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Antibody leads to repair of myelin sheath in lab study of multiple sclerosis and related disorders

Contact: Amelyn Reyes
newsbureau@mayo.edu
507-284-5005
Mayo Clinic

ROCHESTER, Minn. — Mayo Clinic researchers have found that a human antibody administered in a single low dose in laboratory mouse models can repair myelin, the insulating covering of nerves that when damaged can lead to multiple sclerosis and other disorders of the central nervous system.

The study will be presented on Oct. 9 at the American Neurological Association meeting in Washington, D.C.

“The repair of chronic spinal cord injury is seldom modeled in laboratory studies, but it is an important reality for the treatment of humans. The concept of using natural human antibodies to treat disease of this kind has not yet been tested in humans, but these research findings are very promising,” says Moses Rodriguez, M.D., a Mayo Clinic neurologist and the study’s corresponding author. “The findings could eventually lead to new treatments that could limit permanent disability,” states Arthur Warrington, Ph.D., a Mayo Clinic scientist and study author.

Myelin repair normally occurs spontaneously, but in multiple sclerosis and other disorders of the central nervous system, the myelin repair process occurs very slowly or fails altogether. Researchers are trying to determine how to speed up the myelin healing process, which they hope will eventually lead to new treatments for patients.

The antibody, which was genetically engineered from a single cell, binds to myelin and the surface of cells in the brain and spinal cord, then it triggers the cells to begin the repair process called remyelination. This antibody is the first known reagent designed to induce repair by acting within the central nervous system at the damage sites on cells responsible for myelin synthesis.

The study uses laboratory mouse models of chronic progressive multiple sclerosis in humans. The severity of the disease and also success of the treatment were largely defined by how naturally active the mice were, particularly during the night because mice are nocturnal and are especially active at this time. They received a single dose of the antibody. A minimum of 25 mcg/kg was needed to trigger remyelination, which is equivalent to about 2 mg in the average adult, considered a very low dose. The myelin repair plateaued after five weeks in the mice models.

In addition, when combined with daily methylprednisolone, (an immune modulating steroid) the antibody still promotes remyelination in mouse models. This is an important fact because the first multiple sclerosis patients treated with the antibody will have been treated first with methylprednisolone.

As a naturally occurring protein of the immune system, antibodies do not appear to carry any side effects, nor are they toxic — even when administered at 4,000 times the minimal effective dose — though the concept has not yet been tested in humans, the researchers say.

In summary, this antibody:

Promotes remyelination with a single dose as low as 25 mcg/kg in mice models

The remyelination plateaus at five weeks after a single dose

Converts a model of chronic immune mediated demyelination to one that repairs with the speed of a toxin induced model of demyelination

In terms of replicating the findings in humans, the researchers have already produced the antibody through genetic engineering and conducted preliminary toxicology experiments in mice showing that 1,000 times the therapeutic dose is not toxic. The study continues to be explored in animal models and eventually, in clinical trials.

In short, the critical finding is that when combined with methylprednisolone, the antibody still effectively promotes remyelination and does not make the mice worse, Dr. Warrington states.

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About Multiple Sclerosis:

Multiple sclerosis (MS) is a chronic, potentially debilitating disease that affects the central nervous system, which is made up of the brain and spinal cord. Multiple sclerosis is widely believed to be an autoimmune disease, a condition in which the immune system attacks components of the body as if they’re foreign.

Multiple sclerosis affects an estimated 300,000 people in the United States and probably more than 1 million people around the world — including twice as many women as men. Most people experience their first signs or symptoms between ages 20 and 40.

Collaboration and Support

The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, Multiple Sclerosis Society of Canada, the Hilton Foundation and Mr. and Mrs. Eugene Applebaum.

To obtain the latest news releases from Mayo Clinic, go to http://www.mayoclinic.org/news. MayoClinic.com (www.mayoclinic.com) is available as a resource for your health stories. For more on Mayo Clinic research, go to http://www.mayo.edu.

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October 9, 2007 Posted by | Global Health Vision, Global News, Mayo Clinic, MS, Multiple Sclerosis, News, News USA, Ottawa, RSS Feed, Toronto, UK, Washington DC City Feed | 3 Comments

Appendix isn’t useless at all: It’s a safe house for bacteria

Contact: Richard Merritt
Merri006@mc.duke.edu
919-660-1309
Duke University Medical Center

DURHAM, N.C. – Long denigrated as vestigial or useless, the appendix now appears to have a reason to be – as a “safe house” for the beneficial bacteria living in the human gut.

Drawing upon a series of observations and experiments, Duke University Medical Center investigators postulate that the beneficial bacteria in the appendix that aid digestion can ride out a bout of diarrhea that completely evacuates the intestines and emerge afterwards to repopulate the gut. Their theory appears online in the Journal of Theoretical Biology.

“While there is no smoking gun, the abundance of circumstantial evidence makes a strong case for the role of the appendix as a place where the good bacteria can live safe and undisturbed until they are needed,” said William Parker, Ph.D., assistant professor of experimental surgery, who conducted the analysis in collaboration with R. Randal Bollinger, M.D., Ph.D., Duke professor emeritus in general surgery.

