Posts tagged medicine
Articles and news from the latest research reports.
Halting Immune Response Could Save Brain Cells After Stroke
A new study in animals shows that using a compound to block the body’s immune response greatly reduces disability after a stroke.
The study by scientists from the University of Wisconsin School of Medicine and Public Health also showed that particular immune cells – CD4+ T-cells produce a mediator, called interleukin (IL)-21 that can cause further damage in stroke tissue.
Moreover, normal mice, ordinarily killed or disabled by an ischemic stroke, were given a shot of a compound that blocks the action of IL-21. Brain scans and brain sections showed that the treated mice suffered little or no stroke damage.
“This is very exciting because we haven’t had a new drug for stroke in decades, and this suggests a target for such a drug,” says lead author Dr. Zsuzsanna Fabry, professor of pathology and laboratory medicine
Stroke is the fourth-leading killer in the world and an important cause of permanent disability. In an ischemic stroke, a clot blocks the flow of oxygen-rich blood to the brain. But Fabry explains that much of the damage to brain cells occurs after the clot is removed or dissolved by medicine. Blood rushes back into the brain tissue, bringing with it immune cells called T-cells, which flock to the source of an injury.
The study shows that after a stroke, the injured brain cells provoke the CD4+ T-cells to produce a substance, IL-21, that kills the neurons in the blood-deprived tissue of the brain. The study gave new insight how stroke induces neural injury.
Similar Findings in Humans
Fabry’s co-author Dr. Matyas Sandor, professor of pathology and laboratory medicine, says that the final part of the study looked at brain tissue from people who had died following ischemic strokes. It found that CD4+ T-cells and their protein, IL-21 are in high concentration in areas of the brain damaged by the stroke.
Sandor says the similarity suggests that the protein that blocks IL-21 could become a treatment for stroke, and would likely be administered at the same time as the current blood-clot dissolving drugs.
“We don’t have proof that it will work in humans,” he says, “but similar accumulation of IL-21 producing cells suggests that it might.”
The paper was published this week in the Journal of Experimental Medicine.
(Source: med.wisc.edu)
Blood Test Identifies Those At-Risk for Cognitive Decline, Alzheimer’s Within 3 Years
Researchers have discovered and validated a blood test that can predict with greater than 90 percent accuracy if a healthy person will develop mild cognitive impairment or Alzheimer’s disease within three years.
Described in the April issue of Nature Medicine, the study heralds the potential for developing treatment strategies for Alzheimer’s at an earlier stage, when therapy would be more effective at slowing or preventing onset of symptoms. It is the first known published report of blood-based biomarkers for preclinical Alzheimer’s.
The test identifies 10 lipids, or fats, in the blood that predict disease onset. It could be ready for use in clinical studies in as few as two years and, researchers say, other diagnostic uses are possible.
“Our novel blood test offers the potential to identify people at risk for progressive cognitive decline and can change how patients, their families and treating physicians plan for and manage the disorder,” says the study’s corresponding author Howard J. Federoff, MD, PhD, professor of neurology and executive vice president for health sciences at Georgetown University Medical Center.
There is no cure or effective treatment for Alzheimer’s. Worldwide, about 35.6 million individuals have the disease and, according to the World Health Organization, the number will double every 20 years to 115.4 million people with Alzheimer’s by 2050.
Federoff explains there have been many efforts to develop drugs to slow or reverse the progression of Alzheimer’s disease, but all of them have failed. He says one reason may be the drugs were evaluated too late in the disease process.
“The preclinical state of the disease offers a window of opportunity for timely disease-modifying intervention,” Federoff says. “Biomarkers such as ours that define this asymptomatic period are critical for successful development and application of these therapeutics.”
The study included 525 healthy participants aged 70 and older who gave blood samples upon enrolling and at various points in the study. Over the course of the five-year study, 74 participants met the criteria for either mild Alzheimer’s disease (AD) or a condition known as amnestic mild cognitive impairment (aMCI), in which memory loss is prominent. Of these, 46 were diagnosed upon enrollment and 28 developed aMCI or mild AD during the study (the latter group called converters).
