Cerebral Malaria Linked To Epilepsy, Behavior Disorders

Almost a third of cerebral malaria survivors developed epilepsy or other behavioral disorders in the most comprehensive study to date of the disease in African children, solidifying the link between malaria and neuropsychiatric disorders that affect hundreds of thousands of children.

The research – led by Gretchen Birbeck, an associate professor of neurology and ophthalmology in Michigan State University’s College of Osteopathic Medicine – appears in the current edition of The Lancet Neurology.

Cerebral malaria is a severe form of malaria affecting the brain, occurring predominantly in children, with a mortality rate of 15-25 percent. It affects about one million children every year, primarily in sub-Saharan Africa.

“Our findings show that children with cerebral malaria are at risk of developing several adverse neurological outcomes including epilepsy, disruptive behavior disorders and disabilities characterized by motor, sensory or language deficits,” said Birbeck, also director for the International Neurologic & Psychiatric Epidemiology Program. “Specifically, the modifiable risk factors for these disorders in children with cerebral malaria are acute seizures and extreme fevers.”

Since most of the neurologic effects did not present themselves immediately, they were not evident at the time of the child’s discharge from the hospital after the initial malaria illness.

“But if the findings of our study are generalized, then about 135,000 African children younger than 5 years develop epilepsy due to cerebral malaria-induced brain injury each year, and cerebral malaria may be one of the more common causes of epilepsy in malaria-endemic regions,” she said.

The study looked at several hundred children during a nearly five-year period in Blantyre, Malawi; it was the first-ever prospective study of cerebral malaria survivors that included a control group. The study was funded by the National Institutes of Health and the Wellcome Trust.

The impact of the findings on African society is immeasurable, Birbeck said.

“The long-term loss of human potential from these disorders is mind-boggling,” she said. “Yes, these children are surviving the malaria, but their quality of life and what they contribute to society is severely hampered. There is a huge burden of post-malaria neurological disorders.”

But Birbeck said there are steps that can be taken.

“We need to be more aggressive in treating the two major risk factors: seizures and high fever,” she said, adding that the next step will be to start clinical trials to identify treatments aimed at better seizure and fever control.

Previous studies of neurological consequences related to cerebral malaria have been limited by poor retention rates, lack of follow-up and assessments that were stopped when the results of neurological examinations were normal.

Also, cerebral malaria is challenging to diagnose definitively. However, researchers from MSU and the University of Liverpool in England previously had discovered that diagnosing malaria retinopathy – a set of abnormalities in the eye’s retina – greatly enhances the ability to diagnose cerebral malaria. Thus, as part the study published in The Lancet Neurology, Birbeck and her team only looked at children with retinopathy-positive cerebral malaria.

Terrie Taylor, an MSU University Distinguished Professor and co-author on the paper, spends six months each year battling malaria at the Queen Elizabeth Central Hospital in Blantyre, Malawi.

“The challenge now is to devise better treatments during the cerebral malaria episode in hopes of minimizing the risk of epilepsy in years to come,” she said.

Birbeck said MSU’s continued and dedicated presence in Africa is what allows such research to be done.

“The long-term relationships that have been established with ministries of health, medical schools and investigators allow us to bring our expertise to the table,” she said.

Source:
Jason Cody
Michigan State University

Risks Associated With Used Football Faceshields

Game-worn football faceshields are more susceptible to breaking when subjected to high-velocity impact than are new faceshields, according to recent research.

In the study, researchers used an air cannon to hurl baseballs at new and used polycarbonate faceshields. All of the new shields withstood the strongest impact tested, which was designed to match the force of a kick to the face. More than a third of the game-worn faceshields fractured in response to the testing, which included lower forces of impact as well.

In a related survey of college football equipment managers, the researchers found that 98 percent of football programs allow faceshield use, while 18 percent of the players wear a shield. Of the programs that responded, only 21 percent require the use of a faceshield in players with poor vision in one eye. Half of the respondents reported that their school had established a replacement policy for the shields.

The combination of findings led the Ohio State University scientists to recommend that intercollegiate football programs develop a policy for routine inspection and replacement of used faceshields. The researchers also said that coaches or trainers should strongly recommend that football players with poor vision in one eye wear a faceshield during all practices and games.

The most common cause of poor vision in a single eye among children and middle aged adults is a disorder called amblyopia, also known as lazy eye, which affects up to 3 of every 100 children, according to the National Eye Institute. Because the disorder originates in the area of the brain that controls vision, loss of vision in the affected eye can become permanent if it is not treated before about age 8.

