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duminică, 5 august 2012

Paralysis In Mice With Multiple Sclerosis Reversed By Alzheimer's Molecule

A molecule widely assailed as the chief culprit in Alzheimer's disease unexpectedly reverses paralysis and inflammation in several distinct animal models of a different disorder - multiple sclerosis, Stanford University School of Medicine researchers have found.

This surprising discovery, which was reported in a study published online as the cover feature in Science Translational Medicine, comes on the heels of the recent failure of a large-scale clinical trial aimed at slowing the progression of Alzheimer's disease by attempting to clear the much-maligned molecule, known as A-beta, from Alzheimer's patients' bloodstreams. While the findings are not necessarily applicable to the study of A-beta's role in the pathology of that disease, they may point to promising new avenues of treatment for multiple sclerosis.

The short protein snippet, or peptide, called A-beta (or beta-amyloid) is quite possibly the single most despised substance in all of brain research. It comes mainly in two versions differing slightly in their length and biochemical properties. A-beta is the chief component of the amyloid plaques that accumulate in the brains of Alzheimer's patients and serve as an identifying hallmark of the neurodegenerative disorder.

A-beta deposits also build up during the normal aging process and after brain injury. Concentrations of the peptide, along with those of the precursor protein from which it is carved, are found in multiple-sclerosis lesions as well, said Lawrence Steinman, MD, the new study's senior author. In a lab dish, A-beta is injurious to many types of cells. And when it is administered directly to the brain, A-beta is highly inflammatory.

Yet little is known about the physiological role A-beta actually plays in Alzheimer's - or in MS, said Steinman, a professor of neurology and neurological sciences and of pediatrics and a noted multiple-sclerosis researcher. He, first author Jacqueline Grant, PhD, and their colleagues set out to determine that role in the latter disease. (Grant was a graduate student in Steinman's group when the work was done.)

Multiple sclerosis, an inflammatory autoimmune disease, occurs when immune cells invade the brain and spinal cord and attack the insulating coatings of nerve cells' long, cable-like extensions called axons. Damage to these coatings, composed largely of a fatty substance called myelin, disrupts the transmission of signals that ordinarily travel long distances down axons to junctions with other nerve cells. This signal disruption can cause blindness, loss of muscle control and difficulties with speech, thought and attention.

Previous research by Steinman, who is also the George A. Zimmerman Professor, and others showed that both A-beta and its precursor protein are found in MS lesions. In fact, the presence of these molecules along an axon's myelinated coating is an excellent marker of damage there.

Given the peptide's nefarious reputation, Steinman and his associates figured that A-beta was probably involved in some foul play with respect to MS. To find out, they relied on a mouse model that mimics several features of multiple sclerosis - including the autoimmune attack on myelinated sections of the brain that causes MS.

Steinman had, some years ago, employed just such a mouse model in research that ultimately led to the development of natalizumab (marketed as Tysabri), a highly potent MS drug. That early work proved that dialing down the activation and proliferation of immune cells located outside the central nervous system (which is what natalizumab does) could prevent those cells from infiltrating and damaging nerve cells in the CNS.

Knowing that immunological events outside the brain can have such an effect within it, the Stanford scientists were keen on seeing what would happen when they administered A-beta by injecting it into a mouse's belly, rather than directly to the brain.

"We figured it would make it worse," Steinman said.

Surprisingly, the opposite happened. In mice whose immune systems had been "trained" to attack myelin, which typically results in paralysis, A-beta injections delivered before the onset of symptoms prevented or delayed the onset of paralysis. Even when the injections were given after the onset of symptoms, they significantly lessened the severity of, and in some cases reversed, the mice's paralysis.

Steinman asked Grant to repeat the experiment. She did, and got the same results.

