Culprit found for increased stroke injury with diabetes

ScienceDaily (Jan. 24, 2011) — Strokes are a leading cause of mortality and adult disability. Those that involve intracerebral hemorrhage (bleeding in the brain) are especially deadly, and there are no effective treatments to control such bleeding. Moreover, diabetes and hyperglycemia (high blood glucose levels) are associated with increases in bleeding during hemorrhagic stroke and worse clinical outcomes.

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But Joslin Diabetes Center researchers now have identified one key player that contributes to this increased bleeding, a discovery that may pave the way toward treatments that minimize adverse stroke outcomes both for people with pre-existing diabetes and those with hyperglycemia identified at the time of stroke.

Studies in the lab of Joslin Investigator Edward Feener, Ph.D., pinpointed a new mechanism involving a protein called plasma kallikrein that interferes with the normal clotting process in the brain following blood vessel injury with diabetes. Their work is reported online in the journal Nature Medicine.

The scientists began by injecting a small amount of blood into the brains of rats with diabetes and of control animals without diabetes. The difference was dramatic -- the diabetic animals bled over a much greater area of the brain.

Work in the Feener lab had previously implicated plasma kallikrein in diabetic eye complications. When the experimenters pre-treated the diabetic animals with a molecule that inhibits the protein's effects, brain damage from the blood injections dropped to levels similar to that in the control animals. Conversely, when pure plasma kallikrein was injected into the brain, it produced little impact on the control animals but rapidly increased major bleeding in the animals with diabetes.

Further studies by the Joslin researchers showed that normalizing blood glucose levels in diabetic animals could block the effect from plasma kallikrein, and that rapidly inducing hyperglycemia in control animals mimicked the effects of diabetes on brain hemorrhage. This suggests that high blood sugar at the time of brain hemorrhage, rather than diabetes per se, is responsible for the increased bleeding.

"Given the prevalence of strokes and the damage they inflict, these findings are exciting because they suggest the possibility that rapid control of blood sugar levels may provide an opportunity to reduce intracerebral hemorrhage, which is a clinical situation that has very limited treatment options," says Dr. Feener, who is also an associate professor of medicine at Harvard Medical School. "This work could have broad implications since about half of patients with acute hemorrhagic stroke have hyperglycemia, whether or not they have pre-existing diabetes."

The work also raises the possibility of developing drugs that target plasma kallikrein and may provide protective measures in people with diabetes or others at high risk for stroke. Such drugs might also prove useful for patients suffering from the more common ischemic strokes, which usually begin as blocked vessels in the brain but can transform into hemorrhages.

Surprisingly, while plasma kallikrein has been studied for decades, the Joslin scientists found that the protein boosts brain bleeding through a previously unknown mechanism -- by blocking platelet activation near damaged blood vessels.

Joslin's Jia Liu and Ben-Bo Gao were co-lead authors on the Nature Medicine paper. Other contributors include Joslin's Allen Clermont, and Price Blair and Robert Flaumenhaft of Beth Israel Deaconess Medical Center, and Tamie Chilcote and Sukanto Sinha of ActiveSite Pharmaceuticals. Lead funding came from the National Institutes of Health and the American Heart Association.

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A psychopath lacks empathy just like a person with frontal head injury, study suggests

ScienceDaily (Jan. 25, 2011) — People diagnosed as psychopathic have difficulty showing empathy, just like patients who have suffered frontal head injury. This has been shown in a new study from the University of Haifa. "Our findings show that people who have psychopathic symptoms behave as though they are suffering frontal brain damage," said Dr. Simone Shamay-Tsoory, who conducted the study.

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Psychopathy is a personality disorder that finds expression in extreme anti-social behavior and intentional harm to others, including a lack of compassion and empathy. An existing explanation for such behavior suggests inability to comprehend the existence of emotions in others. However, the fact that many psychopaths act with sophistication and deceit with intention to harm others, indicates that they actually have a good grasp of the mental capacity of others -- and are even capable of using that knowledge in order to cause them harm.

Earlier research by Dr. Shamay-Tsoory has examined individuals with frontal head injury, i.e., damage to parts of the brain that are responsible for emotional functioning. She has shown that people suffering this type of brain damage have difficulty showing empathy. Having observed similar emotional deficiency in psychopathic behavior, she set out to see if there is in fact a similarity between the two cases.