The appendix is a slender two- to four-inch pouch located near the juncture of the large and small intestines. While its exact function in humans has been debated by physicians, it is known that there is immune system tissue in the appendix.

The gut is populated with different microbes that help the digestive system break down the foods we eat. In return, the gut provides nourishment and safety to the bacteria. Parker now believes that the immune system cells found in the appendix are there to protect, rather than harm, the good bacteria.

For the past ten years, Parker has been studying the interplay of these bacteria in the bowels, and in the process has documented the existence in the bowel of what is known as a biofilm. This thin and delicate layer is an amalgamation of microbes, mucous and immune system molecules living together atop of the lining the intestines.

“Our studies have indicated that the immune system protects and nourishes the colonies of microbes living in the biofilm,” Parkers explained. “By protecting these good microbes, the harmful microbes have no place to locate. We have also shown that biofilms are most pronounced in the appendix and their prevalence decreases moving away from it.”

This new function of the appendix might be envisioned if conditions in the absence of modern health care and sanitation are considered, Parker said.

“Diseases causing severe diarrhea are endemic in countries without modern health and sanitation practices, which often results in the entire contents of the bowels, including the biofilms, being flushed from the body,” Parker said. He added that the appendix’s location and position is such that it is expected to be relatively difficult for anything to enter it as the contents of the bowels are emptied.

“Once the bowel contents have left the body, the good bacteria hidden away in the appendix can emerge and repopulate the lining of the intestine before more harmful bacteria can take up residence,” Parker continued. “In industrialized societies with modern medical care and sanitation practices, the maintenance of a reserve of beneficial bacteria may not be necessary. This is consistent with the observation that removing the appendix in modern societies has no discernable negative effects.”

Several decades ago, scientists suggested that people in industrialized societies might have such a high rate of appendicitis because of the so-called “hygiene hypothesis,” Parker said. This hypothesis posits that people in “hygienic” societies have higher rates of allergy and perhaps autoimmune disease because they — and hence their immune systems — have not been as challenged during everyday life by the host of parasites or other disease-causing organisms commonly found in the environment. So when these immune systems are challenged, they can over-react.

“This over-reactive immune system may lead to the inflammation associated with appendicitis and could lead to the obstruction of the intestines that causes acute appendicitis,” Parker said. “Thus, our modern health care and sanitation practices may account not only for the lack of a need for an appendix in our society, but also for much of the problems caused by the appendix in our society.”

Parker conducted a deductive study because direct examination the appendix’s function would be difficult. Other than humans, the only mammals known to have appendices are rabbits, opossums and wombats, and their appendices are markedly different than the human appendix.

Parker’s overall research into the existence and function of biofilms is supported by the National Institutes of Health. Other Duke members of the team were Andrew Barbas, Errol Bush, and Shu Lin.

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October 8, 2007 Posted by | Duke University Medical Center, Global Health Vision, Global News, Health, Journal of Theoretical Biology, Medical Journals, News, Public Health, Research, RSS Feed, Washington DC City Feed | 4 Comments

What emotional memories are made of

Mouse experiments reveal ‘flight or fight’ hormone’s role

Contact: Nick Zagorski
nzagors1@jhmi.edu
443-287-2251
Johns Hopkins Medical Institutions

Both extensive psychological research and personal experiences confirm that events that happen during heightened states of emotion such as fear, anger and joy are far more memorable than less dramatic occurrences. In a report this week in Cell, Johns Hopkins researchers and their collaborators at Cold Spring Harbor and New York University have identified the likely biological basis for this: a hormone released during emotional arousal “primes” nerve cells to remember events by increasing their chemical sensitivity at sites where nerves rewire to form new memory circuits.

Describing the brain as a big circuit board in which each new experience creates a new circuit, Hopkins neuroscience professor Richard Huganir, Ph.D. says that he and his team found that during emotional peaks, the hormone norepinephrine dramatically sensitizes synapses – the site where nerve cells make an electro-chemical connection – to enhance the sculpting of a memory into the big board.

Image showing phosphorylated GluR1 receptors congregating around sites of neuronal synapses.

Norepinephrine, more widely known as a “fight or flight” hormone, energizes the process by adding phosphate molecules to a nerve cell receptor called GluR1. The phosphates help guide the receptors to insert themselves adjacent to a synapse. “Now when the brain needs to form a memory, the nerves have plenty of available receptors to quickly adjust the strength of the connection and lock that memory into place,” Huganir says.

Huganir and his team suspected that GluR1might be a target of norepinephrine since disruptions in this receptor cause spatial memory defects in mice. They tested the idea by either injecting healthy mice with adrenaline or exposing them to fox urine, both of which increase norepinephrine levels in brain. Analyzing brain slices of the mice, the researchers saw increased phosphates on the GluR1 receptors and an increased ability of these receptors to be recruited to synapses.

When the researchers put mice in a cage, gave a mild shock, took them out of that cage and put them back in it the next day, mice who had received adrenaline or fox urine tended to “freeze” in fear – an indicator they associated the cage as the site of a shock – more frequently, suggestive of enhanced memory.