His team then conducted similar experiments using a different mouse model: As before, they primed the mice's immune cells to attack myelin. But rather than test the effects of A-beta administration, the researchers harvested the immune cells about 10 days later, transferred them by injection to another group of mice that did not receive A-beta and then analyzed this latter group's response. The results mirrored those of the first set of experiments, proving that A-beta's moderating influence on the debilitating symptoms of the MS-like syndrome has nothing to do with A-beta's action within the brain itself, but instead is due to its effect on immune cells before they penetrate the brain.

Sophisticated laboratory tests showed that A-beta countered not only visible symptoms such as paralysis, but also the increase in certain inflammatory molecules that characterizes multiple-sclerosis flare-ups. "This is the first time A-beta has been shown to have anti-inflammatory properties," said Steinman.

Inspection of the central nervous systems of the mice with the MS-resembling syndrome showed fewer MS-like lesions in the brains and spinal cords of treated mice than in those not given A-beta. There was also no sign of increased Alzheimer's-like plaques in the A-beta-treated animals. "We weren't giving the mice Alzheimer's disease" by injecting A-beta into their bellies, said Grant.

In addition, using an advanced cell-sorting method called flow cytometry, the investigators showed A-beta's strong effects on the immune system composition outside the brain. The numbers of immune cells called B cells were significantly diminished, while those of two other immune-cell subsets - myeloid cells and memory T-helper cells - increased.

"At this point we wanted to find out what would happen if we tried pushing A-beta levels down instead of up," Grant said. The researchers conducted a different set of experiments, this time in mice that lacked the gene for A-beta's precursor protein, so that they could produce neither the precursor nor A-beta. These mice, when treated with myelin-sensitized immune cells to induce the MS-like state, developed exacerbated symptoms and died faster and more frequently than normal mice who underwent the same regimen.

Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease in San Francisco and a veteran Alzheimer's researcher, noted that while A-beta's toxicity within the brain has been established beyond reasonable doubt, many substances made in the body can have vastly different functions under different circumstances.

"A-beta is made throughout our bodies all of the time. But even though it's been studied for decades, its normal function remains to be identified," said Mucke, who is familiar with Steinman's study but wasn't involved in it. "Most intriguing, to me, is this peptide's potential role in modulating immune activity outside the brain."

The fact that the protection apparently conferred by A-beta in the mouse model of multiple sclerosis doesn't require its delivery to the brain but, rather, can be attributed to its immune-suppressing effect in the body's peripheral tissues is likewise intriguing, suggested Steinman.

"There probably is a multiple-sclerosis drug in all this somewhere down the line," he said.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our multiple sclerosis section for the latest news on this subject. Additional Stanford co-authors were associate professor of neurology and neurological sciences Katrin Andreasson, MD; professor of genetics Leonore Herzenberg, DSc; emeritus professor of genetics Leonard Herzenberg, PhD; postdoctoral scholars Eliver Ghosn, PhD, Robert Axtell, PhD, Hedwich Kuipers, PhD, and Katja Herges, MD; and graduate student Nathan Woodling.
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The Immune System Enables HIV-Infected T Cells To Transport The Virus Throughout The Body

A new study has discovered one more way the human immunodeficiency virus (HIV) exploits the immune system. Not only does HIV infect and destroy CD4-positive helper T cells - which normally direct and support the infection-fighting activities of other immune cells - the virus also appears to use those cells to travel through the body and infect other CD4 T cells. The study from Massachusetts General Hospital (MGH) investigators, which will appear in the journal Nature and has received advance online release, is the first to visualize the behavior of HIV-infected human T cells within a lymph node of a live animal, using a recently developed "humanized" mouse model of HIV infection.

"We have found that HIV disseminates in the body of an infected individual by 'hitching a ride' on the T cells it infects," says Thorsten Mempel, MD, PhD, of the MGH Center for Immunology and Inflammatory Diseases, who led the study. "Infected T cells continue doing what they usually do, migrating within and between tissues such as lymph nodes, and in doing so they carry HIV to remote locations that free virus could not reach as easily. There are drugs that can manipulate the migration of T cells that potentially could be used to help control the spread of virus within a patient."

