Critical role discovered for the complement system in early macular degeneration

Main Category: Eye Health / Blindness
Also Included In: Seniors / Aging
Article Date: 20 Aug 2013 - 0:00 PDT Current ratings for:
Critical role discovered for the complement system in early macular degeneration

In a study published on line in the journal Human Molecular Genetics, Drs. Donita Garland, Rosario Fernandez-Godino, and Eric Pierce of the Ocular Genomics Institute at the Massachusetts Eye and Ear, Harvard Medical School, along with their colleagues, reported the unexpected finding that in mice genetically engineered to have an inherited form of macular degeneration, turning off the animals' complement system, a part of the immune system, prevented the disease.

Macular degenerations, which occur in several forms, are important causes of vision loss. Juvenile or early-onset macular degeneration includes several inherited disorders that can affect children and young adults. In contrast, age-related macular degeneration (AMD) affects older individuals; it is the leading cause of blindness for individuals over 65 years of age in developed countries, and its prevalence is increasing worldwide. Both inherited macular degeneration and AMD lead to the loss of central vision. While therapies exist for some forms of late AMD, and nutritional supplements can slow the progression of early AMD for some patients, improved therapies to prevent vision loss from these disorders are needed.

This is the first report to demonstrate a role for the complement system in an inherited macular degeneration. Previous genetic studies have shown that variants in the genes that encode several complement system components are important risk factors for AMD. Based on this, drugs that inhibit specific complement system activities are being tested clinically as treatments for AMD. However, it is not entirely clear how alterations in complement system components lead to AMD.

The new results reported suggest that complement activation by abnormalities in the extracellular matrix or the scaffold secreted by retinal cells plays an important role in the formation of basal deposits, one of the earliest stages of macular degeneration. Basal deposits are precursors of drusen, which appear as spots in the retina on clinical examination, and are accumulations of proteins and lipids outside the retinal cells; their presence is the first clinical indication of a risk of developing macular degeneration.

The findings are important because they suggest that inherited macular degenerations share common features with AMD, such as a complement-mediated response to abnormal extracellular matrix. The results also suggest that alterations in the activity of the complement system are involved in the earliest stages of disease pathogenesis. This finding has important implications for the use of drugs that modulate the complement system for treating macular degenerations.

For these studies, the investigators used a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by the p.Arg345Trp mutation in the EFEMP1 gene. This mutation leads to extensive drusen in patients with DHRD/ML, and the gene targeted Efemp1R345W/R345W mice develop extensive basal deposits.

As a first step in their studies, Dr. Garland and colleagues used proteomic techniques to identify the proteins present in the basal deposits of the Efemp1R345W/R345W mice. Like they do in people, these deposits form between the retinal pigment epithelial cells and their basement membrane, which is called Bruch's membrane and is composed of extracellular matrix. These studies showed that the basal deposits are composed of normal extracellular matrix components that are present in abnormal amounts. This is logical because the EFEMP1 protein is secreted by retinal cells and is thought to be required for maturation of elastin fibers, which are part of Bruch's membrane.

The proteomic analyses also suggest that the altered extracellular matrix stimulates a local immune response, including activation of the complement system. The complement system is part of our innate immune system, and helps fend off infections, but under certain circumstances can also lead to cell and tissue damage.

The investigators plan to continue their studies to help identify additional treatments to prevent vision loss from macular degenerations.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our eye health / blindness section for the latest news on this subject.

The Mass. Eye and Ear team applied the power of mouse genetics to study the role of complement in basal deposit formation, and generated Efemp1R345W/R345W:C3-/- double mutant mice, which have the disease-causing mutation in Efemp1 and also lack the key complement component C3. Without C3, the complement system cannot be activated. In contrast to their single mutant Efemp1-R345W cousins, the double mutant Efemp1R345W/R345W:C3-/- mice did not develop basal deposits, demonstrating that the complement system is required for formation of basal deposits.

Grant support: This work was supported by grants from the Rosanne Silbermann Foundation, Research to Prevent Blindness, and the Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School.

Mouse genetics and proteomic analyses demonstrate a critical role for complement in a model of DHRD/ML, an inherited macular degeneration

Authors: Donita L. Garland, Rosario Fernandez-Godino, Inderjeet Kaur, Kaye D. Speicher, James M. Harnly, John D. Lambris, David W. Speicher, Eric A. Pierce; Hum. Mol. Genet. (2013) doi: 10.1093/hmg/ddt395 First published online: August 13, 2013

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Genes discovered to explain high altitude disease

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Academic Journal
Main Category: Genetics
Also Included In: Cardiovascular / Cardiology
Article Date: 19 Aug 2013 - 0:00 PDT Current ratings for:
Genes discovered to explain high altitude disease

Scientists say they have discovered why some humans develop chronic mountain sickness (CMS) while other people can adapt to high altitudes. According to a study published in the American Journal of Human Genetics, it is all in the genes.

Researchers from the University of California-San Diego (UCSD) say they have decoded a genetic basis for chronic mountain sickness, also known as Monge's disease, which could potentially lead to the development of new treatments.

