

By bringing on brain freeze in a lab of volunteers and studying blood flow in their brains, researchers have shown that ‘brain freeze’ headaches, triggered by cold water, or eating ice cream, seem to be triggered by an abrupt increase in blood flow in the anterior cerebral artery and disappears when this artery constricts. The findings could eventually lead to new treatments for a variety of different headache types.

According to study leader Jorge Serrador of Harvard Medical School, previous studies meant to assess what physiological changes might prompt headaches have mainly relied on various drugs, or brought in patients already in the throes of a migraine to the lab. However, both methods have their limitations. Pharmacological agents can induce other effects that can make research results misleading, he says, and since researchers can’t wait for migraine sufferers to experience a migraine in the lab, those studies miss the crucial period of headache formation that occurs sometimes hours before scientists were able to study these patients.

To induce headache inside the lab and study it from start to finish, Serrador explains, brain freeze is a perfect fit. It’s easy to bring on and resolves quickly without expensive, or complicated equipment, or drugs. The researchers monitored the volunteers’ blood flow in several brain arteries using transcranial Doppler while they first sipped ice water with the straw pressed against their upper palate – ideal conditions for bringing on brain freeze – and then while sipping the same amount of water at room temperature. The volunteers raised their hand once they felt the pain of a brain freeze, then raised it again once the pain dissipated. Findings showed that one particular artery, called the anterior cerebral artery, dilated rapidly and flooded the brain with blood in conjunction to when the volunteers felt pain. Soon after this dilation occurred, the same vessel constricted as the volunteers’ pain receded.

Serrador and his colleagues speculate that the dilation, then quick constriction, may be a type of self-defence for the brain.

Serrador said: “The brain is one of the relatively important organs in the body, and it needs to be working all the time. It’s fairly sensitive to temperature, so vasodilation might be moving warm blood inside tissue to make sure the brain stays warm.” But because the skull is a closed structure, Serrador adds, the sudden influx of blood could raise pressure and induce pain. The following vasoconstriction may be a way to bring pressure down in the brain before it reaches dangerous levels.

He notes that similar alterations in blood flow could be at work in migraines, posttraumatic headaches, and other headache types. If further research confirms these suspicions, then finding ways to control blood flow could offer new treatments for these conditions. Drugs that block sudden odilation or target channels involved specifically in the vasodilation of headaches could be one way of changing headaches’ course.

Housekeeping mechanism for brain stem cells discovered

Researchers at Columbia University Medical Center (CUMC) have identified a molecular pathway that controls the retention and release of the brain’s stem cells. The discovery offers new insights into normal and abnormal neurologic development and could eventually lead to regenerative therapies for neurologic disease and injury. The findings, from a collaborative effort of the laboratories of Drs Anna Lasorella and Antonio Iavarone, were published in the online edition of Nature Cell Biology.

The research builds on recent studies, which showed that stem cells reside in specialised niches, or microenvironments, that support and maintain them. Antonio Iavarone, MD, Professor of Pathology and Neurology at CUMC, said: “From this research, we knew that when stem cells detach from their niche, they lose their identity as stem cells and begin to differentiate into specific cell types.”

Dr Anna Lasorella, MD, associate professor of Pathology and Paediatrics at CUMC and a member of the Columbia Stem Cell Initiative, continued: “However, the pathways that regulate the interaction of stem cells with their niche were obscure.”

In the brain, the stem cell niche is located in an area adjacent to the ventricles, the fluid-filled spaces within the brain. Neural stem cells (NSCs) within the niche are carefully regulated, so that enough cells are released to populate specific brain areas, while a sufficient supply is kept in reserve. The team developed a genetically altered strain of mice in which Id proteins were silenced, or knocked down, in NSCs. In the absence of Id proteins, mice died within 24 hours of birth. Their brains showed markedly lowered NSC proliferative capacity, and their stem cell populations were reduced.

