Yerkes researchers will compare aging nonhuman primates to aging humans in an effort to develop more effective treatment options for aging-related diseases.

The National Institute of Aging has granted researchers at the Yerkes National Primate Research Center more than $10 million during a five-year period to compare changes that occur in normal aging humans, humans with Alzheimer’s disease and humans with mild cognitive impairment to changes that occur in nonhuman primates, in particular chimpanzees and rhesus macaques. The goal of this study is to identify ways to diagnose aging-related diseases earlier in order to increase the chances for effective treatment as well as to develop new treatments based on specific physiological changes.

According to lead researcher Jim Herndon, PhD, “As humans age, verbal knowledge remains stable while short-term memory, working memory, mental processing speed and long-term memory decrease. Using Alzheimer’s disease as the model, we are hopeful this study will help us determine how to detect the disease earlier in its course, thus increasing the chance for effective treatment. The study also may provide better understanding of specific physiological changes in humans that will be key in helping us develop the new treatments.”

This aging study will be the first to use chimpanzees. According to Herndon, chimpanzees may provide the important evolutionary link to answer why humans are the longest living species and to determine if this characteristic is due to special cognitive capacities. This will be the first examination of chimp cognition in correlation with other aspects of aging.

The Yerkes Research Center is uniquely positioned to conduct this study. “With our well-established colony of chimpanzees and onsite, state-of-the-art imaging facility, Yerkes is one of but a few research centers that can undertake such an extensive aging-related study,” said Stuart Zola, PhD, Yerkes director.

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For more than seven decades, the Yerkes National Primate Research Center, Emory University, has been dedicated to advancing scientific understanding of primate biology, behavior, veterinary care and conservation, and to improving human health and well-being. Today, the center, as one of only eight National Institutes of Health-funded national primate research centers, provides specialized scientific resources, expertise and training opportunities. Recognized as a multidisciВ¬plinary research institute, the Yerkes Research Center is making landmark discoveries in the fields of microbiolВ¬ogy and immunology, neuroscience, psychobiolВ¬ogy and sensory-motor systems. Research programs are seeking ways to: develop vaccines for infectious and noninfectious diseases, such as AIDS and Alzheimer’s disease; treat cocaine addiction; interpret brain activity through imaging; increase understanding of progresВ¬sive illnesses such as Parkinson’s and Alzheimer’s; unlock the secrets of memory; determine behavioral effects of hormone replacement therapy; address vision disorders; and advance knowledge about the evolutionary links between biology and behavior.

Contact: Emily Rios

Emory University

Stronger and tougher body armor to shield the chest, abdomen and back may be just what soldiers fighting in the Afghanistan and Iraq wars need to better protect their brains from mild injuries tied to so-called “shell shock,” results of a Johns Hopkins study in mice suggest. Such mild trauma, resulting from the initial shock of exploding mines, grenades and improvised explosive devices (IEDs) now accounts for more than 80 percent of all brain injuries among U.S. troops. Some 160,000 American veteran men and women are estimated to have sustained this kind of trauma.

“Protecting the body is absolutely essential to protecting the brain,” says senior study investigator and Johns Hopkins neuropathologist Vassilis Koliatsos, M.D. “Blast-related injuries, including what we call blast-induced neurotrauma, are the signature medical events of current wars, and improvements to body armor in addition to helmet- wearing are likely going to be needed if we want to minimize their threat to our soldiers’ health,” says Koliatsos, a professor at the Johns Hopkins University School of Medicine.

In a report to be published in the May edition of the Journal of Neuropathology and Experimental Neurology, Koliatsos and his team used a metal shock tube specially designed at Hopkins’ Applied Physics Laboratory to isolate the effects of an explosion’s primary blast wave on mice.

Researchers found that a plastic glass covering around the torso of shocked mice fully protected them from any axonal nerve cell damage in critical parts of the brain responsible for body movement, including the cerebellum and the corticospinal tract, which links nerves in the brain to those in the spinal cord. Body armor also shielded mice from over 80 percent of the axonal damage observed in the brain’s visual pathways when compared to mice wearing no body armor.