The current study assessed 17 people who had been diagnosed by psychiatrists as psychopathic -- and not suffering from any known brain damage; and another 25 individuals suffering frontal lobe injury. Each of the participants underwent a computerized test examining cognitive ability to recognize feelings in another and the ability to demonstrate empathy for another's emotions. They were also tested to gage their capacity to understand another's thoughts. The results of these tests showed that both groups demonstrated a similar difficulty in showing empathy, while two control groups of individuals with no known mental disorders or brain damage and individuals with non-frontal brain damage both showed different results with positive empathy capabilities.

"Seeing as psychopathic behavior is similar to that of a person with brain damage, it could be that it could benefit from similar forms of treatment," Dr. Shamay-Tsoory noted.

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New U.S. national study finds boxing injuries on the rise; Youth head injury rates also concerning

ScienceDaily (Mar. 2, 2011) — The risk and nature of injury in the sport of boxing has generated a great deal of controversy in the medical community, especially in relation to youth boxing. A new study, conducted by researchers in the Center for Injury Research and Policy of The Research Institute at Nationwide Children's Hospital, examined boxing injuries among participants 6 years of age and older from 1990 to 2008.

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During the 19-year study period, an average of 8,700 boxing injuries were treated in United States emergency departments each year, and approximately 2,500 of those injuries were to children and adolescents 6 to 17 years of age. The number of boxing injuries each year increased 211 percent during the study, climbing from 5,361 injuries in 1990 to nearly 17,000 injuries in 2008.

According to the study, released online February 28, 2011 by the American Journal of Preventive Medicine, the most common injury diagnosis was a fracture (28 percent). The hand was the most frequently injured body region (33 percent), followed by the head and neck (23 percent). While the majority of injuries occurred at a sports or recreation facility (54 percent), one-third of the injuries (34 percent) occurred at home.

The most concerning discovery from the study was the similar proportion of concussions/closed head injuries (CHIs) among the age groups (9 percent among 12-17 year olds, 8 percent among 18-24 year olds and 9 percent among 25-34 year olds).

"We expected a smaller proportion of concussions/CHIs among younger boxers, since they generate a lower punch force," said Gary Smith, MD, DrPH, senior author of the study and director of the Center for Injury Research and Policy at Nationwide Children's Hospital. "The fact that young boxers are experiencing a similar proportion of concussions and CHI's as older boxers is extremely concerning given the potential risk of developing chronic traumatic encephalopathy (CTE) with repetitive brain trauma. These repetitive blows to the head may be placing boxers under 18 years of age at risk for neurological impairment and psychological problems due to CTE."

The findings from this study support the position of medical societies that oppose boxing, especially among youth.

"Although there is risk of injury with most sports, boxing is unique because participants are rewarded for intentionally striking their opponent in the face and head with the intent of harming or incapacitating them," said Dr. Smith, also a professor of Pediatrics at The Ohio State University College of Medicine. "The increasing number of boxing injuries, coupled with the potential long-term consequences of these injuries, suggests that increased injury prevention efforts are needed."

This is the first nationally representative study to examine boxing injuries treated in emergency departments. Data for this study were obtained from the National Electronic Injury Surveillance System (NEISS), which is operated by the U.S. Consumer Product Safety Commission. The NEISS dataset provides information on consumer product-related and sports and recreation-related injuries treated in hospital emergency departments across the country. Boxing participation data were obtained from the Superstudy of Sports Participation.

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Self-administered light therapy may improve cognitive function after traumatic brain injury

ScienceDaily (Mar. 18, 2011) — At-home, daily application of light therapy via light-emitting diodes (LEDs) placed on the forehead and scalp led to improvements in cognitive function and post-traumatic stress disorder in patients with a traumatic brain injury (TBI), according to a groundbreaking study published in Photomedicine and Laser Surgery, a peer-reviewed journal published by Mary Ann Liebert, Inc.