In the study’s third year, the researchers selected 53 participants who developed aMCI/AD (including 18 converters) and 53 cognitively normal matched controls for the lipid biomarker discovery phase of the study. The lipids were not targeted before the start of the study, but rather, were an outcome of the study.
A panel of 10 lipids was discovered, which researchers say appears to reveal the breakdown of neural cell membranes in participants who develop symptoms of cognitive impairment or AD. The panel was subsequently validated using the remaining 21 aMCI/AD participants (including 10 converters), and 20 controls. Blinded data were analyzed to determine if the subjects could be characterized into the correct diagnostic categories based solely on the 10 lipids identified in the discovery phase.
“The lipid panel was able to distinguish with 90 percent accuracy these two distinct groups: cognitively normal participants who would progress to MCI or AD within two to three years, and those who would remain normal in the near future,” Federoff says.
The researchers examined if the presence of the APOE4 gene, a known risk factor for developing AD, would contribute to accurate classification of the groups, but found it was not a significant predictive factor in this study.
“We consider our results a major step toward the commercialization of a preclinical disease biomarker test that could be useful for large-scale screening to identify at-risk individuals,” Federoff says. “We’re designing a clinical trial where we’ll use this panel to identify people at high risk for Alzheimer’s to test a therapeutic agent that might delay or prevent the emergence of the disease.”
Experimental stroke drug also shows promise for people with Lou Gehrig’s disease
Keck School of Medicine of USC neuroscientists have unlocked a piece of the puzzle in the fight against Lou Gehrig’s disease, a debilitating neurological disorder that robs people of their motor skills. Their findings appear in the March 3, 2014, online edition of the Proceedings of the National Academy of Sciences of the United States of America, the official scientific journal of the U.S. National Academy of Sciences.
"We know that both people and transgenic rodents afflicted with this disease develop spontaneous breakdown of the blood-spinal cord barrier, but how these microscopic lesions affect the development of the disease has been unclear," said Berislav V. Zlokovic, M.D., Ph.D., the study’s principal investigator and director of the Zilkha Neurogenetic Institute at USC. "In this study, we show that early motor neuron dysfunction related to the disease in mice is proportional to the degree of damage to the blood-spinal cord barrier and that restoring the integrity of the barrier delays motor neuron degeneration. We are hopeful that we can apply these findings to the corresponding disease mechanism in people. "
In this study, Zlokovic and colleagues found that an experimental drug now being studied in human stroke patients appears to protect the blood-spinal cord barrier’s integrity in mice and delay motor neuron impairment and degeneration. The drug, an activated protein C analog called 3K3A-APC, was developed by Zlokovic’s start-up biotechnology company, ZZ Biotech.
Lou Gehrig’s disease, also called amyotrophic lateral sclerosis, or ALS, attacks motor neurons, which are cells that control the muscles. The progressive degeneration of the motor neurons in ALS eventually leads to paralysis and difficulty breathing, eating and swallowing.
According to The ALS Association, approximately 15 people in the United States are diagnosed with ALS every day. It is estimated that as many as 30,000 Americans live with the disease. Most people who develop ALS are between the ages of 40 and 70, with an average age of 55 upon diagnosis. Life expectancy of an ALS patient averages about two to five years from the onset of symptoms.
ALS’s causes are not completely understood, and no cure has yet been found. Only one Food and Drug Administration-approved drug called riluzole has been shown to prolong life by two to three months. There are, however, devices and therapies that can manage the symptoms of the disease to help people maintain as much independence as possible and prolong survival.
Surprising culprit found in cell recycling defect
To remain healthy, the body’s cells must properly manage their waste recycling centers. Problems with these compartments, known as lysosomes, lead to a number of debilitating and sometimes lethal conditions.
Reporting in the Proceedings of the National Academy of Sciences (PNAS), researchers at Washington University School of Medicine in St. Louis have identified an unusual cause of the lysosomal storage disorder called mucolipidosis III, at least in a subset of patients. This rare disorder causes skeletal and heart abnormalities and can result in a shortened lifespan. But unlike most genetic diseases that involve dysfunctional or missing proteins, the culprit is a normal protein that ends up in the wrong place.