“Another aspect,” added Dr Lasorella, “is to determine whether Id proteins also maintain stem cell properties in cancer stem cells in the brain. In fact, normal stem cells and cancer stem cells share properties and functions. Since cancer stem cells are difficult to treat, identifying these pathways may lead to more effective therapies for malignant brain tumours.”

Stephen G. Emerson, MD, PhD, director of the Herbert Irving Comprehensive Cancer Center at New York-Presbyterian Hospital/Columbia University Medical Centre, said: “Understanding the pathway that allows stem cells to develop into mature cells could eventually lead to more effective, less toxic cancer treatments. This beautiful study opens up a wholly unanticipated way to think about treating brain tumours.”

Researchers develop revolutionary new cancer-targeting technology

A revolutionary cancer-targeting technology developed by researchers at Immunocore has been described in the journal Nature Medicine. The new reagents known as ImmTACs (Immune Mobilising mTCR against Cancer) mobilise T cells to kill cancer cells and overcome immune tolerance to cancer.

The most advanced of Immunocore’s ImmTACs, a drug called IMCgp100, is already in clinical trials in the UK and US for the treatment of melanoma. A second oncology ImmTAC, IMCmage1, is set to enter the clinic in both countries later this year and is applicable to the treatment of a large number of poorly served cancer indications.

Antibody-based drugs have become a mainstay of cancer treatment, but their use is limited to the small fraction of cancer targets that present as whole proteins on the cell surface. Most cancer targets are hidden inside cancerous cells where antibodies cannot reach them.

By contrast, T cells employ T Cell Receptors (TCRs) which target the peptide antigens found on the cell surface, as a marker of cancer and viral infection inside the cell. TCRs can potentially target any of the markers that are hallmarks of cancer and enables the development of drugs against cancers for which no antibody targets are known.

Unfortunately, the TCRs found naturally on the surface of killer T cells are primarily designed to recognise virallyinfected cells, and are often not sensitive enough to recognise cancer, which is then ignored by the immune system.

The scientists at Immunocore have managed to overcome this cancer recognition problem by boosting the ability of cancer-specific TCRs to bind to their targets with several million fold higher affinity than natural TCRs. The company has subsequently equipped these engineered TCRs with the ability to activate all the T cells of the body to kill cancer, even those that would normally not recognise cancer.

Immunocore calls this new class of therapeutics ImmTACs (Immune Mobilising mTCR Against Cancer). Dr Bent Jakobsen, Immunocore’s chief scientific officer, said: “The main hindrance to better cancer treatments is finding ways of targeting malignant cells without harming the body’s normal cells too much. This is where TCRs are uniquely compelling: for TCRs, there are potentially more targets available than for all other types of cancer treatments combined. However, for decades it has been thought that there was too little of each target on each cancer cell for it to be possible to make a reagent with which to find them. It’s a great pleasure, after 15 years of research by a dedicated team of scientists, to be able to say that we have finally solved this problem.”

Stem-cell success for heart attack study

A new type of stem cell-seeded patch has shown promising results in promoting healing after a heart attack, according to a study published in the journal Stem Cells Translational Medicine.

Studies have shown the potential of stem cells in regenerating heart tissue damaged during an attack. But even as the list of candidate cells for cardiac regeneration has expanded, none has emerged as the obvious choice, possibly because several cell types are needed to regenerate both the heart’s muscles and its vascular components.

Aside from the choice of the right cell source for tissue regeneration, the best way to deliver the stem cells is up for debate, too, as intravenous delivery and injections can be inefficient and possibly harmful. While embryonic stem cells have shown great promise for heart repairs due to their ability to differentiate into virtually any cell type, less than 10% of injected cells typically survive the engraftment and, of that number, generally only 2% actually colonise the heart.

In order for this type of treatment to be clinically effective, researchers need to find ways to deliver large numbers of stem cells in a supportive environment that can help cells survive and differentiate.