When HIV is introduced into blood or tissues, the virus binds to CD4 molecules on the surface of helper T cells, injecting its contents into cells and setting off a process that leads to the assembly and release of new virus particles. It has long been assumed that these free virus travel by diffusion through tissue fluids to encounter new cells that can be infected. But recent studies have suggested that HIV can also pass directly from cell to cell when structures called virological synapses form during long-lasting interactions between T cells. Since CD4 T cells usually migrate quickly and form only transient contacts with other cells, the current study was designed to examine whether HIV alters the migration of infected T cells, allowing the kind of persistent contact that facilitates the spread of infection.

The team's experiments used the humanized BLT mouse model, which has what is essentially a human immune system and is the only non-primate that can be infected with HIV. After first confirming that human T cells enter and normally migrate within the animals' lymph nodes - known to be important sites of HIV replication - the researchers injected the animals with HIV engineered to express green fluorescent protein (GFP), allowing them to track the movement of infected cells within living animals using a method called intravital microscopy. They first observed that, within two days, infected T cells continued to migrate and were uniformly distributed within lymph nodes but remained in nodes closest to the site of injection.

While the HIV-infected cells actively moved within lymph nodes, they did not move as quickly as comparable but uninfected T cells. In addition, 10 to 20 percent of the HIV-infected T cells formed abnormally long and thin extensions that appeared to trail behind moving cells, often exhibiting branches.

The researchers hypothesized that the HIV envelope protein, which is expressed on the surface of infected T cells before they release new virus particles, might cause infected cells to form tethering contacts with uninfected cells, producing these extensions. A series of experiments verified that the elongated shape of some infected cells requires the presence of the envelope protein and that many of the elongated cells contained multiple nuclei, suggesting they had been formed by the fusion of several cells.

To test the role of T cell migration in HIV infection, the researchers injected another group of BLT mice with HIV and at the same time treated them with an agent that prevents T cells from leaving lymph nodes. Two months later, levels of HIV in the bloodstream and in lymph nodes distant from the site of injection were much lower than in untreated HIV-infected animals, supporting the importance of T cell migration to carry virus throughout the body. Treatment with the migration-suppressing agent, however, did not reduce viral levels in animals with already established HIV infection.

"While our observation of tethering interactions between infected and uninfected CD4-expressing cells suggest that HIV may be transmitted between T cells by direct contact, we will have to clearly show this in future studies and explore how important it is relative to the transmission by free virus," explains Mempel, an assistant professor of Medicine at Harvard Medical School. He adds that the availability of the BLT mouse was instrumental in their ability to carry out this study. "This approach provides a new vantage point to investigate previously unexplored aspects of HIV pathogenesis."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our hiv / aids section for the latest news on this subject. Lead author of the Nature paper is Thomas Murooka, PhD, of the MGH Center for Immunology and Inflammatory Diseases (CIID). Additional co-authors are Maud Deruaz, PhD, Francesco Marangoni, PhD, Vladimir Vrbanac, DVM, Edward Seung, PhD, Andrew Tager, MD, and Andrew Luster, MD, PhD, MGH CIID; and Ulrich von Andrian, Harvard Medical School. The study was supported by grants from the National Institutes of Health and the Ragon Institute of MGH, MIT and Harvard.
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First Genome-Wide Analysis Of Peripheral T-cell Lymphomas Identifies 13 Novel Alterations In This Aggressive Blood Cancer

How Protein Component That Enables Cell Replication Gets Ferried To Chromosome Tips

Stem cells are special. Nestled in muscle and skin, organ and bone, they bide their time over years or decades until called to replace damaged or lost tissue. One secret to their longevity is an enzyme called telomerase, which stills the relentless ticking of the molecular clock that limits the life span of other cells.