However, in a similar experiment with mice genetically engineered to have a defective GluR1 receptor that phosphates cannot attach to, adrenaline injections had no effect on mouse memory, further evidence of the “priming” effect of the receptor in response to norepinephrine.

The researchers plan on continuing their work by going in the opposite direction and engineering another mouse strain that has a permanently phosphorylated or “primed” receptor. “We’re curious to see how these mice will behave,” Huganir says. “We suspect that they’ll be pretty smart, but at the same time constantly anxious.”

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The research was funded by the National Institutes of Health, Damon Runyon Postdoctoral Fellowship, NARSAD, and the Ale Davis and Maxine Harrison Foundation

Authors on the paper are Hailan Hu, Eleonore Real, and Roberto Malinow of Cold Spring Harbor Laboratory; Joe LeDoux of New York University; and Kogo Takamiya, Myoung-Goo Kang, and Huganir of Johns Hopkins

On the Web:
http://neuroscience.jhu.edu/RichardHuganir.php
http://www.cell.com

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October 5, 2007 Posted by | General Psychiatry, Global Health Vision, Global News, Johns Hopkins University, journal Cell, Medical Journals, New York University, Norepinephrine, Research, RSS Feed, Science, W. Garfield Weston Fellows, Washington DC City Feed | 1 Comment

Researchers develop targeted approach to pain management

Contact: Alyssa Kneller
public_affairs@hms.harvard.edu
617-432-0442
Harvard Medical School

BOSTON, Mass. (Oct. 3, 2007)—Imagine an epidural or a shot of Novocain that doesn’t paralyze your legs or make you numb, yet totally blocks your pain. This type of pain management is now within reach. As a result, childbirth, surgery and trips to the dentist might be less traumatic in the future, thanks to researchers at Massachusetts General Hospital (MGH) and Harvard Medical School, who have succeeded in selectively blocking pain-sensing neurons in rats without interfering with other types of neurons.

The pint-sized subjects received injections near their sciatic nerves, which run down their hind limbs, and subsequently lost the ability to feel pain in their paws. But they continued to move normally and react to touch. The injections contained QX-314, a normally inactive derivative of the local anesthetic lidocaine, and capsaicin, the active ingredient in hot peppers. In combination, these chemicals targeted only pain-sensing neurons, preventing them from sending signals to the brain.

“We’ve introduced a local anesthetic selectively into specific populations of neurons,” explains Harvard Medical School Professor Bruce Bean, an author on the paper, which appears in Nature on Oct. 4. “Now we can block the activity of pain-sensing neurons without disrupting other kinds of neurons that control movements or non-painful sensations.”

“We’re optimistic that this method will eventually be applied to humans and change our experience during procedures ranging from knee surgery to tooth extractions,” adds Professor Clifford Woolf of Massachusetts General Hospital, who is senior author on the study.

Despite enormous investments by industry, surgical pain management has changed little since the first successful demonstration of ether general anesthesia at MGH in 1846. General and local anesthetics work by interfering with the excitability of all neurons, not just pain-sensing ones. Thus, these drugs produce dramatic side effects, such as loss of consciousness in the case of general anesthetics or temporary paralysis for local anesthetics.

“We’re offering a targeted approach to pain management that avoids these problems,” says Woolf.

The new work builds on research done since the 1970’s showing how electrical signaling in the nervous system depends on the properties of ion channels, that is, proteins that make pores in the membranes of neurons.

“This project is a perfect illustration of how research trying to understand very basic biological principles can have practical applications,” says Bean.

The new method exploits a membrane-spanning protein called TRPV1, which is unique to pain-sensing neurons. TRPV1 forms a large channel, where molecules can enter and exit the cell. But a “gate” typically blocks this opening. The gate opens when cells are exposed to heat or the chili-pepper ingredient capsaicin. Thus, bathing pain-sensing neurons in capsaicin leaves these channels open, but non-pain sensing neurons are unaffected because they do not possess TRPV1.

The new method then takes advantage of a special property of the lidocaine derivative QX-314. Unlike most local anesthetics, QX-314 can’t penetrate cell membranes to block the excitability of the cell, so it typically lingers outside neurons where it can’t affect them. For this reason it is not used clinically.

When pain-sensing neurons are exposed to capsaicin, however, and the gates guarding the TRPV1 channels disappear, QX-314 can enter the cells and shut them down. But the drug remains outside other types of neurons that do not contain these channels. As a result, these cells fully retain their ability to send and receive signals.

The team first tested their method in the Petri dish. Alexander Binshtok, a postdoctoral researcher in Woolf’s lab, applied capsaicin and QX-314 (separately and in combination) to isolated pain-sensing and other neurons and measured their responses. Indeed, the combination of capsaicin and QX-314 selectively blocked the excitability of pain-sensing neurons, leaving the others unaffected.

Next, Binshtok injected these chemicals into the paws of rats and measured their ability to sense pain by placing them on an uncomfortable heat source. The critters tolerated much more heat than usual. He then injected the chemicals near the sciatic nerve of the animals and pricked their paws with stiff nylon probes. The animals ignored the provocation. Although the rats seemed immune to pain, they continued to move normally and respond to other stimuli, indicating that QX-314 failed to penetrate their motor neurons.