The study also found that wearing similarly secured plastic glass helmets conferred no greater protection from neurological damage from the initial, overpressure wave than in mice shocked without protective headgear.

Koliatsos emphasizes that these results do not undermine the need to wear a helmet to shield their head from flying shrapnel and other bomb debris and protect them from secondary blast waves, some of which are strong enough to throw bodies more than 100 feet.

The study is believed to be the first to show widespread axonal damage in the brain from mild blast explosions and was designed specifically to investigate the ill effects on the body of the primary blast, of extremely fast-moving, high-pressure air, researchers say.

Indeed, the axonal damage observed from mild blast injuries was similar to that seen in many motor vehicle accidents, Koliatsos says, with blast damage possibly due to impulse stress on the brain coming from inside the body, whereas a typical car crash involves impulses coming from outside the body. In mild traumatic brain injury, fluid pressure from the initial explosion could be rippling through a soldier’s chest and lungs to the brain, by way of the major blood vessels of the neck and the cerebrospinal fluid, he says. Another possible explanation is that blasts trigger inflammatory responses, which attack the brain.

“Axons can be quite elastic, and they can expand, slowly, but we suspect that if they stretch too quickly, they will suffer damage or even break,” Koliatsos says.

Among the study’s other findings were that unprotected mice took twice as long as mice who had worn a body shield to socialize with mice newly introduced to their surroundings. Unprotected mice also fell off a mock log-rolling test a minute earlier than shielded mice, who stood up just as long as unshocked mice who heard the blast from outside the tube.

In unshielded mice, researchers found that the lungs were the chest organ most likely to be marred by a blast wave, but the absence of any respiratory injury did not mean the brain was safeguarded, with brain injuries evident in both lung-damaged and lung-undamaged mice.

“Our results should put military physicians in the field on notice that they need to really closely monitor veterans for mild traumatic brain injuries even in the absence of any lung injury,” says Koliatsos. “Regardless of what you call it — shell shock, mild traumatic brain injury, or mild traumatic brain injury combined with post-traumatic stress disorder – it may hide a serious neurological condition.”

Koliatsos and colleagues will analyze brain tissue samples from recently deceased veterans who suffered mild traumatic brain injury to see if there are any permanent signs of axonal damage.

Study co-investigator Ibolja Cernak, M.D., Ph.D., medical director of the biomedicine business area in the Department of National Security Technology of the Applied Physics Laboratory, led development of the shock tube used in the study.

Researchers used a known experimental model, called the Pathology Scoring System for Blast Injuries to help set the strength of the helium blast needed to induce a mild traumatic brain injury. Blast pressure was set at roughly 10 pound-force per square inch.

Study support was provided solely by The Johns Hopkins University.

In addition to Koliatsos and Cernak, other Hopkins researchers involved in this study, conducted from 2007 to 2010, were Leyan Xu, Ph.D.; Yeajin Song, B.S.; Alena Savonenko, M.D., Ph.D.; Barbara Crain, M.D., Ph.D.; Charles Eberhart, M.D., Ph.D.; Constantine Frangakis, Ph.D.; Tatiana Melnikova, M.D., Ph.D.; Hyunsu Kim, B.S.; and Deidre Lee, M.P.H.

Source:
Johns Hopkins Medicine

The UK needs a new system to pay for long-term care for older people, which combines a clear-cut entitlement to care and support with a sharing of costs between individuals and the state. This was the conclusion, published recently (The Future of Care Funding: Time for a change1), of a nine-month consultation initiative involving over 700 people with experience of the long-term care system as users, carers, providers or researchers.

The Caring Choices initiative was run by a coalition of 15 organisations with an interest in the long-term care system, led by the King’s Fund, Joseph Rowntree Foundation, Help the Aged and Age Concern2. Born out of widespread and growing concern that the current system is unsustainable3, it encouraged and facilitated debate across England and Scotland through a series of events and an interactive website.

Five areas of broad agreement emerged from the events and a survey completed by event participants and web visitors:

The present system of funding long-term care is not fit for purpose. People receiving and providing care alike thought the system was unclear and unfair. In particular they disliked the ‘postcode lottery’ giving very different entitlements to people in different areas and the high degree of means-testing that seems to penalise people who have made provision for their old age.