This cellular fountain of youth prevents the progressive shortening of the tips of our chromosomes that occurs with each cell division. But the presence of telomerase can be a double-edged sword: The same activity that ensures long life for stem cells can also keep a cancer cell dividing long after its aging neighbors have thrown in the towel. Conversely, a malfunction can prevent stem cells from doing their job and lead to devastating diseases.

Now, for the first time, researchers at the Stanford University School of Medicine have identified how telomerase is recruited to chromosome ends - and figured out a way to block it.

"If telomerase is unable to maintain the ends of the chromosomes, cells will stop multiplying," said professor of medicine Steven Artandi, MD, PhD. "This would be advantageous in cancer cells, but in normal stem cells it can cause severe dysfunction and lead to diseases such as pulmonary fibrosis, aplastic anemia and a genetic condition called dyskeratosis congenita. We want to understand how telomerase works, and to develop therapies for cancer and these other diseases."

Artandi is the senior author of the research, which was published in Cell. He is also a member of the Stanford Cancer Institute. Graduate student Franklin Zhong is the first author of the study.

Telomerase is normally expressed in adult stem cells and immune cells, as well as in cells of the developing embryo. In these cells, the enzyme caps off the ends of newly replicated chromosomes, allowing unfettered cell division. Without telomerase, cells stop dividing or die when the ends - called telomeres - fall below a minimum length. Unfortunately, the enzyme is also active in nearly all cancer cells.

Earlier research in Artandi's lab identified a protein called TCAB1 that brings the telomerase complex (actually a large clump of many proteins) to a processing area in the cell's nucleus called a Cajal body. But no one knew how the complex was then ferried to the ends of telomeres, and research was stymied by the complex's large size, multiple components and relative scarcity.

"This problem has been really intractable," said Artandi. "The enzyme is extremely hard to study. But we've now found that telomerase is recruited to the telomeres through an interaction with a protein called TPP1 that coats the ends of chromosomes." What's more, the researchers have identified the exact region of TPP1 to which telomerase binds - a section called an OB-fold.

"When we mutated this site in TPP1," said Artandi, "we blocked the interaction between the two proteins and prevented telomerase from going to the telomeres. And when we interfered with this interaction in human cancer cells, the telomeres began to shorten." The researchers are now assessing whether the life span of the cancer cells, and their ability to divide unchecked, will also be affected by the treatment.

To confirm their finding, Artandi and his colleagues used cells from patients with pulmonary fibrosis - a debilitating scarring or thickening of lung tissue associated with telomerase mutations. The disease had been troubling to researchers and clinicians, however, because the patients' mutated telomerase seemed to be fully active when tested in the laboratory. Zhong and Artandi found that the disease-associated mutations occurred in the portion of telomerase that interacted with TPP1, and interfered with their binding. As a result the enzyme, although active, couldn't get to where it was needed.

"It was impossible to even begin to understand this mechanism before we knew how these two molecules interact," said Artandi. "But now that we're getting a handle on this, we can begin to think about developing inhibitors - maybe in the form of peptides or small molecules - that can mimic this disruption. This could be very valuable in cancer therapies."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our genetics section for the latest news on this subject. In addition to Zhong and Artandi, other Stanford researchers involved in the work include postdoctoral scholars Luis Batista, PhD, and Adam Freund, PhD; graduate student Matthew Pech; and former graduate student Andrew Venteicher, PhD.
The research was supported by Singapore's Agency for Science, Technology and Research, the California Institute for Regenerative Medicine, the National Science Foundation, the Leukemia and Lymphoma Society, the Glenn Foundation for Medical Research and the National Institutes of Health.
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'Antisense' Compound Rids Muscle Cells Of Toxic RNA: A Promising Step Toward Muscular Dystrophy Treatment

Scientists have reversed symptoms of myotonic muscular dystrophy in mice by eliminating a buildup of toxic RNA in muscle cells. The work, carried out by scientists at the University of Rochester Medical Center, Isis Pharmaceuticals Inc. and Genzyme, is published in Nature.