The team must overcome several hurdles before this method can be applied to humans. They must figure out how to open the TRPV1 channels without producing even a transient burning pain before QX-314 enters and blocks the neurons, and they must tinker with the formulation to prolong the effects of the drugs. Both Bean and Woolf are confident they’ll succeed.

“Eventually this method could completely transform surgical and post-surgical analgesia, allowing patients to remain fully alert without experiencing pain or paralysis,” says Woolf. “In fact, the possibilities seem endless. I could even imagine using this method to treat itch, as itch-sensitive neurons fall into the same group as pain-sensing ones.”

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Research in the Woolf lab is supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Dental and Craniofacial Research. Research in the Bean lab is supported by NINDS and the National Institute of General Medical Sciences.

Harvard and MGH have filed patents on this technology platform.

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October 3, 2007 Posted by | Boston, Global Health Vision, Global News, News, News USA, Pain, Pain Management, RSS Feed | 1 Comment

Americans consider global warming an urgent threat, according to poll

Contact: Janet Rettig Emanuel
janet.emanuel@yale.edu
203-432-2157
Yale University

Links (in order of appearance in the text) to have active are: Anthony Leiserowitz Yale Project on Climate Change

New Haven, Conn. — A growing number of Americans consider global warming an important threat that calls for drastic action, and 40% say that a presidential candidate’s position on the issue will strongly influence how they vote, according to a national survey conducted by Yale University, Gallup and the ClearVision Institute.

“One of the most surprising findings was the growing sense of urgency,” said Anthony Leiserowitz, director of the Yale Project on Climate Change and the study’s principal investigator. “Nearly half of Americans now believe that global warming is either already having dangerous impacts on people around the world or will in the next 10 years—a 20-percentage-point increase since 2004. These results indicate a sea change in public opinion.”

The survey’s findings include:

Sixty-two percent of respondents believe that life on earth will continue without major disruptions only if society takes immediate and drastic action to reduce global warming.

Sixty-eight percent of Americans support a new international treaty requiring the United States to cut its emissions of carbon dioxide 90 percent by the year 2050. Yet, Leiserowitz notes, the United States has yet to sign the Kyoto Protocol, an international treaty that would require the United States to cut its emissions 7 percent by the year 2012.

A surprising 40 percent of respondents say a presidential candidate’s position on global warming will be either extremely important (16 percent) or very important (24 percent) when casting their ballots. “With the presidential primaries and general election near,” Leiserowitz said, “candidates should recognize that global warming has become an important issue for the electorate.”

Eight-five percent of those polled support requiring automakers to increase the fuel efficiency of cars, trucks and SUVs to 35 miles per gallon, even if it meant a new car would cost up to $500 more; and 82 percent support requiring electric utilities to produce at least 20 percent of their electricity from renewable energy sources, even if it cost the average household an extra $100 a year.

Majorities of Americans, however, continue to oppose carbon taxes as a way to address global warming — either in the form of gasoline (67 percent against) or electricity taxes (71 percent against). —.

Finally, 50 percent of respondents say they are personally worried —15 percent say a “great deal”— about global warming. “Many Americans, however, believe that global warming is a very serious threat to other species, people and places far away,” said Leiserowitz, “but not so serious of a threat to themselves, their own families or local communities. Nonetheless, they do strongly support a number of national and international policies to address this problem.”

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The survey was conducted July 23-26, 2007, using telephone interviews with 1,011 adults, aged 18-plus. Respondents came from Gallup’s household panel, which was originally recruited through random selection methods. The final sample is consideredto be representative of U.S. adults nationwide, with a margin of error of ±4 percentage points. Survey results are available online: http://environment.yale.edu/news/5305-american-opinions-on-global-warming/.

The Yale Project on Climate Change at the Yale School of Forestry & Environmental Studies supports public discourse and engagement with climate-change solutions.

Gallup, Inc., headquartered in Washington, D.C., is one of the world’s leading research companies focusing on studying human nature and behavior. The Gallup Poll has been monitoring U.S. public opinion since 1935, and Gallup now tracks public opinion in over 100 countries worldwide on an ongoing basis.

The ClearVision Institute is a nonprofit organization dedicated to applying entertainment education as a social-change strategy to address climate change through U.S. commercial television.

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October 1, 2007 Posted by | Global, Global Health Vision, Global News, RSS Feed, Science, Yale University | 2 Comments

Occupational exposures may be linked to death from autoimmune disease

Contact: Amy Molnar
amolnar@wiley.com
John Wiley & Sons, Inc.

A new study examined the possible associations between occupation and the risk of dying from systemic autoimmune diseases and found that occupational exposures in farming and industry may be linked to higher death rates from these diseases.

More than 8 million Americans suffer from autoimmune diseases, in which the immune system attacks the body’s own tissues and several occupational exposures have been linked to systemic autoimmune diseases, which affect multiple organs. A new study published in the October issue of Arthritis & Rheumatism (http://www.interscience.wiley.com/journal/arthritis) examined the possible associations between occupation and the risk of dying from systemic autoimmune diseases and found that occupational exposures in farming and industry may be linked to higher death rates from these diseases.