More money will be required to meet growing need. Between 2002 and 2026, the number of older people requiring care is likely to rise by 50 per cent, and costs per head will also rise. Unless the government increases its own contribution, the extra costs will fall on care users. Already today, some people needing care are not getting the help they need, as local authorities short of cash focus only on those with the most critical conditions.

There should be a universal element of long-term care funding. Nine in ten participants supported a system where everyone gets some contribution from the state. Many participants argued for a baseline entitlement available to everyone with care needs, regardless of their income and wealth.

Funding of long-term care should be shared between the state and individuals. Only one in five participants believed that personal care should be funded 100 per cent by the state. Most favoured a system of ‘co-payments’ whereby a care package is paid for mainly by the state but with a fixed percentage contribution from the user.

Better support for unpaid carers is crucial. There was strong resentment about the lack of support for unpaid family carers. Carers and care users emphasised that any effective settlement for long-term care funding needs to involve more generous funding of items such as respite care and Carer’s Allowance.

Other areas of debate were much more contested, generating different views on the best options for the future. These included how far state support should be limited to ‘personal’ care (help with bathing, eating, going to the toilet etc) as opposed to wider social care or measures that could prevent or slow down dependency; the role of benefits such as Attendance Allowance; and how far government should provide help to individuals to enable them to pay their share of care costs, through schemes such as long-term care insurance and equity release. These issues require careful consideration and, ultimately, difficult decisions will have to be made.

Caring Choices does not claim to be a representative survey of public opinion, but it does provide a valuable indication of the thinking of people with a stake in the care system. The conclusions will be fed into the forthcoming government consultation and Green Paper on the funding of adult social care in England, announced in last year’s Comprehensive Spending Review4 which acknowledged that major reforms to care funding are likely to be needed.

Niall Dickson, Chief Executive of the King’s Fund, said:

‘We are at a critical point – in what could be the most important policy shift in this area for many years, the government accepted in the recent Comprehensive Spending Review that the current long-term care system needs to be reformed. Opposition politicians appear to be of a similar view. I hope the forthcoming government consultation will draw on the Caring Choices initiative – and the major King’s Fund and Joseph Rowntree reviews before it – to help us finally achieve the fair, effective and affordable system that is so necessary.’

Julia Unwin, Director of the Joseph Rowntree Foundation, said:

‘This initiative has produced important new evidence on what kind of funding system will gain the confidence of those most closely involved with long-term care. It shows that people yearn for greater clarity about their entitlements: whichever system we have should do what it says on the tin. At present many older people and carers feel unsupported by a system that too often seems to be working against them, rather than giving them essential support at a time of their life when they are at their most vulnerable.’

Paul Cann, Director of Policy for Help the Aged, said:

‘The sad reality is that our care system can’t be relied on to care. Far too often when faced with a life-changing decision after a sudden crisis, people find themselves in the dark with limited choice. Inadequate funding means quality is often unacceptably low. The challenge for government is a big one – but the steps along the way are achievable if the social care of older people is made a top priority. This issue must be brought into the open and treated with the severity it deserves.’

Age Concern England, Director General Gordon Lishman said:

‘The way older people and their families are treated by the care system is a national disgrace. Most people don’t expect the government to pay for everything but they do expect it to make a fairer contribution. More money – from whatever source – will not on its own deliver better results. Older people and their families urgently need a reformed care system that provides good quality support when and where it is required.’

Notes

1. Download the full report: The future of care funding: Time for a change

2. Caring Choices core partners:

- Age Concern
- Help the Aged
- Joseph Rowntree Foundation
- King’s Fund

Partners:

- ADASS
- Association of British Insurers
- Alzheimer’s Society
- Carers UK
- Counsel and Care
- English Community Care Association
- Local Government Association
- IndependentAge
- The NHS Confederation
- Royal College of Nursing
- Social Care Institute for Excellence

3. The extent of the problem was set out in two major independent reviews published in 2006: Securing Good Care for Older People: Taking a long-term view by the King’s Fund and Paying for long-term Care: Moving forward by the Joseph Rowntree Foundation.