Image caption: In normal cells, phosphotransferase (green) is shown overlapping with the Golgi apparatus (red), which indicates that phosphotransferase is located in the Golgi, where it should be (Credit: Eline van Meel, PhD)
“There is a lot of interest and study about how cells distribute proteins to the right parts of the cell,” said senior author Stuart A. Kornfeld, MD, PhD, the David C. and Betty Farrell Professor of Medicine. “Our study has identified one of the few examples of a genetic disease caused by the misplacement of a protein. The protein functions just fine. It just doesn’t stay in the right place.”
The right place, in this case, is the Golgi apparatus, the cell’s protein packaging center. The protein in question – phosphotransferase – normally resides in the Golgi, where its job is to attach address labels to proteins bound for the lysosome. There are 60 such lysosomal proteins, and all of them must be properly labeled if they are to end up in a lysosome, where they recycle waste.
Image caption: In mutant cells, the protein phosphotransferase (green) is spread beyond the Golgi (red). Outside the Golgi, this wayward phosphotransferase is no longer able to perform its job of properly addressing enzymes bound for the lysosome (Credit: Eline van Meel, PhD)
Kornfeld and his colleagues, including first author Eline van Meel, PhD, postdoctoral research associate, showed that the phosphotransferase protein responsible for adding the address label starts out in the Golgi as it should, but seems to lack the signal to keep it there.
“Under normal circumstances, the phosphotransferase moves up through the Golgi, but then it’s recaptured and sent back,” Kornfeld said. “Our study shows that the mutant phosphotransferase moves up but is not recaptured. Ironically, the phosphotransferase that escapes the Golgi ends up in the lysosomes, where it is degraded.”
Because phosphotransferase gradually wanders away from the Golgi, a low level of lysosomal enzymes end up being properly addressed, but at perhaps 20 percent of the normal amount.
“In many lysosomal storage disorders, such as Tay-Sachs or Gaucher’s disease, only one out of the 60 enzymes is missing from the lysosome,” Kornfeld said. “But the mislocalization of phosphotranferase causes the misdirection of all 60 lysosomal enzymes.”
While the errant phosphotransferase ends up being degraded in the lysosome, the resulting misdirected lysosomal proteins end up in the bloodstream. As a result, children with this disorder have lysosomal proteins in their blood at levels 10 to 20 times higher than normal. But because some get to the lysosome at a low level, people with mucolipidosis III don’t have the most severe form of the disease.
“Type III patients live into adulthood, but they’re very impaired,” said Kornfeld. “They have joint and heart problems and have trouble walking. In the most severe form, type II, there is zero activity of phosphotransferase. None of the 60 enzymes are properly tagged, so these patients’ lysosomes are empty. Children with type II usually die by age 10.”
Having implicated wayward phosphotransferase in this lysosomal storage disorder, Kornfeld and his colleagues are investigating what goes wrong that allows it to escape the Golgi.
“We think there must be some protein in the cell that recognizes phosphotransferase when it gets to the end of the Golgi, binds it and takes it back,” said Kornfeld. “Now we’re trying to understand how that works.”
(Source: news.wustl.edu)
New blood cells fight brain inflammation
Hyperactivity of our immune system can cause a state of chronic inflammation. If chronic, the inflammation will affect our body and result in disease. In the devastating disease multiple sclerosis, hyperactivity of immune cells called T-cells induce chronic inflammation and degeneration of the brain. Researchers at BRIC, the University of Copenhagen, have identified a new type of regulatory blood cells that can combat such hyperactive T-cells in blood from patients with multiple sclerosis. By stimulating the regulatory blood cells, the researchers significantly decreased the level of brain inflammation and disease in a biological model. The results are published in the journal Nature Medicine.
Molecule activate anti-inflammatory blood cells
The new blood cells belong to the group of our white blood cells called lymphocytes. The cells express a molecule called FoxA1 that the researchers found is responsible for the cells’ development and suppressive functions.