Led by L.S. Gold and A.J. De Roos, of the Fred Hutchinson Cancer Research Center in Seattle, WA, researchers examined death certificate data from 26 states from 1984 to 1998. Any cases that listed a systemic autoimmune disease (for example, rheumatoid arthritis) as a cause of death, were included, as were disease types with a suspected systemic autoimmune disease origin (such as unspecified connective tissue disorder). Five control subjects matched by age, sex, race, year of death and geographic region were also selected. The researchers established each person’s longest-held occupation from the “usual occupation” listed on the death certificate. In addition, they examined specific exposures based on occupation and industry. These included asbestos, solvents, benzene, pesticides and other substances. Occupations involving significant exposure to the public (such as teachers, and waiters/waitresses) or animals were also tracked.

The results showed that some occupations involving exposure to the public (such as nurses and teachers) were associated with an increased risk of dying from a systemic autoimmune disease but this was not the case with all jobs involving public exposure (for example food service jobs). Farmers showed increased risk of death from systemic autoimmune disease, particularly for those who worked with crops versus livestock. In addition, several industrial occupations such as mining and textile machine operators, as well as timber cutting and logging had an increased risk of death from this group of diseases.

Further analysis showed that the same occupations and exposures were present in those who were older than the typical retirement age when they died, “implying that the occupational exposures were involved in a chronic pathogenic process leading to either disease incidence or slow progression of existing autoimmunity,” according to the authors. They suggest that the higher risk associated with jobs involving public contact may be due to exposure to multiple infectious agents leading to an autoimmune response.

The authors note that autoimmune diseases tend to be underreported on death certificates, and that the increased risk seen with certain occupations, such as teachers, may be due to the fact that these individuals have extensive health benefits even after retirement, and therefore better access to care. This would also help explain why other occupations that involve public contact but lower health insurance coverage, such as waiter/waitress, seemed to have a lower risk of death from autoimmune disease. However, not all the occupational associations they found are expected to be affected by insurance status.

“The size of our study allowed us to estimate associations between specific occupations and death from autoimmune diseases and to generate hypotheses that will be useful as starting points for future studies in this area,” the authors conclude. They note that future studies should focus on obtaining more detailed occupational histories from the groups found to be at increased risk.

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Article: “Systemic Autoimmune Disease Mortality and Occupational Exposures,” L.S. Gold, M.H. Ward, M. Dosemeci, A.J. De Roos, Arthritis & Rheumatism, October 2007; (DOI: 10.1002/art.22880).

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September 28, 2007 Posted by | Arthritis & Rheumatism, Autoimmune Diseases, Fred Hutchinson Cancer Research Center, Global Health Vision, Global News, Medical Journals, Occupational Health, Seattle Washington | 1 Comment

Loss of gene leads to protein splicing and buildup of toxic proteins in neurons

Mayo Clinic in Jacksonville

Thursday, September 27, 2007

JACKSONVILLE, Fla. — Researchers at Mayo Clinic in Jacksonville have discovered how loss of a gene can lead to accumulation of toxic proteins in the brain, resulting in a common dementia, and they say this mechanism may be important in a number of age-related neurological disorders.

In the Sept. 26 issue of the Journal of Neuroscience, the scientists demonstrate that absence of a gene known as progranulin leads to errant splicing of a protein that usually operates within the nucleus of a nerve cell (neuron). When cut these proteins move into the body of the cell, and begin to stick together and form a thicket that grows, eventually disrupting the normal functioning of the neuron, the researchers say.

Clumps of this protein, TDP-43, have been found in a number of older age dementias, including Alzheimer’s Disease (AD), Frontal Temporal Dementia (FTD), and in amyotrophic lateral sclerosis (ALS).

Not only does the study potentially explain why TDP-43 pathology is present in a number of neurodegenerative diseases, it also offers new research routes to take in looking for beneficial treatments, says the study’s lead investigator, Leonard Petrucelli, Ph.D. “Our work opens opportunities on possible future therapeutic applications, from approaches to novel drug discovery to the continued exploration of cell survival systems,” he says.

Mayo investigators filled in this piece of the dementia puzzle by exploring possible connections between two recent ground-breaking discoveries. In July, 2006, Mayo researchers reported in Nature that a form of FTD not caused by tau accumulation in neurons was due to mutations in the progranulin gene. Progranulin produces a protein that helps neurons survive, and so far, the research group has found more than 40 different mutations in the gene can directly cause FTD.

The second study, reported in October, 2006, in Science by researchers at the University of Pennsylvania School of Medicine, found that the protein clogging brains of patients with FTD and ALS is TDP-43. The protein was recovered from post-mortem brain tissue and was found only in areas affected by the diseases. For example, in ALS patients it was found in the spinal cord motor neurons which control movement, and in patients with FTD, which is second most common form of dementia in people under age 65, clumps of TDP-43 were found in the frontal and temporal lobes which control the judgment and thought process disrupted in the disease. In its normal state, TDP-43 is believed to help genes produce proteins.