4. The HMT’s Pre-budget report and comprehensive spending review in October 2007 stated: ‘The Government …intends to develop a reform strategy [for social care], and will spend the next period in consultation with public, private and third sector organisations who have contributed to the debate thus far. Next year the Government will set out a process involving extensive public engagement and ultimately leading to a Green Paper identifying key issues and options for reform.’ (Page 100)

kingsfund

The metallic particles in the smoke emitted by fireworks pose a health risk, particularly to people who suffer from asthma. This is the conclusion of a study led by researchers from the Institute of Environmental Assessment and Water Research (IDAEA-CSIC), published this week in the Journal of Hazardous Materials.

“The toxicological research has shown that many of the metallic particles in the smoke from fireworks are bio-reactive and can affect human health”, Teresa Moreno, a researcher from the IDAEA (CSIC) and lead author tells SINC.

The different colours and effects produced in these displays are achieved by adding metals to the gunpowder. When a pyrotechnic display takes place it releases a lot of smoke, liberating minute metallic particles (of a few microns in size, or even less), which are small enough to be inhaled deeply into the lungs.

“This poses a risk to health, and the effects are probably more acute in people with a background of asthma or cardiovascular problems”, Moreno explains. “The effects in healthy people are still unknown, but common sense tells us it cannot be good to inhale the high levels of metallic particles in this smoke, even if this only happens a few times a year”.

The study focused on the San Juan fiestas (the night of 23 June through to 24 June, 2008) in the Spanish city of Girona. The researchers analysed the levels of more than 30 chemical elements and compounds in May and June in order to confirm that the levels of lead, copper, strontium, potassium and magnesium skyrocketed after the fireworks were launched.

The team found the results were similar in other towns too. During the MascletГ  (18 March), for example, in the Las Fallas fiestas in Valencia, levels of these elements rose once again, as well as others such as aluminium, titanium, barium and antimony, and also concentrations of nitric oxide (NO) and sulphur dioxide (SO2).

Other studies have confirmed that the smoke from fireworks increases the presence of metallic particles in the skies over L’Alcora and Borriana (CastellГіn), Barcelona and even London (United Kingdom) during the Guy Fawkes’ Night celebrations.

“People who live in cities already inhale significant amounts of contaminant particles stemming from traffic emissions, chimneys and cigarettes, and the dense smoke caused by fireworks only worsens this situation”, points out Moreno.

Possible solutions

The researcher compares the problem with that of tobacco. “The less you expose yourself to the smoke, the fewer negative effects it will have on your health, and so the best solution is to avoid inhaling it”.

According to the scientists, in the absence of a ban on fireworks, spectators should stay well back in a place not affected by the smoke and pay attention to the wind direction. They also recommend that fireworks displays should be sited in a place that ensures the plume of smoke will blow away from densely populated areas.

An added problem is the chemical mixtures in the different kinds of fireworks, since some contain extremely toxic metals such as lead. “There should be strict controls on fireworks imports so that those with the potentially most dangerous chemical composition can be avoided”, concludes Moreno.

References:
Teresa Moreno, Xavier Querol, AndrГ©s Alastuey, Fulvio Amato, Jorge Pey, Marco Pandolfi, Nino Kuenzli, Laura Bouso, Marcela Rivera y Wes Gibbons. “Effect of fireworks events on urban background trace metal aerosol concentrations: Is the cocktail worth the show?” Journal of Hazardous Materials 183 (1-3): 945-949, 15 de noviembre de 2010. Doi:10.1016/j.jhazmat.2010.07.082.

Source:
SINC

FECYT – Spanish Foundation for Science and Technology

Requiring a second exam on a person who is considered brain dead may be unnecessary, according to a study on the impact of a second brain death exam on organ donation rates. The research is published in the December 15, 2010, online issue of Neurology®, the medical journal of the American Academy of Neurology.

For the study, scientists reviewed the cases of 1,229 adults and 82 children ages one and older pronounced brain dead. The information was taken from the New York Organ Donor Network database during a 19-month period.