“Any football player who has a vision problem should consider wearing a faceshield,” said Aaron Zimmerman, assistant professor of optometry at Ohio State and lead author of the study. “Something could happen to their good eye. Why take a chance, especially if there’s a way to prevent that?”

The research is published in a recent issue of the journal Optometry.

This study is a follow-up to a previous Ohio State study that determined that the two most popular brands of football helmet faceshields could withstand a hit equivalent to a kick in the face and provide that protection without disrupting players’ vision.

In this more recent study, the researchers sought to determine how the faceshields performed after the rigors of standard football action, as well as exposure to sun or freezing temperatures. The group also sent a survey to equipment managers at 117 Division 1 Football Bowl Subdivision programs in the National Collegiate Athletic Association. Fifty-nine managers responded – a 50-percent response rate.

In the tests of structural integrity, a baseball was used to mimic the hardness and curvature of the toe end of a cleat or a fist. The scientists tested the two most popular collegiate and professional football helmet faceshields by manufacturers Oakley, based in Foothills Ranch, Calif., and Nike, based in Beaverton, Oregon. The average cost is $45 to $50 per shield.

Using game-worn shields donated by two football programs, the researchers tested their impact resistance at five velocities ranging from almost 150 miles per hour to 116 miles per hour. The highest velocity equated to an impact force of about 2,500 Newtons, or 562 pounds of force – comparable to the force generated by an adult soccer player kicking a ball. The lowest velocity equated to an impact force of about 1,933 Newtons, or almost 435 pounds of force.

For this impact study, the scientists randomly assigned groups of the donated used shields to each of the velocity levels. At the highest velocity, 10 faceshields fractured. Three shields broke at the middle-range velocities, and one shield broke at the lowest velocity.

Zimmerman and colleagues also subjected 24 new faceshields to sunlight for an average of 3 ?? hours per day and five days per week for 10 weeks to mimic exposure to ultraviolet radiation during a football season. Previous research has suggested that solar radiation can weaken polycarbonate. None of these shields broke when impact-tested at velocities of 150 miles per hour.

In a small sample of game-worn faceshields exposed to freezing temperatures of 14 degrees Fahrenheit for one hour, four of five used shields broke when tested at velocities of about 130 miles per hour.

Many of the shields that fractured showed the most stress on the sides, where the faceshields attach to the helmet. But a few shattered into multiple pieces that had potential to tear the retina or even penetrate the eye.

“Based on the results, we felt that multiple impacts to shields were probably the likely cause for the lower resistance to impact over time,” Zimmerman said. “No matter what the cause is, you do not want to have a protective device fail and potentially cause a more severe injury.”

The survey of football equipment managers confirmed for the researchers that no universal guidelines exist for inspecting and replacing faceshields to prevent such equipment failures.

Forty-one percent of the programs had established faceshield-related policies for players with poor vision in one eye: 21 percent required the use of faceshields for those players, and 20 percent recommended faceshields. Fifty percent of the programs had established replacement policies for the faceshields, and a fourth of the programs instructed players to inspect their own shields for signs of damage.

Use of the faceshields in most cases is driven by player choice, according to the survey. Fifty-two percent of programs approve the use of a faceshield if a player asks for one. The rest of the programs require approval from a trainer, coach or team physician.

The main reason players ask for faceshields, according to the survey: About half of the players want to wear them because the shields look good and resemble the equipment worn by professional football players. More than a third use the faceshields for general protection, 11 percent are protecting their eyes from a repeat injury, and 1.5 percent of players have good vision in only one eye.

About 70 percent of programs issue new faceshields at the start of a season. A little over half of the programs replace faceshields that show a small scratch or crack, and about one-third replace faceshields only if the scratch or crack is considered substantial. Ten percent of the programs replace faceshields only when the player’s vision is impaired by a damaged shield. One manager reported that players receive a new faceshield for every game.

Faceshields have been recommended for younger football players for more than a decade. The sports safety committees of the American Academy of Pediatrics and the American Academy of Ophthalmology issued a report in 1996 recommending that football helmets be equipped with a polycarbonate faceshield for face and eye protection. They were responding to a 1993 report by Prevent Blindness America indicating that football was the fifth-greatest contributor to sports-related eye injuries in patients younger than 25.

“We feel that each institution should have some sort of similar policy,” Zimmerman said. “Once a week the shields should be inspected, particularly where they fasten to the helmet. But players should be encouraged to glance a faceshield over before each practice and game. And if there’s a deep scratch or crack present, it definitely needs to be replaced.”