The team conducted their research based on previous studies showing that many people who live in high-altitude regions, such as the Andes mountain region of South America, are not adapted to their environment and continue to suffer from CMS.

Around 140 million people have permanently settled within high-altitude regions, the researchers say. These environments have low-oxygen conditions, which can cause residents to suffer from hypoxia - low levels of oxygen in the blood, causing CMS.

CMS usually develops after spending an extended time living in altitudes over 3,000 meters. Symptoms include headache, depression, fatigue and sleepiness. People with the disease can often have strokes or heart attacks during early adulthood as a result of the decrease in oxygen getting to organs and tissues.

For the study, the researchers recruited 20 Peruvian residents of the Andes region: ten residents who suffered from CMS and ten residents without the disease. Their genetic variation was measured using whole genome sequencing.

Two genes were identified - ANP32D and SENP1. According to the study authors, both genes showed increased presence in residents who suffered from CMS, compared with those who did not have the disease.

The researchers looked to assess whether "down-regulating" these genes would limit the symptoms of hypoxia, and they looked at a species with corresponding gene sequences - the fruit fly.

Gabriel Haddad, distinguished professor and chair of the Department of Pediatrics at UCSD, explains:

"While a number of published articles have described an association between certain genes and the ability for humans to withstand low oxygen at high levels, it was very hard to be sure if the association was causal.

We found that flies with these genes down-regulated had a remarkably enhanced survival rate under hypoxia."

The researchers say that the findings in this study may lead to potential treatments, not only for those living at high altitudes, but also for those at any altitude who suffer from cardiovascular and brain diseases related to low oxygen levels.

Further research will involve conducting whole genome sequencing on 100 participants to determine if biomarkers - a substance used as an indicator of a biological state - exist to predict CMS.

The researchers have already taken skin samples from the 100 participants, which will be "reprogramed" into pluripotent stem cells (IPS). The study authors add that the IPS cells, if they have the capacity to become glia or red blood cells, may be used to "test the resilience to low oxygen levels."

Written by Honor Whiteman

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Newly discovered safety risks related to anti-epileptic drugs not passed to neurologists

Main Category: Epilepsy
Also Included In: Regulatory Affairs / Drug Approvals;  Neurology / Neuroscience
Article Date: 17 Aug 2013 - 0:00 PDT Current ratings for:
Newly discovered safety risks related to anti-epileptic drugs not passed to neurologists

A study by Johns Hopkins researchers shows that a fifth of U.S. neurologists appear unaware of serious drug safety risks associated with various anti-epilepsy drugs, potentially jeopardizing the health of patients who could be just as effectively treated with safer alternative medications.

The findings suggest that the U.S. Food and Drug Administration needs a better way to communicate information to specialists about newly discovered safety risks, the researchers say, since the warnings are in many cases not getting through to doctors making important prescribing decisions. And, the researchers add, while their new study, reported online in the journal Epilepsy and Behavior, was focused on neurologists and anti-epilepsy drugs, they believe their findings are applicable to a wide spectrum of medical specialists and medications.

"There is poor communication from the FDA to specialists, and there's some risk to patients because of this," says study leader Gregory L. Krauss, M.D., a professor of neurology at the Johns Hopkins University School of Medicine. "Unless it's a major change requiring the FDA to issue a black box warning on a product, important information appears to be slipping through the cracks. We need a more systematic and comprehensive method so that doctors receive updated safety warnings in a format that guarantees they will see and digest what they need to protect patients."

Krauss and his colleagues surveyed 505 neurologists from across the nation in different types of medical practices between March and July of 2012. They asked about several new safety risks for antiseizure drugs recently identified by the FDA: increased suicidal thoughts or behavior with newer agents; high risks for birth defects and cognitive impairment in offspring of mothers taking divalproex (sold by the brand name Depakote); and risks for serious hypersensitivity reactions in some patients of Asian descent starting treatment with carbamazepine (Tegretol). One in five of the neurologists surveyed said they knew of none of the risks. Those neurologists who treat two hundred epilepsy patients a year or more were most likely to know all of the risks.

Krauss says he was most struck by the lack of understanding of the risk to certain Asian patients who take carbamazepine to control their seizures. The FDA in 2007 recommended that before initiating the drug in patients of Asian heritage, neurologists should screen to see if those patients have a specific haplotype, a specific section of DNA found in a few percent of Asian people, before prescribing the drug.

The researchers found that 70 percent of the neurologists who responded knew of the recommendation. While 147 neurologists (29.1 percent) reported initiating carbamazepine treatment in Asian patients, only 33 of them (22.5 percent) said they performed haplotype screening. Eighteen neurologists reported that their Asian patients developed carbamazepine-related hypersensitivity reactions - severe skin rashes that can lead to scarring, blisters in the mouth and shredding of the skin - during this time period.

"If their doctors were more educated about the risks," Krauss says, "these patients may have avoided these severe hypersensitivity reactions."

Krauss says doctors may not do the screening because it is difficult to find laboratories able to perform the haplotyping, and he notes that it may make more sense to prescribe an alternate drug to Asian patients.

The researchers found that 80 percent of respondents knew that the FDA had newly warned that the risk of suicide with newer drugs is 4.3 per 1,000, double what had previously been believed. Seventy percent said they counseled patients about the risk.