After experimental antisense compounds were administered to mice twice a week for four weeks, symptoms of the disease were reduced for up to one year - a significant portion of a mouse's lifespan.

The investigators say that while the work is an encouraging step forward against myotonic dystrophy, one of the most common forms of muscular dystrophy, it's too soon to know whether the approach will work in patients. But they are cautiously optimistic, noting that the compound is extremely effective at reversing the disease - whose genetic underpinnings make it particularly vulnerable to an antisense approach - in a mouse model.

"These results give us strong encouragement about the possibility of developing a treatment that could fundamentally alter the disease. It's an important step on a long path," said senior author Charles Thornton, M.D., a neurologist at the University of Rochester Medical Center who has been pursuing new treatments for the disease for more than two decades.

"But, it's too early to know if this treatment will work as well in people as it did in the laboratory. Unfortunately, in biomedical research there are previous examples of compounds that worked in mice but not in people," added Thornton, the Saunders Family Distinguished Professor in Neuromuscular Research.

About 35,000 Americans have myotonic dystrophy, an inherited disorder that is marked by progressive muscle weakness and stiffness; eventually many patients have difficulty walking, swallowing, and breathing. The disease can also affect the eyes, the heart, and the brain. While there are medications to treat some of the disease symptoms, there is no drug to stop its progression.

The recent progress comes about a decade after several scientists, including Thornton, discovered that the genetic defect that causes the disease works quite differently than most other inherited diseases. In many diseases, a genetic flaw means that an important protein is not made correctly, or not made at all.

But in myotonic dystrophy, the defect results in the creation of an abnormal messenger RNA, which accumulates in the nucleus, getting in the way and stopping other proteins from doing their jobs. One of those proteins is MBNL1, which helps create chloride channels that are important for electrical control of muscles. When that process is thwarted, muscles send errant electrical signals, causing symptoms.

The approach outlined in the Nature paper exploits the roots of the defect, harnessing an enzyme whose usual job is to cut RNA into pieces. Working closely with the Rochester and Genzyme teams, scientists at Isis created synthetic compounds - short snippets of chemically modified DNA - that bind to the toxic RNA, modifying it in such a way that it was targeted for destruction by one of the body's own enzymes, RNase H.

With the team's most effective compounds, symptoms in the mice were reversed. The level of toxic RNA was reduced by more than 80 percent; stiffness in muscles eased dramatically; the microscopic structure of muscle was improved; and electrical signaling in muscles returned to normal.

The possibility of targeting "toxic RNA" - a buildup of abnormal RNA causing cellular processes to go awry - makes myotonic dystrophy an excellent target for antisense drugs, said Thornton.

The compounds are called "antisense" because their genetic code is the mirror image of the target RNA strand, known in scientific parlance as the "sense" molecule. The antisense compound will only stick to the precise RNA that is part of the myotonic dystrophy gene, leaving thousands of other vitally important RNAs alone.

While antisense technology has been in development for a couple of decades, it has not been effective at eliminating RNA in muscle cells until now. Results like those in the Nature paper are creating enthusiasm particularly among scientists who study neurodegenerative diseases, Thornton says. He points to promising work by a team from the University of California at San Diego on Huntington's disease, as well as research out of Cold Spring Harbor Laboratory on spinal muscular atrophy.

"For 20 years we studied myotonic dystrophy, hoping that someday we would learn enough to spot its Achilles heel," said Thornton. "This work comes close to doing that.

"I know it is unscientific for me to think so, but I can't help but see a little glimmer of 'medical justice' in this approach. For the same reason that the toxic RNA makes people sick, by hanging around too long in the nucleus and gumming up the works, it also becomes more susceptible to antisense drugs, because these drugs seem to work extraordinarily well against RNA in the nucleus," he added.