Researchers from the Faculty of Medicine of the Geneva University worked with colleagues at the Ecole Polytechnique Federale de Lausanne (EPFL) tried encouraging cardiaccommitted mouse embryonic stem cells (mESC) toward a cardiac fate using a protein growth factor called BMP2 and then embedded them into a fibrin hydrogel that is both biocompatible and biodegradable. The cells were loaded with superparamagnetic iron oxide nanoparticles so they could be tracked using magnetic resonance imaging, which also enabled the researchers to more accurately assess regional and global heart function.

The patches were engrafted onto the hearts of laboratory rats that had induced heart attacks. Six weeks later, the animals showed significant improvement over those receiving patches loaded with iron oxide nanoparticles alone. The patches had degraded, the cells had colonised the infarcted tissue and new blood vessels were forming in the vicinity of the transplanted patch. Improvements reached beyond the part of the heart where the patch had been applied to manifest globally.

Marisa Jaconi of the Geneva University Department of Pathology and Immunology and Prof Jeffrey Hubbell, professor of bioengineering at the EPFL, were leaders on the investigative team. Their findings could make a significant impact on how heart patients are treated in the future. Jaconi said: “Altogether, our data provide evidence that stem-cell based cardiopatches represent a promising therapeutic strategy to achieve efficient cell implantation and improved global and regional cardiac function after myocardial infarction.”

Helicopter transfer for trauma patients boosts survival rate

Seriously injured trauma patients transported to hospitals by helicopter are 16% more likely to survive than similarly injured patients brought in by ground ambulance, new Johns Hopkins research shows.

Study senior author Adil Haider, MD, MPH, an associate professor of surgery, anesthesiology and critical care medicine at the Johns Hopkins University School of Medicine, said: “We know helicopter trips are costly and carry some risks, but this research shows they do save lives. It also tells us that we need to sharpen our ability to identify trauma patients who need the helicopter most to ensure that we deploy the helicopter for people who really will benefit from its use.”

The research team used sophisticated analysis techniques to examine records from more than 223,000 patients 16 years of age and older from the 2007-2009 US National Trauma Data Bank. All patients sustained at least moderately severe injuries and were taken to trauma centres. The researchers compared the more than 161,500 patients who were transported by ambulance to the nearly 62,000 who were transported by helicopter. Among their conclusions was that one in 65 significantly injured patients brought to a Level I trauma centre by helicopter would die if ground transportation was the only option. doi:10.1001/jama.2012.467

US diabetes study suggests two drugs better than one

A study funded by the US National Institutes of Health (NIH) has found that a combination of two diabetes drugs, metformin and rosiglitazone, is more effective in treating youth with recentonset type 2 diabetes than metformin alone.

Adding an intensive lifestyle intervention to metformin provided no more benefit than metformin therapy alone. The study also found that metformin therapy alone was not an effective treatment for many of these youth. In fact, metformin had a much higher failure rate in study participants than has been reported in studies of adults treated with metformin alone.

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study is the first major comparative effectiveness trial for the treatment of type 2 diabetes in young people. TODAY was funded by the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of NIH. Philip Zeitler, MD PhD, the TODAY study chair and a paediatric endocrinologist at Children’s Hospital Colorado, said: “The results of this study tell us it might be good to start with a more aggressive drug treatment approach in youth with Type 2 diabetes.”

The study found that treatment with metformin alone was inadequate for maintaining acceptable, long-term, blood glucose control in 51.7% of youth over an average follow-up of 46 months. The failure rate was 38.6% in the metformin and rosiglitazone group, a 25.3% reduction from metformin alone. In the metformin plus lifestyle group the failure rate was 46.6%.

Currently, metformin is the standard treatment for young people with Type 2 diabetes and the only oral drug approved for this use by the US FDA. The longer a person has type 2 diabetes, the greater the likelihood of developing complications including coronary artery disease, stroke, kidney and eye disease, and nerve damage, making it critical for young people with type 2 diabetes to quickly achieve and sustain control of their blood glucose.