“One of the most disturbing findings of our study is the prolonged anguish imposed on grieving families in the intensive care unit waiting for the second brain death exam,” said study author Dana Lustbader, MD, FCCM, FCCP, with The North Shore LIJ Health System in Manhasset, New York. “Not only is the opportunity for organ donation reduced, but families may endure unnecessary suffering while waiting an average of 19 hours for the second exam to be completed.”

“Since organ viability decreases the longer a person is brain dead, our results show that conducting more than one brain death examination results in the loss of potentially life-saving organs,” reports Lustbader. “A repeat exam adds an extra day of intensive care resulting in additional costs of about a million dollars per year in the New York region alone.”

The study found that none of the people declared brain dead in the first exam were found to have restored brain stem function in the second exam.

Lustbader noted that 166 people, or 12 percent, sustained a cardiac arrest while awaiting a second exam or after the second exam, making them ineligible for organ donation.

The average time between the two exams in the study was 19 hours, three times longer than recommended by the New York State Health Department. As the time between exams increased, consent for organ donation decreased from 57 percent to 45 percent. In addition, refusal of organ donation increased from 23 percent to 36 percent as the time between exams increased.

In New York, the State Department of Health’s 2005 brain death guidelines require a breathing test and two clinical brain death exams, carried out six hours apart. In 2010, the American Academy of Neurology updated its brain death guidelines, which now call for only one brain death examination.

“These findings illustrate why there’s a crucial need to standardize approaches for determining brain death,” said Gene Sung, MD, MPH, of the University of Southern California in Los Angeles and a member of the American Academy of Neurology, who wrote an editorial regarding the article that is published in Neurology.

Source: American Academy of Neurology (AAN)

Although alcohol consumption is known to be associated with chronic pancreatitis, new evidence indicates that a threshold of five or more drinks per day is required to significantly raise risk; however, most patients with chronic pancreatitis do not drink this amount, according to a report in the June 8 issue of Archives of Internal Medicine, one of the JAMA/Archives journals. In addition, smoking is an independent, dose-dependent risk factor.

“Chronic pancreatitis is an inflammatory syndrome of the pancreas characterized by progressive parenchymal fibrosis [scarring of the organ], maldigestion, diabetes mellitus and pain,” the authors write as background information in the article. “Recurrent acute pancreatitis [acute pancreatitis that occurs on two or more occasions and may become chronic] and chronic pancreatitis are associated with alcohol consumption and cigarette smoking. The etiology of recurrent acute pancreatitis and chronic pancreatitis is complex, and effects of alcohol and smoking may be limited to specific patient subsets.”

Dhiraj Yadav, M.D., M.P.H., of the University of Pittsburgh, and colleagues in the North American Pancreatic Study Group examined the current prevalence of alcohol use and smoking and their association with pancreatitis in patients evaluated at U.S. referral centers. Between 2000 and 2006, 1,000 patients (540 with chronic pancreatitis and 460 with recurrent acute pancreatitis) were enrolled in the North American Pancreatitis Study 2 (NAPS2), as were 695 healthy controls. All participants (average age 49.7) reported their alcohol consumption and smoking habits.

About one-fourth of both controls and patients were lifetime abstainers. Among those with chronic pancreatitis, 38.4 percent of men and 11 percent of women were very heavy drinkers (five or more drinks per day), compared with 16.9 percent of men and 5.5 percent of women with recurrent acute pancreatitis and 10 percent of men and 3.6 percent of women in the control group.

“We found the threshold drinking amount for association between alcohol use and chronic pancreatitis to be five or more drinks per day,” the authors write. Compared with abstaining and light drinking (half a drink per day or less), very heavy drinking was associated with approximately triple the odds of developing chronic pancreatitis. However, fewer patients with chronic pancreatitis than expected (about one-fourth) drank at this level. Other factors, including genetic mutations, also contribute to pancreatitis risk.

Although many heavy drinkers also smoked, cigarette use was an independent risk factor for both chronic pancreatitis and recurrent acute pancreatitis. Among smokers, those with chronic pancreatitis tended to smoke more (26.6 pack-years, vs. 19.5 pack-years for those with recurrent acute pancreatitis and 16.2 pack-years for controls; one pack-year is about 7,300 cigarettes smoked) and had smoked for a longer period of time (a median or midpoint of 30.5 years, vs. 21.9 years for controls and 22.7 years for those with recurrent acute pancreatitis), suggesting a dose-dependent effect.