"Based upon these exciting preclinical data, we have initiated a drug discovery project for myotonic dystrophy with Dr. Thornton's team to identify an antisense drug to begin clinical testing," said C. Frank Bennett Ph.D., Senior Vice President, Research at Isis Pharmaceutical, Inc. "Myotonic dystrophy represents an ideal opportunity for an antisense drug as the disease-causing gene produces a toxic RNA that is not easily targeted with other therapeutic approaches. In just a few years, we have been able to expand our severe and rare disease franchise and maintain a broad research program, in which we are evaluating many different diseases that could be treated with an antisense drug."

Thornton was inspired to create a robust research effort to address the disease largely because of his experience treating patients. He is co-director of the Medical Center's Wellstone Muscular Dystrophy Cooperative Research Center, one of the world's top centers for the treatment of muscular dystrophy. He is also a scientist in the Center for Neural Development and Disease, where he runs a laboratory looking at the roots of the disease and exploring new treatments. On any given day, he is both seeing patients coping with conditions like myotonic dystrophy, as well as running laboratory experiments aimed at stopping the disease altogether.

As the research progressed, Thornton struck up a collaboration with Isis Pharmaceuticals Inc., the creator of the only antisense medication on the market, and Genzyme, a company with experience treating muscle diseases. Earlier this summer Isis announced an agreement with Biogen Idec Inc. to explore antisense treatments for myotonic dystrophy - an effort closely linked to Thornton's work.

Now scientists at Isis and the University of Rochester are working to improve their lead compound further, developing antisense compounds with stronger activity against the toxic RNA, but with minimal effects on the rest of the body. An unknown factor at this point, Thornton says, is whether the compounds will also improve the muscle-wasting aspect of the disease. That symptom, which causes great difficulty for patients, has been hard for scientists to create in mice, and so it's difficult to predict how it might respond to antisense knockdown technology.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our muscular dystrophy / als section for the latest news on this subject. The first author of the paper is Thurman Wheeler, M.D., assistant professor of Neurology at the University of Rochester Medical Center, who conducted many of the experiments. Other authors include Masayuki Nakamori, now at the University of Osaka in Japan; Sanjay Pandey, A. Robert MacLeod, and C. Frank Bennett of Isis Pharmaceuticals; and Andrew Leger, Seng Cheng, and Bruce Wentworth of Genzyme.
The work was funded by the National Institute of Neurological Disorders and Stroke, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Saunders Family Neuromuscular Research Fund, Run America, the Muscular Dystrophy Association, and the Uehara Memorial Foundation.
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First Indication Of People Naturally Protected Against Rabies Found In Remote Amazonian Communities

Challenging conventional wisdom that rabies infections are 100 percent fatal unless immediately treated, scientists studying remote populations in the Peruvian Amazon at risk of rabies from vampire bats found 11 percent of those tested showed protection against the disease, with only one person reporting a prior rabies vaccination. Ten percent appear to have survived exposure to the virus without any medical intervention. The findings from investigators at the U.S. Centers for Disease Control and Prevention (CDC) were published in the August 2012 issue of the American Journal of Tropical Medicine and Hygiene.

"The overwhelming majority of rabies exposures that proceed to infections are fatal. However, our results open the door to the idea that there may be some type of natural resistance or enhanced immune response in certain communities regularly exposed to the disease," said Amy Gilbert with the CDC's National Center for Emerging and Zoonotic Infectious Diseases, who is the paper's lead author. "This means there may be ways to develop effective treatments that can save lives in areas where rabies remains a persistent cause of death."

Rabies experts estimate the disease kills 55,000 people each year in Africa and Asia alone, and appears to be on the rise in China, the former Soviet Republics, southern Africa, and Central and South America. According to the CDC, in the United States, human deaths from rabies have declined over the past century from 100 annually to an average of two per year thanks to an aggressive campaign to vaccinate domestic animals against the disease.