Notes:

The impact testing was performed at ICS Laboratories Inc. in Brunswick, Ohio.

Zimmerman conducted the study with co-authors Gregory Good of the College of Optometry and ophthalmologists W. Randy McLaughlin and Steven Katz of the Havener Eye Institute, all at Ohio State.

Source:
Aaron Zimmerman

Ohio State University

Study Finds Lack Of Diffusible VEGF Growth Factor Can Cause Retinal Defects Similar To Dry Macular Degeneration

Scientists at Schepens Eye Research Institute have found that when the eye is missing a diffusible form of vascular endothelial growth factor (VEGF), i.e. one that when secreted can reach other cells at a distance, the retina shows defects similar to “dry” macular degeneration, also called geographic atrophy (GA). This finding, published in the November 3, 2009 print edition of PNAS (Proceedings of the National Academy of Sciences), not only increases the understanding of the causes of this blinding disease, but it may also impact the use of anti-VEGF drugs, such as Lucentis, which are designed to neutralize VEGF in eyes with “wet” macular degeneration.

“These results are significant for several reasons. We know little about what causes GA or how to treat it. Our discovery may be an important piece of the puzzle. It shows that reduced VEGF from the retinal pigment epithelium (RPE), the bottommost layer of the retina, to the choriocapillaris (CC) – the small blood vessels beneath retina– leads to degeneration of the CC. Therefore, the continuous blockage of VEGF may contribute to the development of or a worsening of GA,” says Patricia D’Amore, principal investigator of the study and senior scientist at Schepens.

VEGF is a protein that stimulates the growth of new blood vessels. The eye produces several different forms of VEGF that differ in their size and their ability to move away from the producing cell.

Age-related macular degeneration (AMD) is a disease that destroys the macula, the central part of the retina responsible for detailed vision needed for reading, driving and face recognition. It comes in two types–“wet” and “dry.” In wet AMD, a pathological overproduction of VEGF leads to the development of abnormal blood vessels, which leak and damage the retina. Wet AMD can be treated with some success with anti-VEGF drugs that block abnormal blood vessel growth and leakage. Dry macular degeneration develops less rapidly, and is related to an accumulation of debris under the retina that can advance to GA where RPE and underlying vessels are lost.

Knowing that the RPE in the adult produced VEGF, the Schepens team hypothesized that in a healthy individual, the RPE produces forms of VEGF that, when secreted, can move away from the RPE and reach the underlying CC to support its function and survival. The CC vessels are extremely important as they supply the photoreceptors (the light- and color-sensitive cells in the macula) with oxygen and nutrients necessary for vision.

In the PNAS study, the researchers tested their hypothesis using a genetic mouse model in which the RPE produced a form of VEGF that was unable to diffuse. As the mice aged, they began to display an age-dependent degeneration of both the CC and RPE, culminating with the death of photoreceptors and vision loss, similar to that observed in GA.

The next step in the research, according to the first author Dr. Magali Saint-Geniez, is to determine if this model can be used to investigate the role of RPE-CC interaction in AMD and to design new therapies.

Authors of the study include: Magali Saint-Geniez(1)(2), Tomoki Kurihara(1), Eiichi Sekiyama(1)(2), Angel E. Maldonado(1), and Patricia A. D’Amore(1),(2),(3).

(1) Schepens Eye Research Institute and the Departments of (2)Ophthalmology and (3)Pathology Harvard Medical School.

Schepens Eye Research Institute is an affiliate of Harvard Medical School and the largest eye research institute in the natio.

Source: Schepens Eye Research Institute

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Signal That Switches On Eye Development Discovered By UK Researchers

Researchers at the University of Warwick, funded by Wellcome Trust, have uncovered a crucial signal that switches on eye development. This discovery will greatly assist researchers looking at stem cells connected to eye development and opens up an avenue of research that could eventually lead to an “eye in a dish”.

The University of Warwick research team led by Professor Nick Dale and Professor Elizabeth Jones from the University of Warwick’s Biological Sciences Department have published their work in Nature in a paper entitled Purine-mediated signaling triggers eye development.

The researchers were exploring whether release of ATP (an important signaling and energy carrying molecule) influenced the development of locomotion in frogs. Their experiment introduced molecules called ectoenzymes (normally found on the outside surface of cells) into frog embryos at one of the earliest stages when the frogs-to-be were just 8 cells in size. Three ectoenzymes were used: E-NTPDase1, E-NTPDase2 and E-NTPDase3. These ectoenzymes degrade ATP following its release from cells, however each version of the ectoenzyme has slightly different effects on this degradation.