“In conclusion, only very heavy alcohol consumption and cigarette smoking are independent risk factors for chronic pancreatitis,” the authors write. “Risk for chronic pancreatitis from alcohol consumption occurs above a threshold level, while risk due to smoking is dose dependent. Drinking levels in subjects with recurrent acute pancreatitis are similar to controls. Only a minority of patients with recurrent acute pancreatitis and chronic pancreatitis currently seen at secondary or tertiary U.S. centers could be categorized as very heavy drinkers.”

Arch Intern Med. 2009;169[11]:1035-1045.

Source
Archives of Internal Medicine

In one of the first studies to focus on the relationship between racial discrimination and health risk behaviors, researchers at the Columbia University Mailman School of Public Health with colleagues from the Universities of Minnesota, Alabama (Birmingham), and California (San Francisco), and Harvard University found African Americans experiencing racial discrimination were more likely to report current tobacco use or recent alcohol consumption and lifetime use of marijuana and cocaine.

Although racial discrimination was far less common in Whites (38%) than in African Americans (89%), the researchers assessed whether parallel associations exist in Whites and found similar associations with smoking, alcohol, and lifetime use of marijuana and cocaine as they did in African Americans. Thus, substance use may be an unhealthy coping response to perceived unfair treatment for some individuals regardless of their race/ethnicity. “However, it is worth noting that racial discrimination may be a different phenomenon for African Americans than it is for Whites, and thus, lead to very different consequences,” said Luisa N. Borrell, DDS, PhD, of the Mailman School of Public Health’s Department of Epidemiology and principal investigator of the study.

African Americans experiencing racial discrimination also reported having more education, higher income, and a stronger social network than those reporting no racial discrimination. In contrast to African Americans, Whites reporting racial discrimination reported less education and lower income than did those who reported none. Similar to African Americans, Whites reporting any discrimination were more likely to report less control of their life, more anger, less emotional support, and more negative interactions than did their counterparts reporting none.

“We found that African Americans reporting discrimination in three or more domains in both years had higher levels of education and income than did those who reported experiencing less or no discrimination,” said Dr. Borrell. “Possibly, African Americans with a higher socioeconomic position report more discrimination because they are more exposed to situations in which they are discriminated, or they may be more aware of subtle forms of discrimination,” noted Dr. Borrell.

According to the findings, in contrast, Whites with a low socioeconomic position may be more likely to be exposed to environments in which they are the minority and, therefore, be more likely to feel discriminated.

Among the strengths of the study are its population-based nature, the focus on young to middle-aged adults, the wide ranges of educational attainment and income, the information on illicit substance use, and socioeconomic position indicators. “It is possible that use of a recreational drug helps to cope with life stress resulting from perceived unfair treatment because of one’s race/ethnicity,” observed Dr. Borrell. “Our findings that current use of marijuana was not related to discrimination and that risk of being a former smoker was increased suggest that, by early middle age (average age, 40 years), people may have found other ways to cope. However, the finding of an excess of current smoking in this population, suggest that this addictive habit may be long lasting, even when alternative coping behaviors are adopted.”

Source of the data was the CARDIA study, a prospective study of cardiovascular risk among young adults. 3,330 persons aged 18-30 years examined at baseline (1985-1986) and re-examined again seven (1992-1993) and 15 years (2000-2001) later in the (CARDIA) Study were included in this study.

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The study was supported by the National Institute of Dental and Craniofacial Research, the National Heart, Lung, and Blood Institute and the Robert Wood Johnson Health and Society Scholars Program. The findings are published online in the American Journal of Epidemiology at aje.oxfordjournals/cgi/reprint/kwm180v1

About the Mailman School of Public Health

The only accredited school of public health in New York City, and among the first in the nation, Columbia University’s Mailman School of Public Health provides instruction and research opportunities to more than 950 graduate students in pursuit of masters and doctoral degrees. Its students and more than 300 multi-disciplinary faculty engage in research and service in the city, nation, and around the world, concentrating on biostatistics, environmental health sciences, epidemiology, health policy and management, population and family health, and sociomedical sciences.mailman.hslumbia.edu/

Source: Stephanie Berger

Columbia University’s Mailman School of Public Health

167 Arizona children were hospitalized or seen in an emergency department for a non-fatal drowning in 2007. 25 children died as a result of drownings or submersions. 1 child died from carbon monoxide poisoning while swimming behind a boat. The longest hospital stay for a non-fatal drowning was 105 days.