As for pregnancy risks related to divalproex, fewer than half of the respondents knew that a warning had been issued noting high risks of birth defects and of developmental risks in offspring (an 8 to 9 point drop in IQ). While 93 percent of respondents reported counseling women planning pregnancies about the birth defect risks of divalproex, Krauss says safer drugs should be used if possible during pregnancy.

Krauss says part of the problem is the absence of a single place for neurologists to find updated risk information. Neurologists get safety information from scattered sources; only a few get emails from the FDA, while others get the information from neurology societies, from continuing medical education courses or from newly published journal articles.

"The FDA needs to do better getting the warnings to prescribing doctors," he says. "There has to be a direct way to communicate risks without overwhelming physicians with messages."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our epilepsy section for the latest news on this subject.

New antiepileptic drug safety information is not transmitted systematically and accepted by U.S. neurologists, doi:10.1016/j.yebeh.2013.06.008

Other Johns Hopkins researchers who contributed to the study include Sarah G. Bell, B.A.; Martha Matsumoto, B.A.; and Jason C. Brandt, Ph.D.

Johns Hopkins Medicine

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Origin of MRSA strain in humans discovered in cattle

Main Category: Immune System / Vaccines
Also Included In: Water - Air Quality / Agriculture
Article Date: 14 Aug 2013 - 1:00 PDT Current ratings for:
Origin of MRSA strain in humans discovered in cattle

A strain of bacteria that causes skin and soft tissue infections in humans originally came from cattle, according to a study to be published in mBio®, the online open-access journal of the American Society for Microbiology. The researchers who conducted the genetic analysis of strains of Staphylococcus aureus known as CC97 say these strains developed resistance to methicillin after they crossed over into humans around forty years ago. Today, methicillin-resistant S. aureus (MRSA) strain CC97 is an emerging human pathogen in Europe, North and South America, Africa, and Asia. The findings highlight the potential for cows to serve as a reservoir for bacteria with the capacity for pandemic spread in humans.

The researchers sequenced the genomes of 43 different CC97 isolates from humans, cattle, and other animals, and plotted their genetic relationships in a phylogenetic tree. Corresponding author Ross Fitzgerald of the Roslin Institute and the University of Edinburgh in Scotland says strains of CC97 found in cows appear to be the ancestors of CC97 strains from humans.

"Bovine strains seemed to occupy deeper parts of the phylogenetic tree - they were closer to the root than the human strains. This led us to conclude that the strains infecting humans originated in cows and that they had evolved from bovine to human host jumps," says Fitzgerald.

Although the CC97 strains from animals were quite genetically diverse, the human isolates cluster together in two tight, distinct "clades", or relatedness groups, indicating that S. aureus CC97 in cattle crossed over into humans on two separate occasions. Using mutation rates as a molecular clock, the authors determined that the ancestor of clade A jumped from a bovine host to humans between 1894 and 1977 and clade B made the jump between 1938 and 1966.

After they made the jump, the human CC97 strains acquired some new capabilities, says Fitzgerald, thanks to genes encoded on portable pieces of DNA called mobile genetic elements.

"It seems like these elements, such as pathogenicity islands, phages, and plasmids, are important in order for the bacterium to adapt to different host species," says Fitzgerald. "The reverse is true as well: the bovine strains have their own mobile genetic elements."

Perhaps the most problematic new capability the human strains acquired is the ability to resist methicillin, an important antibiotic for fighting staphylococcal infections. Only human strains of CC97 were able to resist the drug, which indicates that the bacteria acquired resistance after they crossed over into humans, presumably through exposure to antibiotics prescribed for treating human infections.

This sequence of events contrasts with the case of a S. aureus strain from pigs, Fitzgerald points out, since a study in 2012 revealed that MRSA ST398 strains evolved the ability to resist methicillin before they crossed over into humans.* Any number of factors could create these differences, making pigs - but not cattle - a source of a drug-resistant bacterium. At this point, though, there isn't enough information to say whether differences in the S. aureus strains, differences between pigs and cattle, or differences between swine and dairy farming practices might be responsible.

Moving forward, Fitzgerald says he and his colleagues plan to widen the investigation.

"We have a relatively small sample size, and the findings are robust, but we want to extend the study now to include a greater number of clones to get a bigger picture of what's going on across the S. aureus species," says Fitzgerald.

A wider variety of S. aureus strains, Fitzgerald says, from a wider variety of locations and hosts and a wider range of time, will allow them to better pinpoint the timing and circumstances of the host jump events. Understanding how and when MRSA has crossed over from other species in the past can help us to put the brakes on these crossovers in the future and hopefully prevent the birth of the next pandemic S. aureus strain.

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Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy

Main Category: Parkinson's Disease
Article Date: 27 Jul 2013 - 0:00 PDT Current ratings for:
Potential cause of Parkinson's disease discovered that points to a new therapeutic strategy

Biologists at The Scripps Research Institute (TSRI) have made a significant discovery that could lead to a new therapeutic strategy for Parkinson's disease.