In this study, Mayo researchers investigated whether progranulin is involved in TDP-43 processing. Suppressing progranulin expression in neurons led to accumulation of TDP-43 fragments, they found, and further discovered that this cleavage depends on the caspase 3 enzyme. Caspases cut other proteins and thus play a crucial role in pushing a cell to die when it needs to. It makes sense that these caspase might be activated when progranulin is mutated, Dr. Petrucelli says, because loss of progranulin can activate cell death signaling. “We are now looking into how mutations in progranulin leads to an increase in caspase activity,” he says. “Progranulin could be acting a protective chaperone where it binds to TDP-43, and may protect it from cleavage.”

Theoretically, suppression of caspase 3 might stop the cutting and accumulation of TDP-43, but such a strategy could not work clinically given that caspases are needed throughout the body for normal functioning, Dr. Petrucelli says. “However, it might be possible to identify other compounds that specifically prevent the fragmentation and redistribution of TDP-43, and that is an issue we are now studying.”

At this point, researchers don’t know if progranulin mutations are present in ALS or in AD.

The study was funded by the Mayo Clinic Foundation and by the National Institute on Aging, part of the National Institutes of Health. In this study, Yong-Jie Zhang, Ph.D., and Ya-fei Xu, M.D., both of whom contributed equally as first authors, and other Mayo Clinic, Jacksonville, contributors include Dennis Dickson, M.D., and Rachel Bailey, B.S. Other authors include Chad Dickey, Ph.D., from the University of South Florida; Emanuele Buratt,i Ph.D., and Francisco Baralle, M.D., from the International Center for Genetic Engineering and Biotechnology in Trieste, Italy; and Stuart Pickering-Brown, Ph.D., from the University of Manchester in the United Kingdom.

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To obtain the latest news releases from Mayo Clinic, go to http://www.mayoclinic.org/news. MayoClinic.com (www.mayoclinic.com) is available as a resource for your health stories.

Journalists:
For more information, contact:

Kevin Punsky

904-953-2299 (days)
904-953-2000(evenings)
punsky.kevin@mayo.edu

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September 27, 2007 Posted by | Alzheimers, Dementia, Genes, Genetic, Genetics, Global Health Vision, Global News, Mayo Clinic, News, RSS Feed | 3 Comments

Mixing large doses of both acetaminophen painkiller and caffeine may increase risk of liver damage

WASHINGTON, Sept. 26 2007 — Consuming large amounts of caffeine while taking acetaminophen, one of the most widely used painkillers in the United States, could potentially cause liver damage, according to a preliminary laboratory study reported in the Oct. 15 print issue of ACS’ Chemical Research in Toxicology, a monthly journal. The toxic interaction could occur not only from drinking caffeinated beverages while taking the painkiller but also from using large amounts of medications that intentionally combine caffeine and acetaminophen for the treatment of migraine headaches, menstrual discomfort and other conditions, the researchers say.

Health experts have warned for years that consuming excess alcohol while taking acetaminophen can trigger toxic interactions and cause liver damage and even death. However, this is the first time scientists have reported a potentially harmful interaction while taking the painkiller with caffeine, the researchers say.

While the studies are preliminary findings conducted in bacteria and laboratory animals, they suggest that consumers may want to limit caffeine intake — including energy drinks and strong coffee — while taking acetaminophen.

Chemist Sid Nelson, Ph.D., and colleagues, of the University of Washington in Seattle, tested the effects of acetaminophen and caffeine on E. coli bacteria genetically engineered to express a key human enzyme in the liver that detoxifies many prescription and nonprescription drugs. The researchers found that caffeine triples the amount of a toxic byproduct, N-acetyl-p-benzoquinone imine (NAPQI), that the enzyme produces while breaking down acetaminophen. This same toxin is responsible for liver damage and failure in toxic alcohol-acetaminophen interactions, they say.

In previous studies, the same researchers showed that high doses of caffeine can increase the severity of liver damage in rats with acetaminophen-induced liver damage, thus supporting the current finding.

“People should be informed about this potentially harmful interaction,” Nelson says. “The bottom line is that you don’t have to stop taking acetaminophen or stop taking caffeine products, but you do need to monitor your intake more carefully when taking them together, especially if you drink alcohol.”

Nelson points out that the bacteria used in the study were exposed to ‘megadoses’ of both acetaminophen and caffeine, much higher than most individuals would normally consume on a daily basis. Most people would similarly need to consume unusually high levels of these compounds together to have a dangerous effect, but the toxic threshold has not yet been determined, he says.

Certain groups may be more vulnerable to the potentially toxic interaction than others, Nelson says. This includes people who take certain anti-epileptic medications, including carbamazepine and phenobarbital, and those who take St. John’s Wort, a popular herbal supplement. These products have been shown to boost levels of the enzyme that produces the toxic liver metabolite NAPQI, an effect that will likely be heightened when taking both acetaminophen and caffeine together, he says.

Likewise, people who drink a lot of alcohol may be at increased risk for the toxic interaction, Nelson says. That’s because alcohol can trigger the production of yet another liver enzyme that produces the liver toxin NAPQI. The risks are also higher for those who take large amounts of medications that combine both acetaminophen and caffeine, which are often used together as a remedy for migraine headaches, arthritis and other conditions.

The researchers are currently studying the mechanism by which this toxic interaction occurs and are considering human studies in the future, they say. The National Institutes of Health funded the initial animal and bacterial studies.