The 95 non-fatal emergency department visits totaled $214,000 in hospital charges. On average, each non-fatal inpatient hospitalization cost $6,900. Total hospital charges for all non-fatal inpatient hospitalizations was $1.7 million.

You can prevent drownings!

- Supervise children around any water, even if they know how to swim
- Learn CPR
- Install a 4-sided isolation fence with a self-closing, self-latching gate.
- Do not prop open pool gates
- Wear life jackets in and around natural bodies of water

Source
Arizona Department of Health Services

Under normal circumstances, adult stem cells reside in muscle tissue, where they can differentiate into a number of different cell types. After an injury (or even a tough workout), muscles are inflamed as cells and molecules flood the area to control damage and begin repairs. When called upon to replace muscle tissue damaged by injury or genetic disease, some muscle stem cells differentiate, becoming new muscle cells, while others make more stem cells. At Sanford-Burnham Medical Research Institute (Sanford-Burnham), a team of scientists led by Pier Lorenzo Puri, M.D., Ph.D., recently uncovered the molecular messengers that translate inflammatory signals into the genetic changes that tell muscle stem cells to differentiate. Writing in the October 8 issue of the journal Cell Stem Cell, Dr. Puri and colleagues reveal fundamental mechanisms that could be manipulated to enhance how muscle stem cells regenerate injured or diseased muscles. These findings could lead to new treatments for diseases like muscular dystrophy.

“This study helps us understand how muscle stem cells decipher external signals and elaborate them to turn genes on and off,” explained Dr. Puri, who is also an associate faculty member at the Dulbecco Telethon Institute in Rome, Italy. “Now we’re applying this information to help patients with muscular dystrophies, a group of genetic diseases characterized by progressive muscle loss.”

Dr. Puri’s findings begin with an inflammatory molecule called tumor necrosis factor (TNF), which initiates a chain reaction of molecular events when it wakes up a protein called p38 alpha MAPK. This protein is known to play a role in many processes, but here Dr. Puri and his colleagues show that TNF tells p38 alpha MAPK to enter the nucleus, where it keeps a damper on the part of the genome that defines the identity of muscle cells. Essentially, p38 alpha MAPK determines whether stem cells loitering in adult muscle tissue keep refreshing the pool of stem cells or differentiate into functioning muscle cells.

This new information on p38 alpha MAPK’s role in muscle is important because it gives Dr. Puri’s group a target to artificially dial the stem cell population up or down. In this study they used a chemical inhibitor and antibodies directed against TNF to block the p38 alpha MAPK activity specifically in stem cells, thus producing more stem cells. Anti-TNF antibodies provide a potential mechanism to generate more muscle stem cells in muscular dystrophy patients, especially since they are already FDA-approved to treat septic shock and arthritis. The team verified their discoveries in a mouse model of Duchenne muscular dystrophy.

“In muscular dystrophy patients, the pool of stem cells capable of regenerating new muscle becomes exhausted,” said Dr. Puri. “Here we’ve found a strategy to refresh the pool by modulating p38 alpha MAPK. Since the effect of this treatment is reversible, withdrawing the drug could then force the expanded population of stem cells to repopulate muscle cells.” Overall, these findings suggest that turning inflammatory signals off and on in regenerating muscles might enhance the ability of injured or diseased skeletal muscles to self-repair.

This study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health, Telethon Italy, Europe’s ENDOSTEM project, Association Francaise contre les Myopathies, Associazione Italiana Ricerca sul Cancro and Parent Project Onlus.

Original paper

Palacios D, Mozzetta C, Consalvi S, Caretti G, Saccone V, Proserpio V, Marquez VE, Valente S, Mai A, Forcales SV, Sartorelli V, Puri PL. TNF/p38О±/Polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell. Published online October 8, 2010.