The findings, recently published online ahead of print in the journal Molecular and Cell Biology, focus on an enzyme known as parkin, whose absence causes an early-onset form of Parkinson's disease. Precisely how the loss of this enzyme leads to the deaths of neurons has been unclear. But the TSRI researchers showed that parkin's loss sharply reduces the level of another protein that normally helps protect neurons from stress.

"We now have a good model for how parkin loss can lead to the deaths of neurons under stress," said TSRI Professor Steven I. Reed, who was senior author of the new study. "This also suggests a therapeutic strategy that might work against Parkinson's and other neurodegenerative diseases."

Genetic Clues

Parkinson's is the world's second-most common neurodegenerative disease, affecting about one million people in the United States alone. The disease is usually diagnosed after the appearance of the characteristic motor symptoms, which include tremor, muscle rigidity and slowness of movements. These symptoms are caused by the loss of neurons in the substantia nigra, a brain region that normally supplies the neurotransmitter dopamine to other regions that regulate muscle movements.

Most cases of Parkinson's are considered "sporadic" and are thought to be caused by a variable mix of factors including advanced age, subtle genetic influences, chronic neuroinflammation and exposure to pesticides and other toxins. But between 5 and 15 percent of cases arise specifically from inherited gene mutations. Among these, mutations to the parkin gene are relatively common. Patients who have no functional parkin gene typically develop Parkinson's-like symptoms before age 40.

Parkin belongs to a family of enzymes called ubiquitin ligases, whose main function is to regulate the levels of other proteins. They do so principally by "tagging" their protein targets with ubiquitin molecules, thus marking them for disposal by roving protein-breakers in cells known as proteasomes. Because parkin is a ubiquitin ligase, researchers have assumed that its absence allows some other protein or proteins to evade proteasomal destruction and thus accumulate abnormally and harm neurons. But since 1998, when parkin mutations were first identified as a cause of early-onset Parkinson's, consensus about the identity of this protein culprit has been elusive.

"There have been a lot of theories, but no one has come up with a truly satisfactory answer," Reed said.

Oxidative Stress

In 2005, Reed and his postdoctoral research associate (and wife) Susanna Ekholm-Reed decided to investigate a report that parkin associates with another ubiquitin ligase known as Fbw7. "We soon discovered that parkin regulates Fbw7 levels by tagging it with ubiquitin and thus targeting it for degradation by the proteasome," said Ekholm-Reed.

Loss of parkin, they found, leads to rises in Fbw7 levels, specifically for a form of the protein known as Fbw7ß. The scientists observed these elevated levels of Fbw7ß in embryonic mouse neurons from which parkin had been deleted, in transgenic mice that were born without the parkin gene, and even in autopsied brain tissue from Parkinson's patients who had parkin mutations.

Subsequent experiments showed that when neurons are exposed to harmful molecules known as reactive oxygen species, parkin appears to work harder at tagging Fbw7ß for destruction, so that Fbw7ß levels fall. Without the parkin-driven decrease in Fbw7ß levels, the neurons become more sensitive to this "oxidative stress" - so that more of them undergo a programmed self-destruction called apoptosis. Oxidative stress, to which dopamine-producing substantia nigra neurons may be particularly vulnerable, has long been considered a likely contributor to Parkinson's.

"We realized that there must be a downstream target of Fbw7ß that's important for neuronal survival during oxidative stress," said Ekholm-Reed.

A New Neuroprotective Strategy

The research slowed for a period due to a lack of funding. But then, in 2011, came a breakthrough. Other researchers who were investigating Fbw7's role in cancer reported that it normally tags a cell-survival protein called Mcl-1 for destruction. The loss of Fbw7 leads to rises in Mcl-1, which in turn makes cells more resistant to apoptosis. "We were very excited about that finding," said Ekholm-Reed. The TSRI lab's experiments quickly confirmed the chain of events in neurons: parkin keeps levels of Fbw7ß under control, and Fbw7ß keeps levels of Mcl-1 under control. Full silencing of Mcl-1 leaves neurons extremely sensitive to oxidative stress.

Members of the team suspect that this is the principal explanation for how parkin mutations lead to Parkinson's disease. But perhaps more importantly, they believe that their discovery points to a broad new "neuroprotective" strategy: reducing the Fbw7ß-mediated destruction of Mcl-1 in neurons, which should make neurons more resistant to oxidative and other stresses.

"If we can find a way to inhibit Fbw7ß in a way that specifically raises Mcl-1 levels, we might be able to prevent the progressive neuronal loss that's seen not only in Parkinson's but also in other major neurological diseases, such as Huntington's disease and ALS [amyotrophic lateral sclerosis]," said Reed.

Finding such an Mcl-1-boosting compound, he added, is now a major focus of his laboratory's work.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our parkinson's disease section for the latest news on this subject.

“Parkin-Dependent Degradation of the F-box protein Fbw7 ß Promotes Neuronal Survival in Response to Oxidative stress by Stabilizing Mcl-1,” Susanna Ekholm-Reed, Matthew S. Goldberg, Michael G. Schlossmacher and Steven I. Reed, Published ahead of print 15 July 2013, doi: 10.1128/MCB.00535-13

Funding for the study was provided in part by the National Institutes of Health (NS059904 and CA078343).