The Warwick research team’s interest in locomotion was quickly eclipsed when they were amazed to find that the introduction of just one of the ectoenzemes (E-NTPDase2) had a dramatic affect on eye development in the tadpoles grown from these embryos. When introduced in cells that would form the head area of the tadpole multiple eyes appeared to be created. That was not the only surprise. When it was introduced in some cells that formed body parts outside the head area it could still produce an additional “ectopic” eye leading to tadpoles with an additional eye in their side, abdomen or even along their tail.

E-NTPDase2 quickly latches on to ATP converting it to ADP. This meant that where and when the researchers introduced E-NTPDase2 it led to nearby cells experiencing much higher levels of ADP. The Warwick team hypothesized that ATP must be released in a short burst from the location where the eye will develop so that it can be converted to ADP by E-NTPDase2, thereby providing the trigger for eye development. They were able to measure these short bursts of ATP using ATP sensors specially developed by Professor Dale. This is the first time researchers have been able to see and measure bursts of ATP so early in the development of living creatures.

The genes that initiate and direct eye development are well known and are collectively termed the Eye Field Transcription Factors” (EFTFs). One of the mysteries of the field is how these genes get turned on in the correct location and at the correct time to initiate eye development. The Warwick research shows that this short burst of ATP followed by accumulation of ADP is a key signal for initiating expression of the EFTFs and hence the development of the eye.

The discovery of this surprising new signal that literally switches on eye development it is not restricted to frogs. Mutations to the E-NTPDase2 gene on the human 9th chromosome is already known to cause severe head and eye defects. This suggests that this newly discovered mechanism for triggering eye development applies across a wide range of species.

This new understanding of how eye development is triggered will greatly assist researchers exploring stem cells connected to eye development and opens up an avenue of a research that could in just a few decades lead to the ability to produce an “eye in a dish”.

The University of Warwick is consistently ranked in the top ten of UK universities in the national newspaper league tables and is ranked 5th among the UK’s 100 universities for quality of research.

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending around ??500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. wellcome.ac/

Source: Peter Dunn

University of Warwick

Two Therapies Slow Diabetic Eye Disease Progression

In high-risk adults with type 2 diabetes, researchers have found that two therapies may slow the progression of diabetic retinopathy, an eye disease that is the leading cause of vision loss in working-age Americans.

Intensive blood sugar control reduced the progression of diabetic retinopathy compared with standard blood sugar control, and combination lipid therapy with a fibrate and statin also reduced disease progression compared with statin therapy alone. However, intensive blood pressure control provided no additional benefit to patients compared with standard blood pressure control.

Results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study, supported by the National Institutes of Health, were recently published in the New England Journal of Medicine (NEJM) and presented at the 70th Scientific Sessions of the American Diabetes Association.

“This is the largest study to date examining the effects of blood sugar, combination lipid therapy, and blood pressure control on the prevention of diabetic retinopathy progression using retinal photographs,” said Walter T. Ambrosius, Ph.D., a professor of biostatistical sciences in the Division of Public Health Sciences at Wake Forest University Baptist Medical Center, and principal investigator of the ACCORD Eye study’s coordinating center. “Many people with diabetes have microvascular problems, which can result in problems with the kidneys and amputation of toes and feet, and the only place that you can directly observe the microvasculature is in the back of the eyes. What we have seen in the eyes is potentially an indicator of what is happening in other parts of the body.”

Wake Forest Baptist was involved in many ways with the multi-site ACCORD study serving as the coordinating center, a clinical site, and as the head of the study’s southeastern clinical center network, under the leadership of David C. Goff, Jr., Ph.D., a professor and chair of epidemiology and prevention, also in the Division of Public Health Sciences.

“The ACCORD Eye Study clearly indicates that intensive glycemic control and fibrate treatment added to statin therapy separately reduce the progression of diabetic retinopathy,” said Emily Chew, M.D., chair of the Eye Study and chief of the Clinical Trials Branch of the Division of Epidemiology and Clinical Applications at the National Eye Institute (NEI). “The main ACCORD findings showed that fibrate treatment added to statin therapy is safe for patients like those involved in the study. However, intensive blood sugar control to near normal glucose levels increased the risk of death and severe low blood sugar, so patients and their doctors must take these potential risks into account when implementing a diabetes treatment plan.”