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Paper:
“Cooperative Binding of Acetaminophen and Caffeine within the P450 3A4 Active Site,” tx7000702
Print publication date: Oct. 15, 2007
ASAP (online) date: 9-26-07

Contact: Michael Bernstein
m_bernstein@acs.org
202-872-4400
American Chemical Society

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September 26, 2007 Posted by | Acetaminophen and Caffeine, American Chemical Society, Global Health Vision, Global News, Health, News, Preventive Medicine, RSS Feed, WASHINGTON | 2 Comments

Stem cells show promise for treating Huntington’s disease

The song of the canary aids the quest to create medium spiny neurons

Paying close attention to how a canary learns a new song has helped scientists open a new avenue of research against Huntington’s disease – a fatal disorder for which there is currently no cure or even a treatment to slow the disease.

In a paper published Sept. 20 in the Journal of Clinical Investigation, scientists at the University of Rochester Medical Center have shown how stem-cell therapy might someday be used to treat the disease. The team used gene therapy to guide the development of endogenous stem cells in the brains of mice affected by a form of Huntington’s. The mice that were treated lived significantly longer, were healthier, and had many more new, viable brain cells than their counterparts that did not receive the treatment.

While it’s too early to predict whether such a treatment might work in people, it does offer a new approach in the fight against Huntington’s, says neurologist Steven Goldman, M.D., Ph.D., the lead author of the study. The defective gene that causes the disease has been known for more than a decade, but that knowledge hasn’t yet translated to better care for patients.

“There isn’t much out there right now for patients who suffer from this utterly devastating disease,” said Goldman, who is at the forefront developing new techniques to try to bring stem-cell therapy to the bedside of patients. “While the promise of stem cells is broadly discussed for many diseases, it’s actually conditions like Huntington’s – where a very specific type of brain cell in a particular region of the brain is vulnerable – that are most likely to benefit from stem-cell-based therapy.”

The lead authors of the latest paper are Abdellatif Benraiss, Ph.D., research assistant professor at the University, and former post-doctoral associate Sung-Rae Cho, Ph.D., now at Yonsei University in South Korea.

The latest results have their roots in research Goldman did more than 20 years ago as a graduate student at Rockefeller University. In basic neuroscience studies, Goldman was investigating how canaries learn new songs, and he found that every time a canary learns a new song, it creates new brain cells called neurons. His doctoral thesis in 1983 was the first report of neurogenesis – the production of new brain cells – in the adult brain, and opened the door to the possibility that the brain has a font of stem cells that could serve as the source for new cells.

The finding led to a career for Goldman, who has created ways to isolate stem cells. These techniques have allowed Goldman’s group to discover the molecular signals that help determine what specific types of cells they become, and re-create those signals to direct the cells’ development. Benraiss has worked closely with Goldman for more than 10 years on the Huntington’s project.

“The type of brain cell that allows a canary to learn a new song is the same cell type that dies in patients with Huntington’s disease,” said Goldman, professor of Neurology, Neurosurgery, and Pediatrics, and chief of the Division of Cell and Gene Therapy. “Once we worked out the molecular signals that control the development of these brain cells, the next logical step was to try to trigger their regeneration in Huntington’s disease.”

Huntington’s is an inherited disorder that affects about 30,000 people in the U.S. A defective gene results in the death of vital brain cells known as medium spiny neurons, resulting in involuntary movements, problems with coordination, cognitive difficulties, and depression and irritability. The disease usually strikes in young to mid adulthood, in a patient’s 30s or 40s; there is currently no way to slow the progression of the disease, which is fatal.

Stem cells offer a potential pool to replace neurons lost in almost any disease, but first scientists must learn the extensive molecular signaling that shapes their development. The fate of a stem cell depends on scores of biochemical signals – in the brain, a stem cell might become a dopamine-producing neuron, perhaps, or maybe a medium spiny neuron, cells that are destroyed by Parkinson’s and Huntington’s diseases, respectively.

To do this work, Goldman’s team set up a one-two molecular punch as a recipe for generating new medium spiny neurons, to replace those that had become defective in mice with the disease. The team used a cold virus known as adenovirus to carry extra copies of two genes into a region of the mouse brain, called the ventricular wall, that is home to stem cells. This area happens to be very close to the area of the brain, known as the neostriatum, which is affected by Huntington’s disease.

The team put in extra copies of a gene called Noggin, which helps stop stem cells from becoming another type of cell in the brain, an astrocyte. They also put in extra copies of the gene for BDNF (brain-derived neurotrophic factor), which helps stem cells become neurons. Basically, stem cells were bathed in a brew that had extra Noggin and BDNF to direct their development into medium spiny neurons.

The results in mice, which had a severe form of Huntington’s disease, were dramatic. The mice had several thousand newly formed medium spiny neurons in the neostriatum, compared to no new neurons in mice that weren’t treated, and the new neurons formed connections like medium spiny neurons normally do. The mice lived about 17 percent longer and were healthier, more active and more coordinated significantly longer than the untreated mice.