Scripps Research Institute

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'Promising' blood test discovered for Alzheimer's dementia

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Main Category: Alzheimer's / Dementia
Also Included In: Neurology / Neuroscience;  Mental Health;  Psychology / Psychiatry
Article Date: 29 Jul 2013 - 0:00 PDT Current ratings for:
'Promising' blood test discovered for Alzheimer's dementia

Researchers in Germany have identified a new blood test that may in future provide much earlier diagnosis of Alzheimer's disease and other degenerative disorders.

The team, from Saarland University and Siemens Healthcare, describe their test in the open access journal Genome Biology. They found it could be used to discriminate between people with Alzheimer's from healthy people without the dementia.

Alzheimer's disease, the most common form of dementia, can currently only be diagnosed with certainty at autopsy, so there is considerable interest in finding reliable, non-invasive biomarkers for diagnosis in living people.

Andreas Keller focused on microRNAs (miRNAs), working with colleagues from Siemens Healthcare, Saarland University at Homburg, and three other German universities, as well as The Scripps Research Institute, of La Jolla, California. The small non-coding RNA molecules are known to influence the way genes are expressed, and miRNAs can be found circulating in bodily fluids, including blood. ?

The team highlighted and tested a 'signature' panel of 12 miRNAs among 48 people with Alzheimer's and 22 healthy controls and discovered different levels in the people with the dementia.

They then developed the tests in a larger cohort of 202 people, comprising not only people with Alzheimer's disease alongside healthy controls, but also patients with other neurological and neurodegenerative disorders.

Here, the new test not only reliably distinguished people with Alzheimer's from the controls with normal health but was also able to identify other conditions.

Useful biomarkers need to be accurate, sensitive (correctly identifying people with the disease) and specific (correctly filtering out people without the disease).

The new test scored highly on all three measures. It was:

93% accurate95% sensitive92% specific.

However, the authors caution that while their blood test shows obvious promise, it still needs to be validated for clinical use, and may eventually work best when combined with other standard diagnostic tools, such as imaging.

Since people with other brain disorders can sometimes show Alzheimer's-like symptoms, the team also looked for the miRNA signature in other patient groups. Interestingly, while the 12 miRNAs were chosen for their potential to separate Alzheimer's disease from controls, the same signature was more than 95% accurate in distinguishing controls from people with various psychiatric disorders, such as schizophrenia, depression and bipolar conditions.

It was less accurate (around 82%) in distinguishing patients with other neurodegenerative disorders, such as mild cognitive impairment, Parkinson's disease and multiple sclerosis, from controls.

The test was also able to discriminate between Alzheimer's patients and those with other neurodegenerative disorders, with an accuracy of around 75%.

The authors believe accuracy in distinguishing Alzheimer's disease from the wider range of neurodegenerative conditions might be improved by tweaking the miRNAs used in the test. They explained:

"Since the 12-miRNA signature has been tailored to differentiate between Alzheimer's disease and controls, other miRNAs may likely contribute to a signature that permits also a better differentiation between the other tested diseases and Alzheimer's disease."

The work at Saarland builds on previous studies highlighting the potential of miRNAs as blood-based biomarkers for many diseases, including numerous cancers. It also suggests that miRNAs could yield useful biomarkers for various brain disorders and sheds further light on the mechanisms underpinning Alzheimer's disease.

Two of the miRNAs are known to be involved in amyloid precursor protein processing, which itself is involved in the formation of plaques, a classic hallmark of Alzheimer's disease. Further, many of the miRNAs are believed to influence the growth and shape of neurons in the developing brain. ?

Written by Nick Valentine

Copyright: Medical News Today
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Mechanism discovered behind development of autoimmune hepatitis

Main Category: Liver Disease / Hepatitis
Also Included In: Immune System / Vaccines;  Genetics
Article Date: 25 Jul 2013 - 1:00 PDT Current ratings for:
Mechanism discovered behind development of autoimmune hepatitis

A gene mutation disrupts the activity of certain immune cells and causes the immune system to erroneously attack the liver, according to a new animal study from the Icahn School of Medicine at Mount Sinai. The findings, published in the Journal of Clinical Investigation, will provide a new model for studying drug targets and therapies for Autoimmune Hepatitis (AIH), a condition for which the only treatment options are short-acting steroids or liver transplant.

T-cells, immune cells created in an organ called the thymus, grow into healthy T-cells with the help of medullary thymic epithelial cells (mTECs). mTECs act as coaches to T-cells to teach them when to attack tissue that might be harmful and when to leave it alone. T-cells that attack healthy body tissue are programmed to die. Led by Konstantina Alexandropoulos, PhD, Associate Professor of Medicine in the Division of Clinical Immunology at Mount Sinai, the research team sought to create a model for understanding why certain immune cells called T-cells inappropriately attack healthy tissues in the body, leading to inflammation and autoimmune diseases like lupus, rheumatoid arthritis, and AIH.