"We knew that some unidentified blood cells were able to inhibit multiple sclerosis-like disease in mice and through gene analysis we found out, that these cells are a subset of our lymphocytes expressing the gene FoxA1. Importantly, when inserting FoxA1 into normal lymphocytes with gene therapy, we could change them to actively regulate inflammation and inhibit multiple sclerosis", explains associated professor Yawei Liu leading the experimental studies.
Image caption: Tissue sections from an untreated diseased brain and a FoxA1-treated brain from the researchers biological model. (Photo: Yawei Liu)
Activating own blood cells for treatment of disease
FoxA1 expressing lymphocytes were not known until now, and this is the first documentation of their importance in controlling multiple sclerosis. The number of people living with this devastating disease around the world has increased by 10 percent in the past five years to 2.3 million. It affects women twice more than men and no curing treatment exists. The research group headed by professor Shohreh Issazadeh-Navikas from BRIC examined blood of patients with multiple sclerosis, before and after two years of treatment with the drug interferon-beta. They found that patients who benefit from the treatment increase the number of this new blood cell type, which fight disease.
Image caption: FoxA1-lymphocytes. (Photo: Yawei Liu)
“From a therapeutic viewpoint, our findings are really interesting and we hope that they can help finding new treatment options for patients not benefiting from existing drugs, especially more chronic and progressive multiple sclerosis patients. In our model, we could activate lymphocytes by chemical stimulation and gene therapy, and we are curios whether this can be a new treatment strategy”, says professor Shohreh Issazadeh-Navikas.
And this is exactly what the research group will focus on at next stage of their research. They have already started to test whether the new FoxA1-lymphocytes can prevent degradation of the nerve cell’s myelin layer and brain degeneration in a model of progressive multiple sclerosis. Besides multiple sclerosis, knowledge on how to prevent chronic inflammation will also be valuable for other autoimmune diseases like type 1 diabetes, inflammatory bowel disease and rheumatoid arthritis, where inflammation is a major cause of the disease.
(Source: news.ku.dk)
Can a virtual brain replace lab rats?
Testing the effects of drugs on a simulated brain could lead to breakthrough treatments for neurological disorders such as Parkinson’s, Huntington’s and Alzheimer’s disease.
Researchers from the University of Waterloo in Canada hope Spaun, the world’s largest functioning model of the brain, will be used to test new drugs that lead to medical breakthroughs for brain disorders.
Terrence Stewart, a post-doctoral researcher with the Centre for Theoretical Neuroscience at Waterloo and project manager for Spaun, will tell an audience at the American Association for the Advancement of Science (AAAS) annual meeting in Chicago about the advantages of using whole-brain simulation as a tool to aid new discoveries in medicine.
“Our hope is that you could try out different possible treatments quickly to see how the brain reacts and how each one changes behaviour before testing them in people,” said Stewart. “Our brain model offers a new way to test treatments. For Alzheimer’s disease or a stroke that causes memory loss, we could see how a new drug affects the firing pattern of individual brain cells and measure how it changes brain performance on memory tests before trying it on people.”
Stewart’s team has already made progress simulating Parkinson’s and Huntington’s diseases. Their next step is to simulate Alzheimer’s disease after giving Spaun a hippocampus, the brain region involved in forming new memories.
Spaun is more like the human brain than other computer brain models because it makes mistakes and loses abilities in similar ways to people. To simulate the cognitive decline associated with aging, for example, Stewart and his team killed off neurons in the brain model and observed it gradually forgetting more numbers on a memory test.
To reproduce movement problems associated with Huntington’s disease and damage to the cerebellum, Stewart damaged parts of the simulated brain affected by those conditions.
“We showed that errors made in reaching behaviour seen in people with those disorders correspond to the errors made by our brain model when neurons in the affected brain regions are damaged,” he said.
Spaun can see, remember, think and write using a mechanical arm. Most importantly, this virtual brain – which mimics the neuron firing patterns seen in the human brain – allows the researchers to study and understand how damage to individual cells affects the behaviour of the whole brain in different neurological diseases.