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Margaret Naeser, PhD, LAc, VA Boston Healthcare System, Boston University School of Medicine, and colleagues from Massachusetts General Hospital, and Harvard-MIT Division of Health Sciences and Technology, in Boston, and MedX Health Inc. (Mississauga, ON, Canada), report on the use of transcranial LED-based light therapy to treat two patients with longstanding traumatic brain injury (TBI). Each patient applied LEDs nightly and demonstrated substantial improvement in cognitive function, including improved memory, inhibition, and ability to sustain attention and focus. One patient was able to discontinue medical disability and return to full-time work. These cognitive gains decreased if the patients stopped treatment for a few weeks and returned when treatment was restarted. Both patients are continuing LED treatments in the home. The findings are presented in "Improved Cognitive Function After Transcranial, Light-Emitting Diode Treatments in Chronic, Traumatic Brain Injury: Two Case Reports."

Low-level light therapy using lasers or externally placed LEDs to deliver red and near-infrared (NIR) light energy has been shown in cell-based studies to improve cellular metabolism and to produce beneficial physiological effects. In acute stroke in humans, for example, transcranial NIR light therapy applied less than 24 hours post-stroke was associated with improved outcomes.

"The results of this study will provide a basis for future therapeutic use of phototherapy to improve recovery after injury and facilitate management of other CNS disorders. The development of novel therapies to restore function after neurologic injury, stroke, or disease is an increasingly important goal in medical research as a result of an increase in non-fatal traumatic wounds and the increasing prevalence of dementias and other degenerative disorders in our aging population," says Raymond J. Lanzafame, MD, MBA, Editor-in-Chief of the Journal.

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Anti-depressants boost brain cells after injury in early studies

ScienceDaily (Apr. 22, 2011) — Anti-depressants may help spur the creation and survival of new brain cells after brain injury, according to a study by neurosurgeons at the University of Rochester Medical Center.

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Jason Huang, M.D., and colleagues undertook the study after noticing that patients with brain injuries who had been prescribed anti-depressants were doing better in unexpected ways than their counterparts who were not taking such medications. Not only did their depression ease; their memory also seemed improved compared to patients not on the medication.

"We saw these patients improving in multiple ways -- their depression was improved, but so were their memory and cognitive functioning. We wanted to look at the issue more, so we went back to the laboratory to investigate it further," said Huang, associate professor of Neurosurgery and chief of Neurosurgery at Highland Hospital, an affiliate of the University of Rochester Medical Center.

The team's findings were published online recently in the Journal of Neurotrauma.

Huang said many patients who have a traumatic brain injury also experience depression -- by some estimates, half of such patients are depressed. Doctors aren't sure whether the depression is a byproduct of the sudden, unfortunate change in circumstances that patients find themselves in, or whether the depression is a direct consequence of brain damage.

Previous research by other groups indicated that anti-depressants help generate new brain cells and keep them healthy in healthy animals. That, together with the experience of his patients, led Huang to study the effects of the anti-depressant imipramine (also known as Tofranil) on mice that had injuries to their brains.

Scientists found that imipramine boosted the number of neurons in the hippocampus, the part of the brain primarily responsible for memory. By one measure, mice treated with imipramine had approximately 70 percent more neurons after four weeks than mice that did not receive the medication.

That change was borne out on behavioral tests as well. The team tested mice by using what scientists call a novel object recognition test. Like human infants, mice tend to spend more time sizing up objects that they haven't encountered before -- or don't remember encountering -- than they do objects that they've seen before. This gives scientists a way to measure a mouse's memory.

The team found that mice that had been treated with imipramine had a better memory. They were more likely to remember objects they had seen previously and so spent more time exploring truly novel objects, compared to mice that did not receive the compound.

The benefits did not extend to the motor skills of the mice -- a finding that parallels what neurosurgeons like Huang have seen in their patients on anti-depressants, who don't show improved mobility after use of the medications.

Scientists aren't sure whether the drug helps spur the creation of more new neurons, or whether it helps newly created neurons survive -- or both. Some of the team's evidence indicates that the drug helps immature stems evolve into useful cells such as neurons and astrocytes, and to travel to the exact areas of the brain where they're needed.

In addition to sorting out those questions, investigators will try to identify the molecular pathway that prompts the brain to create more neurons in response to anti-depressants. The team suspects that a molecule known as BDNF or brain-derived neurotrophic factor may play a role.