Source:

Sanford-Burnham Medical Research Institute

A new study has found that a currently available yet underused vaccine against typhoid fever is highly effective in young children and protects unvaccinated neighbors of vaccinees.

The study, conducted by the International Vaccine Institute (IVI) in collaboration with the National Institute of Cholera and Enteric Diseases (NICED) in Kolkata, India, was published in the July 23 issue of the New England Journal of Medicine (NEJM). The IVI, based in Seoul, Korea, is a non-profit international organization devoted exclusively to development and deployment of new vaccines primarily for people in developing countries.

Typhoid fever remains an important cause of illness and death in the developing world, killing an estimated 216,000 to 600,000 people annually. Multidrug-resistant Salmonella typhi has spread to many parts of the world, limiting the ability to treat typhoid fever with available antibiotics. Typhoid is both a waterborne and food-borne gastrointestinal infection, with incidence approaching one percent of the population annually in certain endemic areas. Experts say that in the absence of affordable programs to assure safe water and better sanitation, short and medium-term efforts need to be directed towards prevention through vaccines.

Safe and effective vaccines against typhoid fever exist, but they are used primarily for affluent travelers to developing countries, rather than for the poor residing in these countries, who account for almost all the global burden of typhoid morbidity and mortality. One of these vaccines, Vi polysaccharide, is ideally suited to use in developing countries because it is cheap (about $.50 per dose) and requires only a single dose.

Despite a recommendation by the World Health Organization for use of Vi vaccines in developing countries, its use has been limited, partly because of doubts about Vi’s ability to protect pre-school age children. This age group is at exceptionally high risk in the poorest settings. There are also doubts about Vi’s ability to confer “herd protection,” or protection of unvaccinated residents living in highly vaccinated areas.

To address these uncertainties, the IVI in collaboration with NICED conducted a phase 4 cluster-randomized effectiveness trial, which randomized 80 geographic clusters of an urban Kolkata slum to either Vi or a control vaccine. Over two years of follow-up, the Vi group was shown to have 61 percent fewer episodes of typhoid than the control group. Protection of vaccinated children under five years of age by Vi was even higher, 80%. Interestingly, unvaccinated neighbors of Vi vaccinated persons had a 44 percent lower risk of typhoid, indicating that Vi vaccine conferred substantial herd protection. The overall level of protection among all residents of the Vi clusters, regardless of whether they were vaccinated was 57 percent. Since the coverage of residents of the Vi clusters was about 60%, this observation indicates that Vi vaccine prevented as many cases of typhoid in the total population as a vaccine that was nearly 100% protective in vaccinated persons.

“The protection for children under the age of five years is important because this age group has been shown to be at high risk for typhoid fever in many areas where the disease is endemic,” said Dr. John Clemens, Director-General of the IVI and an international expert in vaccine evaluation. In a separate IVI study conducted in five Asian countries and supported by the Bill and Melinda Gates Foundation, children less than five years of age were found to have high rates of typhoid in Kolkata, India, Jakarta, Indonesia and Karachi, Pakistan, confirming that the disease is not limited to school-aged children and adults.

The IVI-NICED study, which was supported by the Gates Foundation and the governments of Korea, Sweden, and Kuwait, also revealed that delivering the low-cost Vi typhoid vaccine is logistically and programmatically possible. “The fact that the level of overall protection (57 percent) was similar to the adjusted level of total protection among vaccinees (61 percent), despite vaccine coverage of only about 60 percent of the subjects, underscores the importance of herd protection by the Vi vaccine,” said Dr. Clemens, a co-author of the study. “It also suggests the need for consideration of herd protective effects in future deliberations about the use of this vaccine in developing countries.”

Meanwhile, in a separate vaccine development project, IVI laboratories have more than tripled the manufacturing yield of Vi polysaccharide, which is expected to further reduce the vaccine’s production cost, thus making it more accessible for developing countries. The production technology for the high-yield Vi polysaccharide is being transferred to high-quality producers in developing countries.

Source:
Tae Kyung Byun

International Vaccine Institute