Dr. Alexandropoulos and her team, consisting of Anthony Bonito, first author and PhD candidate at Mount Sinai and contributing author Costica Aloman, PhD, former Assistant Professor of Medicine in the Division of Liver Diseases at Mount Sinai, created mutations in a gene called Traf6 in a mouse model, which caused depletion of mTECs. The research team hypothesized that without mTECs to coach them, T-cells would aberrantly attack healthy cells. Surprisingly, while the depletion of mTECs did cause an autoimmune reaction, the T-cells homed directly to the liver and attacked it rather than other healthy tissue.

"We thought that deleting Traf6 would trigger an autoimmune reaction due to a depletion of mTECs, but did not expect the autoimmune response to be specific to the liver," said Dr. Alexandropoulos. "These findings provide an exciting new animal model to study AIH. We hope that this research will pave the way for new therapies to address a significant unmet need for people with this disease."

Dr. Alexandropoulos and her team hope to identify and study compounds or proteins that prevent the depletion of mTECs using cells from humans with AIH. Mount Sinai has one of the largest cohort of patients in the country to support research on liver diseases such as AIH.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our liver disease / hepatitis section for the latest news on this subject.

This research was supported by grants R01 AI49387-01, R56 AI049387-05, and R01 AI068963-01 from the National Institute of Allergy and Infectious Disease, a division of the National Institutes of Health.

The Mount Sinai Hospital / Mount Sinai School of Medicine

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'Mechanism discovered behind development of autoimmune hepatitis'

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No link discovered between mercury exposure and autism-like behaviors

Main Category: Pregnancy / Obstetrics
Also Included In: Autism;  Nutrition / Diet
Article Date: 25 Jul 2013 - 1:00 PDT Current ratings for:
No link discovered between mercury exposure and autism-like behaviors

The potential impact of exposure to low levels of mercury on the developing brain - specifically by women consuming fish during pregnancy - has long been the source of concern and some have argued that the chemical may be responsible for behavioral disorders such as autism. However, a new study that draws upon more than 30 years of research in the Republic of Seychelles reports that there is no association between pre-natal mercury exposure and autism-like behaviors.

"This study shows no evidence of a correlation between low level mercury exposure and autism spectrum-like behaviors among children whose mothers ate, on average, up to 12 meals of fish each week during pregnancy," said Edwin van Wijngaarden, Ph.D., an associate professor in the University of Rochester Medical Center's (URMC) Department of Public Health Sciences and lead author of the study which appears online today in the journal Epidemiology. "These findings contribute to the growing body of literature that suggest that exposure to the chemical does not play an important role in the onset of these behaviors."

The debate over fish consumption has long created a dilemma for expecting mothers and physicians. Fish are high in beneficial nutrients such as, selenium, vitamin E, lean protein, and omega-3 fatty acids; the latter are essential to brain development. At the same time, exposure to high levels of mercury has been shown to lead to developmental problems, leading to the claim that mothers are exposing their unborn children to serious neurological impairment by eating fish during pregnancy. Despite the fact that the developmental consequences of low level exposure remain unknown, some organizations, including the U.S. Food and Drug Administration, have recommended that pregnant women limit their consumption of fish.

The presence of mercury in the environment is widespread and originates from both natural sources such as volcanoes and as a byproduct of coal-fired plants that emit the chemical. Much of this mercury ends up being deposited in the world's oceans where it makes its way into the food chain and eventually into fish. While the levels of mercury found in individual fish are generally low, concerns have been raised about the cumulative effects of a frequent diet of fish.

The Republic of Seychelles has proven to be the ideal location to examine the potential health impact of persistent low level mercury exposure. With a population of 87,000 people spread across an archipelago of islands in the Indian Ocean, fishing is a both an important industry and a primary source of nutrition - the nation's residents consume fish at a rate 10 times greater than the populations of the U.S. and Europe.

The Seychelles Child Development Study - a partnership between URMC, the Seychelles Ministries of Health and Education, and the University of Ulster in Ireland - was created in the mid-1980s to specifically study the impact of fish consumption and mercury exposure on childhood development. The program is one of the largest ongoing epidemiologic studies of its kind.

"The Seychelles study was designed to follow a population over a very long period of time and focus on relevant mercury exposure," said Philip Davidson, Ph.D., principal investigator of the Seychelles Child Development Study and professor emeritus in Pediatrics at URMC. "While the amount of fish consumed in the Seychelles is significantly higher than other countries in the industrialized world, it is still considered low level exposure."

The autism study involved 1,784 children, adolescents, and young adults and their mothers. The researchers were first able to determine the level of prenatal mercury exposure by analyzing hair samples that had been collected from the mothers around the time of birth, a test which can approximate mercury levels found in the rest of the body including the growing fetus.

The researchers then used two questionnaires to determine whether or not the study participants were exhibiting autism spectrum-like behaviors. The Social Communication Questionnaire was completed by the children's parents and the Social Responsiveness Scale was completed by their teachers. These tests - which include questions on language skills, social communication, and repetitive behaviors - do not provide a definitive diagnosis, but they are widely used in the U.S. as an initial screening tool and may suggest the need for additional evaluation.