In general, people who believe they may have been exposed to rabies are advised to immediately seek treatment which involves post-exposure prophylaxis (PEP) - a series of injections - to prevent the exposure from causing an active infection. These preventive treatments, when administered promptly, are 100 percent successful at preventing disease. Scientists have documented only a small number of individual cases, including one last year in California, in which an exposure to rabies proceeded to infection and the victim survived. Most of those survivors still required intensive medical attention, including one case in Wisconsin in which doctors induced a coma, though this approach has not been successful in most subsequent cases.

This CDC study was conducted in collaboration with the Peruvian Ministry of Health as part of a larger project to understand better bat-human interactions and its relation to rabies and emerging diseases that may be transmitted by bats. For their research, scientists traveled to two communities (Truenococha and Santa Marta) in a remote section of the Peruvian Amazon where outbreaks of fatal infections with rabies caused by bites from vampire bats - the most common "natural reservoir" for the disease in Latin America - have occurred regularly over the last two decades. They interviewed 92 people, 50 of whom reported previous bat bites. Blood samples were taken from 63 individuals and seven (11 percent) were found to have "rabies virus neutralizing antibodies."

One out of the seven individuals reported receiving a rabies vaccination - which generates antibodies to the rabies virus?"but there was no evidence that the other six had received anti-rabies vaccine prior to the blood sampling or had sought out any medical attention for a bat bite, evidence that they had harbored the virus itself.

The researchers acknowledged that they could not conclusively determine whether the antibodies were caused by an exposure to the virus that was somehow insufficient to produce disease. But they believe their evidence "suggests that (rabies virus) exposure is not invariably fatal to humans."

Gilbert said non-fatal exposures may happen more often than some think because "unless people have clinical symptoms of the disease they may not go to the hospital or clinic, particularly where access is limited."

"We all still agree that nearly everyone who is found to be experiencing clinical symptoms of rabies dies," Gilbert said. "But we may be missing cases from isolated high-risk areas where people are exposed to rabies virus and, for whatever reason, they don't develop disease."

In the Amazon region where the study was conducted - the Province Datem del Maranon in the Loreto Department of northern Peru - vampire bats, which live off of mammalian blood, regularly come out at night and prefer to feed on livestock. But in the absence of those food sources, they are known to seek out a meal from humans. They can use their extremely sharp teeth and the anticoagulant that naturally occurs in their saliva (appropriately referred to as "draculin") to feed on a sleeping person without awakening them. The rabies virus circulates extensively among vampire bat colonies in the region, and when an infected bat feeds, it passes along the virus to its host.

"This type of thorough and persistent scientific rabies investigation lends continued support to the belief that even the most dangerous of infectious diseases may be amenable to treatment," said James W. Kazura, MD noted infectious disease expert and president of the American Society of Tropical Medicine and Hygiene (ASTMH). "Continued investment of resources is essential for us to protect the health and well-being of innocent people whose lives and livelihoods are needlessly threatened by infectious diseases like rabies."

Gilbert and her colleagues hope their findings will prompt further studies in remote, at-risk communities to see if the results are replicated. In an editorial accompanying the study, Rodney E. Willoughby, a pediatric disease specialist at Children's Hospital of Wisconsin, said if it turns out there are distinct populations of people with "complete or relative resistance to rabies," there could be the potential to use whole genome sequencing to help develop new, life-saving treatments for rabies infections.

"Careful, respectful genetic study of these genetically unique populations may provide information on which pathways in human biochemistry and physiology promote resistance to human rabies," he wrote. "Equally important, knowing that there is a continuum of disease, even for infectious diseases like rabies, should push us harder to try for cures when confronted by so-called untreatable infectious diseases...."

Gilbert noted that the study was done as part of a larger public health effort to address a series of rabies outbreaks in the Amazon, where some health officials are now considering conducting pre-emptive vaccination campaigns in areas where risk of rabies is high and availability of medical care low. She said that while her study highlights people who appear to have survived an exposure to the virus, the fact remains that rabies outbreaks in small communities in the region have left tragic results.