Barbara Linder, MD PhD, NIDDK senior advisor for childhood diabetes research, said: “Despite a rigorous lifestyle intervention, we were unable to achieve sustained lifestyle changes in these youth, though similar strategies have proven effective in adults. TODAY investigators will look more closely at those youth who succeeded in losing weight to better understand how to achieve effective lifestyle change in this population.”

Researchers turn heart attack scar tissue into heart muscle

Scientists at Duke University Medical Center have shown the ability to turn scar tissue that forms after a heart attack into heart muscle cells using a new process that eliminates the need for stem cell transplant. The study, published in the journal Circulation Research, used molecules called microRNAs to trigger the cardiac tissue conversion in a lab dish and, for the first time, in a living mouse, demonstrating the potential of a simpler process for tissue regeneration.

If additional studies confirm the approach in human cells, it could lead to a new way for treating many of the 23 million people worldwide who suffer heart failure each year, which is often caused by scar tissue that develops after a heart attack.

Victor J. Dzau, MD, a senior author on the study and Professor of Medicine and Chancellor of Health Affairs at Duke University, said: “This is a significant finding with many therapeutic implications. If you can do this in the heart, you can do it in the brain, the kidneys, and other tissues. This is a whole new way of regenerating tissue.”

To initiate the regeneration, Dzau's team used microRNAs – molecules that serve as master regulators controlling the activity of multiple genes. Tailored in a specific combination, the microRNAs were delivered into scar tissue cells called fibroblasts, which develop after a heart attack and impair the organ’s ability to pump blood. Once deployed, the microRNAs reprogrammed fibroblasts to become cells resembling the cardiomyocytes that make up heart muscle.

Neuroprosthesis restores hand movement after paralysis

An artificial connection between the brain and muscles can restore complex hand movements in monkeys following paralysis, according to a study published in the journal Nature.

Researchers describe how they combined two pieces of technology to create a neuroprosthesis – a device that replaces lost or impaired nervous system function. One piece is a multi-electrode array implanted directly into the brain which serves as a brain-computer interface (BCI). The array allows researchers to detect the activity of about 100 brain cells and decipher the signals that generate arm and hand movements. The second piece is a functional electrical stimulation (FES) device that delivers electrical current to the paralysed muscles, causing them to contract. The brain array activates the FES device directly, bypassing the spinal cord to allow intentional, brain-controlled muscle contractions and restore movement.

Super-sensitive tests could detect diseases earlier

Scientists have developed an ultra-sensitive test that should enable them to detect signs of a disease in its earliest stages, according to research published in the journal Nature Materials.

The scientists, from Imperial College London and the University of Vigo, have created a test to detect particular molecules that indicate the presence of disease, even when these are in very low concentrations.

There are already tests available for some diseases that look for such biomarkers using biological sensors or ‘biosensors’. However, existing biosensors become less sensitive and predictable at detecting biomarkers when they are in very low concentrations, as occurs when a disease is in its early stages.

Professor Molly Stevens, senior author of the study from the Departments of Materials and Bioengineering at Imperial College London, said: “It is vital to detect diseases at an early stage if we want people to have the best possible outcomes – diseases are usually easier to treat at this stage, and early diagnosis can give us the chance to halt a disease before symptoms worsen. However, for many diseases, using current technology to look for early signs of disease can be like finding the proverbial needle in a haystack. Our new test can actually find that needle. We only looked at the biomarker for one disease in this study, but we’re confident that the test can be adapted to identify many other diseases at an early stage.”

New autism diagnosis time reduced by 95% through online assessment

With the recent rise in incidence autism spectrum disorder to 1 in 88 children, the need for accurate and widely deployable methods for screening and diagnosis is substantial. Dennis Wall, associate professor of pathology and director of Computational Biology Initiative at the Centre for Biomedical Informatics at Harvard Medical School, has been working to address this problem and has discovered a highly accurate strategy that could significantly reduce the complexity and time of the diagnostic process.