Huang notes that one of his mentors, co-author Douglas H. Smith, M.D., of the University of Pennsylvania, has found that a brain injury itself also seems to prompt the brain to create more brain cells, perhaps as a way to compensate for injury.

"The brain has an intrinsic mechanism to repair itself to a certain extent," said Huang. "Our goal is to learn more about that mechanism and improve it, to help patients recover even more brain function than they can now, even with extensive work and rehabilitation."

Some of Huang's work is based on his experiences treating soldiers and civilians while working for four months as a neurosurgeon with the U.S. Army Reserve in Iraq, as well as more than a decade of experience treating patients affected by incidents like motor vehicle accidents.

He said that traumatic brain injury -- an injury experienced by approximately 1.4 million Americans each year -- must be treated aggressively. Often this involves surgery to relieve pressure on the brain, other procedures to protect the brain against immediate further injury, and then rehabilitation for months or years.

"It's exciting that the study involves a drug that is already safe and approved by FDA and is used clinically. If we could add a medication to the treatment regimen -- even a slight improvement would be a big gain for these patients. It's our hope that the work will ultimately make a difference in patient care," added Huang, who is also a scientist in the Center for Neural Development and Disease.

In addition to Huang, other authors at Rochester include post-doctoral associates Xiaodi Han, M.D., Ph.D., Jing Tong, M.D., and Jiankai Yang, M.D.; neurosurgery resident Arash Farahvar, M.D.,; and undergraduate Ernest Wang. Other authors include Jun Zhang, M.D., of the Chinese PLA General Hospital in Beijing; Uzma Samadani, M.D., Ph.D., of New York University; and Douglas H. Smith, M.D., of the University of Pennsylvania.

The work was funded by the National Institute of Neurological Disorders and Stroke and by the University of Rochester.

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Protein and calories can help lessen effects of severe traumatic brain injury, report says

ScienceDaily (Apr. 21, 2011) — To help alleviate the effects of severe traumatic brain injury (TBI), the U.S. Department of Defense should ensure that all military personnel with this type of injury receive adequate protein and calories immediately after the trauma and through the first two weeks of treatment, says a new report from the Institute of Medicine. Evidence from several studies of severely brain-injured patients shows that providing energy and protein to patients early reduces inflammation and improves their outcomes, said the committee of experts who wrote the report.

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This is the only nutrition-related approach to treating TBI that the committee recommended DOD implement at this time based on its review of the possible benefits of nutrients, dietary supplements, and specific diets to improve outcomes for TBI ranging from mild to severe. Several other nutritional approaches show potential for reducing the symptoms of brain injury, but there is not yet enough evidence about their effectiveness to recommend their adoption.

The committee identified the B vitamin choline, the amino acid-like compound creatine, n-3 fatty acids commonly known as EPA and DHA, and zinc as the most promising areas of investigation and recommended that DOD scientists and other researchers give them priority attention. These approaches are ones for which human clinical trials have been undertaken or are ongoing.

Other approaches, including antioxidants, flavonoids, ketogenic diets, and vitamin D, have less supporting evidence that has come solely from animal studies or from studies in people with different conditions. Although researchers must prioritize resources, DOD should continue to monitor the clinical literature for any new findings about the potential of these nutrients and diets in lessening brain injury effects, the report says.

The research priorities outlined in the report could generate information that provides health professionals with a fuller picture of which nutrients and dietary approaches work safely and most effectively. This information could also lead to new evidence-based clinical guidelines. There are few well-supported guidelines to inform health professionals' use of foods and dietary supplements to treat brain-injured patients, so clinicians employ a wide range of practices.

The IOM study focused on the potential role of nutrition in protecting against or treating the immediate and near-term effects of TBI. It did not evaluate the role of nutritional therapies in the rehabilitation phase or address long-term health effects associated with brain trauma, such as post-traumatic stress disorder, Alzheimer's disease, pain, and depression. A review of nutrition approaches to lessen long-term effects of TBI would be useful, the committee noted.

TBI is a significant cause of death and disability among personnel serving in the wars in Iraq and Afghanistan. It also contributes to nearly one-third of all injury-related deaths in the United States, making it a major health concern for the civilian population as well. According to recent estimates, between 1.6 million and 3.8 million sports-related TBIs occur annually, including those not treated by a health care provider.