"These are very small villages and, when they witness ten people dying from what is a horrible disease, it is incredibly traumatic," Gilbert said. "We want to help raise awareness of the problem and try to develop a more proactive response."

Article adapted by Medical News Today from original press release. Source: Burness Communications
Visit our tropical diseases section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:

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Researchers Develop First Potential Medicine For Patients With Most Severe Form Of Congenital Hyperinsulinism

A pilot study in adolescents and adults has found that an investigational drug shows promise as the first potential medical treatment for children with the severest type of congenital hyperinsulinism, a rare but potentially devastating disease in which gene mutations cause insulin levels to become dangerously high.

"There is currently no effective medicine for children with the most common and most severe form of hyperinsulinism," said study leader Diva D. De Leon, M.D., a pediatric endocrinologist at The Children's Hospital of Philadelphia. "Our new research shows that this investigational drug, a peptide called exendin-(9-39), controls blood sugar levels in people, a very promising result."

The study appears online ahead of print in the journal Diabetes.

In congenital hyperinsulinism (HI), mutations disrupt the insulin-secreting beta cells in the pancreas. Uncontrolled, excessive insulin levels thus sharply reduce blood glucose levels, a condition called hypoglycemia. If untreated, hypoglycemia may cause irreversible brain damage or death in children. Congenital HI occurs in an estimated one in 50,000 U.S. children, with a higher incidence among Ashkenazic Jews and certain other groups.

The standard treatment for some forms of congenital HI is diazoxide, a drug that controls insulin secretion by opening potassium channels in beta cells. However, this drug does not work in the most common types of HI, in which mutations prevent these potassium channels from forming.

When abnormal beta cells occur only in a discrete portion of the pancreas, precise surgery on the tiny organ can remove the lesion and cure HI. The Congenital Hyperinsulinism Center at The Children's Hospital of Philadelphia is a world leader in diagnosing such lesions and performing the curative surgery on newborns.

However, in roughly half of congenital HI cases, abnormal cells are diffused through the pancreas, and surgeons must remove nearly the entire pancreas. This leaves the majority of patients at high risk of developing diabetes.

The current study, which builds on previous research by De Leon and colleagues in animals, uses exendin-(9-39), which blocks the action of a hormone receptor, glucagon-like peptide-1 (GLP-1), in beta cells. The GLP-1 receptor is currently the target of drugs that treat diabetes, using the opposite effect from that investigated in this HI study.

The current pilot study included nine subjects, aged 15 to 47 years old, who had hyperinsulinism caused by mutations in potassium channels. None were being treated for HI at the time of the study, but all were at risk of hypoglycemia during periods of fasting.

In all nine subjects, the drug controlled blood glucose levels during fasting. Exendin also controlled insulin secretion in cell studies of beta cells taken from newborns with HI. The current research did not focus on the biological mechanisms that occurred, but De Leon said the results are encouraging enough to progress to a clinical study in children with HI over the next year.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our diabetes section for the latest news on this subject. Financial support for this study came from the National Institutes of Health (grant 1R03DK07835), the Lester and Liesel Baker Foundation, and the Clifford and Katherine Goldsmith Foundation. De Leon's co-authors, all from Children's Hospital, were Charles A. Stanley, M.D., Andrew C. Calabria, M.D., Changhong Li, M.D., and Paul R. Gallagher In addition to their positions at Children's Hospital, De Leon, Stanley and Li also are in the Perelman School of Medicine at the University of Pennsylvania.
"The GLP-1 Receptor Antagonist Exendin-(9-39) Elevates Blood Fasting Glucose Levels in Congenital Hyperinsulinism due to Inactivating Mutations in the ATP-sensitive Potassium Channel," Diabetes, published online Aug.1, 2012, to appear in print, October 2012. doi: 10.2337/db12-0166.
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