The mercury levels of the mothers were then matched with the test scores of their children and the researchers found that there was no correlation between prenatal exposure and evidence of autism-spectrum-like behaviors. This is similar to the result of previous studies of the nation's children which have measured language skills and intelligence, amongst other outcomes, and have not observed any adverse developmental effects.

The study lends further evidence to an emerging belief that the "good" may outweigh the possible "bad" when it comes to fish consumption during pregnancy. Specifically, if mercury does adversely influence child development at these levels of exposure then the benefits of the nutrients found in the fish may counteract or perhaps even supersede the potential negative effects of the mercury.

"This study shows no consistent association in children with mothers with mercury level that were six to ten times higher than those found in the U.S. and Europe," said Davidson. "This is a sentinel population and if it does not exist here than it probably does not exist."

"NIEHS has been a major supporter of research looking into the human health risks associated with mercury exposure," said Cindy Lawler, Ph.D., acting branch chief at the National Institute of Environmental Health Sciences, part of National Institutes of Health. "The studies conducted in the Seychelles Islands have provided a unique opportunity to better understand the relationship between environmental factors, such as mercury, and the role they may play in the development of diseases like autism. Although more research is needed, this study does present some good news for parents."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our pregnancy / obstetrics section for the latest news on this subject.

Additional co-authors of the study include Tristram Smith, Katie Evans, Kelley Yost, Tanzy Love, Sally Thurston, Gene Watson, Grazyna Zareba, Christine Burns, and Gary Myers with URMC and Conrad Shamlaye with the Seychelles Ministry of Health. Funding for the study was provided by the National Institute of Environmental Health Sciences and the Government of the Republic of Seychelles.

University of Rochester Medical Center

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

University of Rochester Medical Center. "No link discovered between mercury exposure and autism-like behaviors." Medical News Today. MediLexicon, Intl., 25 Jul. 2013. Web.
26 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

posted by RA Jensen on 25 Jul 2013 at 5:51 am

Autism is a strongly genetically influenced condition. The mercury studies in this article are examining mercury exposure in the womb or in post natal exposures. The studies are not examining the role of environmental pathogens as it relates to reproductive fitness.

McAuliffe and colleagues discovered that increasing levels of exposure to PCB and DDT congeners, as measured in blood, is associated with increased production of XY and YY sperm in volunteer donors recruited from fertility clinics. Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and polybrominated diphenylethers
6 (PBDEs) has been found in post mortem brain tissues in samples with maternal 15q11-q13 duplication (Dup15) or deletion (Prader-Willi syndrome). POPs, PBDE’s and PCB’s may predispose to genetic copy number variation of 15q11-q13, in most cases likely via sperm or egg
mutations. Sperm mutations have been found in men exposed to benzene in the workplace at levels below the EPA’s recommended levels.

I have a review of the genetically determined syndromes associated with extraordinarily high rates of co-occurring autism and specific pre-conception sperm mutations:

‘ Jensen RA. The origins of de novo gene mutations in the genetic syndromes with high autism spectrum disorder (ASD) risk. OA Autism 2013 Apr 01;1(1):8’.

A full text provisional PDF is available here:

http://www.oapublishinglondon.com/oa-autism

| post followup | alert a moderator |

'No link discovered between mercury exposure and autism-like behaviors'

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If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

No link discovered between mercury exposure and autism-like behaviors

Main Category: Pregnancy / Obstetrics
Also Included In: Autism;  Nutrition / Diet
Article Date: 25 Jul 2013 - 1:00 PDT Current ratings for:
No link discovered between mercury exposure and autism-like behaviors

The potential impact of exposure to low levels of mercury on the developing brain - specifically by women consuming fish during pregnancy - has long been the source of concern and some have argued that the chemical may be responsible for behavioral disorders such as autism. However, a new study that draws upon more than 30 years of research in the Republic of Seychelles reports that there is no association between pre-natal mercury exposure and autism-like behaviors.

"This study shows no evidence of a correlation between low level mercury exposure and autism spectrum-like behaviors among children whose mothers ate, on average, up to 12 meals of fish each week during pregnancy," said Edwin van Wijngaarden, Ph.D., an associate professor in the University of Rochester Medical Center's (URMC) Department of Public Health Sciences and lead author of the study which appears online today in the journal Epidemiology. "These findings contribute to the growing body of literature that suggest that exposure to the chemical does not play an important role in the onset of these behaviors."

The debate over fish consumption has long created a dilemma for expecting mothers and physicians. Fish are high in beneficial nutrients such as, selenium, vitamin E, lean protein, and omega-3 fatty acids; the latter are essential to brain development. At the same time, exposure to high levels of mercury has been shown to lead to developmental problems, leading to the claim that mothers are exposing their unborn children to serious neurological impairment by eating fish during pregnancy. Despite the fact that the developmental consequences of low level exposure remain unknown, some organizations, including the U.S. Food and Drug Administration, have recommended that pregnant women limit their consumption of fish.

The presence of mercury in the environment is widespread and originates from both natural sources such as volcanoes and as a byproduct of coal-fired plants that emit the chemical. Much of this mercury ends up being deposited in the world's oceans where it makes its way into the food chain and eventually into fish. While the levels of mercury found in individual fish are generally low, concerns have been raised about the cumulative effects of a frequent diet of fish.