The study was sponsored by the U.S. Army Medical Research and Materiel Command of the U.S. Department of Defense. Established in 1970 under the charter of the National Academy of Sciences, the Institute of Medicine provides independent, objective, evidence-based advice to policymakers, health professionals, the private sector, and the public. The National Academy of Sciences, National Academy of Engineering, Institute of Medicine, and National Research Council make up the National Academies.

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CT scans are frequently unnecessary after head injury in children, large study finds

ScienceDaily (May 9, 2011) — Overall, roughly half of U.S. children taken to hospital emergency departments (EDs) for a head injury receive a head CT scan, often to ease worried parents' concerns. Yet true traumatic brain injury is uncommon. A multi-center study of more than 40,000 children with minor blunt head trauma, led by Children's Hospital Boston and UC Davis, shows that allowing a period of observation can reduce the use of head CT by as much as half without compromising care -- and without exposing children to ionizing radiation.

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Results appear in the June 2011 issue of Pediatrics (published online May 9).

"Only a small percentage of children with blunt head trauma really have something serious going on," says Lise Nigrovic, MD, MPH, of Children's Hospital Boston, who co-led the study with Nathan Kuppermann, MD, MPH, chair of the Department of Emergency Medicine at UC Davis. "If you can be watched in the ED for a few hours, you may not need a CT."

This change in practice would not only be cost-saving, but is better medicine, the researchers say.

Nigrovic, Kuppermann and colleagues analyzed the outcomes of children presenting at 25 different emergency departments, as part of a large prospective study conducted by the Pediatric Emergency Care Applied Research Network (PECARN). Of 40,113 children whose records could be analyzed, 5,433 (14 percent) were observed before making a decision about CT use. Observation times varied, as did the severity of head trauma.

Overall, the children who were observed had a lower rate of CT than those not observed (31 vs. 35 percent). When the researchers matched the observed and non-observed groups for severity of head injury and the practice style of different hospitals, this difference was more pronounced: The likelihood of a CT scan in the observed group was about half that of similar non-observed patients (odds ratio, 0.53). In particular, children whose symptoms improved during observation were less likely to eventually have CT.

Allowing for an observation period did not compromise safety, the study found: Clinically important traumatic brain injury -- resulting in death, neurosurgical intervention, intubation for more than 24 hours or hospital admission for two nights or more -- was equally uncommon in the observed and non-observed groups (0.75 vs. 0.87 percent).

Nigrovic and Kuppermann note that cranial CT itself presents additional risks for children. Children's growing brain tissue is more sensitive to ionizing radiation than adults', and because of their longer life expectancy, their lifetime risk of developing a radiation-induced malignancy is greater.

"CT isn't bad if you really need, but you don't want to use it in children who are at low risk for having a significant injury," says Nigrovic. "For parents, this means spending a couple of extra hours in the ED in exchange for not getting a CT. It's the children in the middle risk groups -- those who don't appear totally normal, but whose injury isn't obviously severe -- for whom observation can really help."

The researchers were unable to determine the actual length of time the children were observed in the ED, a question they would like to investigate in the future. Practice guidelines from the American Academy of Pediatrics recommend a child be carefully observed for 4 to 6 hours after injury.

"There is a clear need to develop appropriate and safe guidelines for decreasing the number of inappropriate head CT scans that we do on children," says Kuppermann. "The results of this analysis demonstrate that a period of observation before deciding to use head CT scans on many injured children can spare children from inappropriate radiation when it is not called for, while not increasing the risk of missing important brain injuries."

Nigrovic offers the following general guidelines for parents whose child has a head injury:

Check with your primary care clinician before taking the child to the ED. If your child has headache, vomiting and/or confusion, or symptoms that worsen over time, an ED visit is appropriate. The ED clinician may reasonably choose to observe your child for several hours once you arrive before deciding about a head CT. The change of symptoms over time is an important factor in deciding whether to obtain a cranial CT.

The study was funded by the Health Resources and Services Administration/Maternal and Child Health Bureau, Division of Research, Training, and Education, and the Emergency Medical Services of Children Program.

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