The experiment was designed to test the idea that scientists could generate new medium spiny neurons in an organism where those neurons had already become sick. Now that the capability has been demonstrated, Goldman is working on ways to extend the duration of the improvement. Ultimately he hopes to assess this potential approach to treatment in patients.

“This offers a strategy to restore brain cells that have been lost due to disease. That could perhaps be coupled with other treatments currently under development,” said Goldman. Many of those treatments are being studied at the University, which is home to a Huntington’s Disease Center of Excellence and is the base for the Huntington Study Group.

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In addition to Benraiss, Cho, and Goldman, other authors include former Cornell graduate student Eva Chmielnicki, Ph.D.; Johns Hopkins neurosurgeon Amer Samdani, M.D., now at Shriners Children’s Hospital in Philadelphia; and Aris Economides of Regeneron Pharmaceuticals. The work was funded by the National Institute of Neurological Disorders and Stroke, the Hereditary Disease Foundation, and the High Q Foundation.

Contact: Tom Rickey
tom_rickey@urmc.rochester.edu
585-275-7954
University of Rochester Medical Center

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September 25, 2007 Posted by | Global Health Vision, Global News, Huntington's disease, Journal of Clinical Investigation, RSS Feed, Stem Cells, University of Rochester | 3 Comments

Political decisions harming cancer treatment in Europe

Time to stand up and be counted, say oncologists

Barcelona, Spain: Recent political decisions have had serious consequences for European oncology, said Professor John Smyth at ECCO 14, the European Cancer Conference, today (Monday 24 September 2007). Professor Smyth, President of the Federation of European Cancer Societies (FECS) said that the new European CanCer Organisation (ECCO) would take an active role in engaging with policymakers to ensure that future legislation did not have a similarly negative impact.

Professor Smyth cited the Clinical Trials Directive and the recent Directive on Physical Agents (Electromagnetic Fields) as two examples of legislation that had had a major negative impact on oncology in Europe. “In the first, the academic oncology community woke up too late and found that the administrative and financial burden of running clinical trials had increased to the extent that many simply gave up,” he said. “Now the Directive on Electromagnetic Fields looks as though it may stop all MRI scanning in Europe. We simply cannot continue to bury our heads in the sand on these issues, which affect doctors and patients alike.”

Forthcoming topics of concern were the problems of international collaboration on stem cell research where European countries had widely differing legislation, and the whole area of the escalating cost of cancer treatment. “The successful development of many new anti-cancer drugs in recent years is challenging every health economic programme in Europe,” said Professor Smyth. “It is imperative to find ways to improve the cost effectiveness of cancer treatment in general, and particularly the use of drugs. Improving the cost effective use of medicines is a major priority for industry, politicians and the public at large.

“Due to these new and improved treatments, screening, and earlier and better diagnosis, cancer patients are living longer and better lives. But how will the huge financial burden on society that this implies be met” ECCO will be asking governments and the European Commission to consider these issues as a matter or urgency.”

ECCO will bring together major players in cancer research, treatment, and care in order to create awareness of patients’ wishes and needs, encourage progressive thinking in cancer policy, education, and training, and continue to promote European cancer research and its application through the organisation of multi-disciplinary meetings and conferences, he said.

“The difference between the new ECCO and the old FECS will be that the new organisation has decided to take a far more active role in engaging with policymakers to promote the interests of both cancer patients, those who care for them; and those without whose research there would be no advances in treatment and care,” he said. “For too long oncologists have sat back and said that getting involved in politics is not their business, and recent events have shown us that this is an attitude which is no longer sustainable.”

The last two years had given ample opportunity for reflection, said Professor Smyth. “Not only did we consult our members, but we also carried out an audit of many players in oncology, patient groups, media, and other stakeholders. They all told us the same thing – they wanted to see a democratic, representative, and visionary organisation tackle the problems that are currently besetting oncology science and practice. An organisation that would provide consistently dependable information on the state of oncology in Europe, and through that information provision would strive to improve the lot of everyone involved in cancer.

“It is a daunting task, but one that needs to be undertaken. And we will do our very best to carry it out.”

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Notes for Editors:

1. Invitations to join ECCO (http://www.ecco-org.eu/) have been sent to the FECS Founding Members: EACR, EONS, ESSO, ESMO, ESTRO, and SIOP Europe.
Members and Advisory Council: EANO, EORTC, ESGO, ESO, ESOP, Euroskin, and EUSOMA, EBMT, ECL, Europa Donna, FAC, OECI, and UICC.

2. The Clinical Trials Directive 2001/20/EC came into force in 2004. Its aim was to harmonise national legislation on the conduct of clinical trials and to create a level playing field for European clinical research. In fact it seems to have had the opposite effect, with academic researchers finding that the extra administrative and financial burden that it imposes impedes severely their chances of carrying independent, objective research.

3. The Physical Agents (Electromagnetic Fields) Directive 2004/40/EC is intended to protect workers from electromagnetic radiation. However, its implementation in its current form would effectively ban all MRI scanning in Europe, since the limits it sets to occupational radiation exposure would mean that anyone working or moving near MRI equipment will breach them, thus making it possible for them to sue their employers.

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September 24, 2007 Posted by | Cancer, European Cancer Conference, Global Health Vision, Global News, News, News UK | 2 Comments