Wall has been developing algorithms and associated deployment mechanisms to detect autism rapidly and with high accuracy. The algorithms are designed to work within a mobile architecture, combining a small set of questions and a short home video of the subject, to enable rapid online assessments. This procedure could reduce the time for autism diagnosis by nearly 95% – from hours to minutes, and could be easily integrated into routine child screening practices to enable a dramatic increase in reach to the population at risk.

Wall explained that the current autism diagnosis process, including the Autism Diagnostic Interview, Revised, known as the ADI-R, a 93-question questionnaire, and the Autism Diagnostic Observation Schedule, known as the ADOS exam, can take up to three hours to complete and must be administered by a trained clinician. Often, there is a delay of more than a year between initial warning signs and diagnosis because of the waiting times to see a clinical professional who can administer the tests and deliver the formal diagnosis.

Using machine learning techniques, Wall and his team found that only seven questions were sufficient to diagnose autism with nearly 100% accuracy, equivalent to the full 93-question exam. They validated the accuracy of the seven question survey against answers from more than 1,600 individuals from the Simons Foundation and more than 300 individuals from the Boston Autism Consortium.

Wall applied similar techniques to the ADOS exam, this time classifying more than 1,050 individuals with near perfect sensitivity and slightly less than 95% specificity. The outcome of this work was not only a shortened mechanism for evaluating a child (8 out of 29 steps), but also a roadmap for evaluating short homevideo clips.

Wall has made a survey and video site available to the public for free to continue evaluating the effectiveness of the shortened approaches. His team has also launched a Facebook page to spread the word and to share the survey more broadly. To date, 2,500 people have taken the Autworks survey.

Autworks survey

Doctors recommend unnecessary cancer screening for the old

A significant number of physicians would recommend colorectal cancer screening for elderly patients with a severe illness, according to David Haggstrom from the Richard L. Roudebush VA Medical Center in Indianapolis in the US and his team. Such patients would not benefit from the procedure and, in fact, unnecessary screening may do more harm than good. Their work appears online in the Journal of General Internal Medicine.

Medical evidence does not indicate that colorectal cancer screening has any benefit among patients with limited life expectancy. Although guidelines recommend screening for patients aged 50 years and older, elderly patients with severe illnesses are unlikely to benefit from early cancer detection.

Haggstrom and colleagues explored whether colorectal cancer screening decisions are influenced by the patient's age and state of health. They surveyed 1,266 physicians - a mix of general internal medicine, family practice and obstetricsgynaecology physicians – between September 2006 and May 2007. The physicians were given nine patient scenarios that varied the patient's age and existing illness. Patient age was split into three categories: age 50, 65 and 80. There were three underlying illness states: healthy patient with no illness; patient with moderately severe illness (ischemic cardiomyopathy*); and patient with severe illness (advanced lung cancer). For each vignette, the physicians were asked which screening test they would recommend, if any.

Overall, the more serious the underlying illness, the less likely physicians were to recommend screening. The likelihood of recommending screening also fell with a patient’s advancing age. In addition, the healthier the patient, the more likely physicians were to recommend more invasive screening e.g. colonoscopy versus non-invasive tests such as faecal occult blood testing (FOBT).

However, 25% of primary care physicians recommended colorectal cancer screening for an 80-year-old patient with advanced lung cancer who would not benefit.

Interestingly, physicians who were obstetrics-gynaecology physicians were more likely to recommend colorectal cancer screening for 80-year-old patients with advanced lung cancer than other physicians. Physicians who had access to electronic medical records were less likely to recommend screening of elderly patients with severe illness.

The authors conclude: “Most physicians appear to shift their recommendations in an appropriate manner in response to varying patient age and underlying illness. Yet there is a significant proportion of outliers who recommend screening among patients with limited life expectancy, for whom screening tests have no benefit and are potentially harmful. Further work is needed to better understand how physicians can develop more confidence in stopping screening when there is no clinical benefit, as well as quantifying the impact of over-screening with risky procedures on patient outcomes.”

doi: 10.1007/s11606-012-2093-6


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