The ACCORD study was a landmark clinical trial that included 10,251 adults with type 2 diabetes who were at especially high risk for heart attack, stroke or cardiovascular death. The study evaluated three intensive strategies compared with standard treatments for lowering cardiovascular risks associated with diabetes.

Intensive treatments included control of blood sugar to near normal levels, control of blood pressure to normal levels, and combination treatment of blood lipids with fenofibrate and simvastatin compared to standard treatment with simvastatin alone. Fenofibrate treatment lowers triglycerides and raises the “good” high density lipoprotein (HDL) cholesterol levels, while simvastatin lowers the “bad” low density lipoprotein (LDL) cholesterol levels. All participants were enrolled in the blood sugar trial and in either the blood pressure or lipid trial.

The ACCORD Eye Study involved a subset of 2,856 participants. Researchers analyzed the effects of the treatment strategies on blood vessels in the eye by identifying diabetic retinopathy progression over four years. Diabetic retinopathy is a disease in which blood vessels in the eye’s light-sensitive retinal tissue are damaged by diabetes. Blood vessels can begin to leak, causing swelling in the retina, and abnormal new blood vessels can develop, both causing vision loss. In the study, disease progression was identified through retinal photographs that indicated blood vessel changes or by the need for laser or eye surgery to treat abnormal blood vessels.

Compared with standard blood sugar control, intensive control decreased the progression of diabetic retinopathy by about one-third, from 10.4 percent to 7.3 percent, over four years. Participants in the intensive control group had a median blood sugar level of 6.4 percent hemoglobin A1c – a level close to values in people without diabetes. The standard blood sugar control group maintained a median level of 7.5 percent.

“Previous clinical trials have shown the beneficial effects of intensive blood sugar control on slowing the progression of diabetic retinopathy in people with type 1 diabetes or newly diagnosed type 2 diabetes,” said NEI director Paul A. Sieving, M.D., Ph.D. “The ACCORD Eye

Study expands these findings to a larger population of adults who had type 2 diabetes for an average of 10 years, and demonstrates that the eye benefits from the reduction of glucose below previously established levels.”

In addition, compared with simvastatin treatment alone, combination lipid therapy with fenofibrate plus simvastatin also reduced disease progression by about one-third, from 10.2 percent to 6.5 percent, over four years. No prior clinical trial has shown that the combination of fenofibrate and simvastatin reduces diabetic eye disease progression.

There were no differences in diabetic retinopathy progression among participants treated to an intensive systolic blood pressure (top number in a reading) target of less than 120 mm Hg compared with those treated to a standard target of less than 140 mm Hg.

“The results of the ACCORD Eye Study are exciting, and have provided new and useful information to ophthalmologists managing patients with diabetic retinopathy,” said Craig M. Greven, M.D., professor and chair of the Department of Ophthalmology at Wake Forest Baptist and consultant to the ACCORD Eye Study. “We look forward to using these findings to improve outcomes and prevent visual loss in our patients.”

In the main ACCORD study, none of the three treatment strategies resulted in a significant decrease in the combined rates of heart attack, stroke or cardiovascular death compared with standard treatments. However, over about three-and-a-half years of follow up, participants in the intensive blood sugar group had a 22 percent higher risk of death (5.0 percent versus 4.0 percent) and a three times higher risk of seriously low blood sugar (10.5 percent versus 3.5 percent) compared with participants in the standard blood sugar control group.

The ACCORD study began in 2001, and participants were treated and monitored for an average of five years. Results of the blood sugar clinical trial were reported in 2008, when the intensive blood sugar therapy was stopped 18 months early due to an increased risk of death in that treatment group compared with the standard blood sugar control group. Findings from the blood pressure and lipid clinical trials appeared in the April 29, 2010 edition of NEJM.

“A key question in the main ACCORD study was whether intensive glucose control, previously demonstrated to reduce risk of microvascular disease – including eye problems – in diabetes, would reduce large vessel disease that causes problems like heart attacks. Investigators are continuing to evaluate the risks and benefits of the treatment strategies in these high-risk patients with type 2 diabetes,” said Susan B. Shurin, M.D., acting director of the National Heart, Lung, and Blood Institute, the primary sponsor of the ACCORD study. “Clinicians should individualize treatment for each patient to prevent complications, also incorporating information about conditions such as cardiovascular or visual problems. Lifestyle interventions, including physical activity, weight loss and healthy diets, can improve diabetes control and reduce onset of diabetes.”

Find more information about this trial (NCT00542178) click here. Visit here for more information about diabetic retinopathy.

Source: Wake Forest University Baptist Medical Center

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