The Republic of Seychelles has proven to be the ideal location to examine the potential health impact of persistent low level mercury exposure. With a population of 87,000 people spread across an archipelago of islands in the Indian Ocean, fishing is a both an important industry and a primary source of nutrition - the nation's residents consume fish at a rate 10 times greater than the populations of the U.S. and Europe.

The Seychelles Child Development Study - a partnership between URMC, the Seychelles Ministries of Health and Education, and the University of Ulster in Ireland - was created in the mid-1980s to specifically study the impact of fish consumption and mercury exposure on childhood development. The program is one of the largest ongoing epidemiologic studies of its kind.

"The Seychelles study was designed to follow a population over a very long period of time and focus on relevant mercury exposure," said Philip Davidson, Ph.D., principal investigator of the Seychelles Child Development Study and professor emeritus in Pediatrics at URMC. "While the amount of fish consumed in the Seychelles is significantly higher than other countries in the industrialized world, it is still considered low level exposure."

The autism study involved 1,784 children, adolescents, and young adults and their mothers. The researchers were first able to determine the level of prenatal mercury exposure by analyzing hair samples that had been collected from the mothers around the time of birth, a test which can approximate mercury levels found in the rest of the body including the growing fetus.

The researchers then used two questionnaires to determine whether or not the study participants were exhibiting autism spectrum-like behaviors. The Social Communication Questionnaire was completed by the children's parents and the Social Responsiveness Scale was completed by their teachers. These tests - which include questions on language skills, social communication, and repetitive behaviors - do not provide a definitive diagnosis, but they are widely used in the U.S. as an initial screening tool and may suggest the need for additional evaluation.

The mercury levels of the mothers were then matched with the test scores of their children and the researchers found that there was no correlation between prenatal exposure and evidence of autism-spectrum-like behaviors. This is similar to the result of previous studies of the nation's children which have measured language skills and intelligence, amongst other outcomes, and have not observed any adverse developmental effects.

The study lends further evidence to an emerging belief that the "good" may outweigh the possible "bad" when it comes to fish consumption during pregnancy. Specifically, if mercury does adversely influence child development at these levels of exposure then the benefits of the nutrients found in the fish may counteract or perhaps even supersede the potential negative effects of the mercury.

"This study shows no consistent association in children with mothers with mercury level that were six to ten times higher than those found in the U.S. and Europe," said Davidson. "This is a sentinel population and if it does not exist here than it probably does not exist."

"NIEHS has been a major supporter of research looking into the human health risks associated with mercury exposure," said Cindy Lawler, Ph.D., acting branch chief at the National Institute of Environmental Health Sciences, part of National Institutes of Health. "The studies conducted in the Seychelles Islands have provided a unique opportunity to better understand the relationship between environmental factors, such as mercury, and the role they may play in the development of diseases like autism. Although more research is needed, this study does present some good news for parents."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our pregnancy / obstetrics section for the latest news on this subject.

Additional co-authors of the study include Tristram Smith, Katie Evans, Kelley Yost, Tanzy Love, Sally Thurston, Gene Watson, Grazyna Zareba, Christine Burns, and Gary Myers with URMC and Conrad Shamlaye with the Seychelles Ministry of Health. Funding for the study was provided by the National Institute of Environmental Health Sciences and the Government of the Republic of Seychelles.

University of Rochester Medical Center

Please use one of the following formats to cite this article in your essay, paper or report:

MLA

University of Rochester Medical Center. "No link discovered between mercury exposure and autism-like behaviors." Medical News Today. MediLexicon, Intl., 25 Jul. 2013. Web.
26 Jul. 2013. APA

Please note: If no author information is provided, the source is cited instead.

posted by RA Jensen on 25 Jul 2013 at 5:51 am

Autism is a strongly genetically influenced condition. The mercury studies in this article are examining mercury exposure in the womb or in post natal exposures. The studies are not examining the role of environmental pathogens as it relates to reproductive fitness.

McAuliffe and colleagues discovered that increasing levels of exposure to PCB and DDT congeners, as measured in blood, is associated with increased production of XY and YY sperm in volunteer donors recruited from fertility clinics. Persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs) and polybrominated diphenylethers
6 (PBDEs) has been found in post mortem brain tissues in samples with maternal 15q11-q13 duplication (Dup15) or deletion (Prader-Willi syndrome). POPs, PBDE’s and PCB’s may predispose to genetic copy number variation of 15q11-q13, in most cases likely via sperm or egg
mutations. Sperm mutations have been found in men exposed to benzene in the workplace at levels below the EPA’s recommended levels.

I have a review of the genetically determined syndromes associated with extraordinarily high rates of co-occurring autism and specific pre-conception sperm mutations:

‘ Jensen RA. The origins of de novo gene mutations in the genetic syndromes with high autism spectrum disorder (ASD) risk. OA Autism 2013 Apr 01;1(1):8’.

A full text provisional PDF is available here:

http://www.oapublishinglondon.com/oa-autism

| post followup | alert a moderator |

'No link discovered between mercury exposure and autism-like behaviors'

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam). We reserve the right to amend opinions where we deem necessary.

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here