Stewart presented new research on successfully simulating the effects of aging and Huntington’s disease in Spaun at a symposium panel, “Virtual Humans: Helping Facilitate Breakthroughs in Medicine” on Friday, February 14, 2014.
Stress gives cells a ‘second childhood’
What doesn’t kill cells may make them stronger—or considerably more flexible, at least. New findings from Haruko Obokata of the RIKEN Center for Developmental Biology in Kobe and Charles Vacanti at Brigham and Women’s Hospital in the United States suggest that exposing mouse cells to acidic stress can make them regress to an extremely developmentally immature state, transcending even that of embryonic stem (ES) cells (1, 2).
ES cells have the developmental capacity to form any tissue type in the body and this ‘pluripotency’ makes them of great interest to both scientists and clinicians. As these cells must be harvested from early-stage embryos, however, human ES cell research remains a politically and ethically fraught issue. As an alternative, researchers can ‘reprogram’ adult cells into ES cell-like induced pluripotent stem (iPS) cells, which offer the advantage of being genetically matched to their donor—an important consideration for regenerative medicine. However, the generation of iPS cells typically requires the introduction of reprogramming genes, which may affect their function or risk of cancerous transformation.
Obokata and colleagues have now discovered an alternative route to pluripotency, drawing on inspiration from the plant world. “Plants [such as] carrots can produce stem cells from totally differentiated cells when they are exposed to strong external stresses like dissection,” Obokata said in a recent interview with Nature. “I instinctively felt that we may have a similar mechanism to plants.”
New risk factor found for schizophrenia
Scientists have discovered a link between a largely unstudied gene and schizophrenia.
They also found a link between the same gene and bipolar disorder, depression and autism.
The University of Aberdeen-led research - published in the Journal of Cell Science - set out to look for genes that might be important for schizophrenia.
During analysis of five major patient cohorts, scientists picked out the poorly-understood gene ULK4 which has previously been associated with hypertension but never before with mental health disorders.
They discovered that a mutation of the gene ULK4 was found far more frequently in patients with schizophrenia.
Researchers also found mutation of ULK4 in some people with bipolar disorder, depression and autism.
First author Dr Bing Lang, Research Fellow at the University of Aberdeen, said: “Schizophrenia is a severe psychiatric disorder affecting about 1% of the population. Genetics are estimated to be between 60 and 80% responsible for the condition, but very few specific susceptibility genes for schizophrenia have been firmly confirmed in humans.
“However our results suggest that mutation of the gene UKL4 can be a rare genetic risk factor for schizophrenia as well as other psychiatric disorders.”
The researchers found evidence that ULK4 regulates many important signalling pathways within nerve cells involved in schizophrenia and stress.
They also discovered that mutation of the gene reduced communication between brain cells.
Professor Colin McCaig, one of the researchers and Head of the University’s School of Medical Sciences, added: “This is an important discovery of a gene involved in major mental health disorders which affects basic nerve cell growth and nerve to nerve communication. We expect it will form another important piece of the jigsaw that will produce a fuller understanding of what goes wrong in the brain in conditions such as schizophrenia.”
Dr Lang added: “We are very excited by our findings. We still need to do much more work to understand the mechanisms underlying the role of UKL4 in schizophrenia in the hope that this may lead to the discovery of new drug targets for a condition that deprives some sufferers of the ability to lead normal, independent lives.”
(Source: abdn.ac.uk)
Researchers ID more pesticides linked to Parkinson’s, gene that increases risk
Studies have shown that certain pesticides can increase people’s risk of developing Parkinson’s disease. Now, UCLA researchers have found that the strength of that risk depends on an individual’s genetic makeup, which, in the most pesticide-exposed populations, could increase a person’s chance of developing the debilitating disease two- to six-fold.
In an earlier study, published January 2013 in Proceedings of the National Academy of Sciences, the UCLA team discovered a link between Parkinson’s and the pesticide benomyl, a fungicide that has been banned by the U.S. Environmental Protection Agency. That study found that benomyl prevents the enzyme aldehyde dehydrogenase (ALDH) from converting aldehydes — organic compounds that are highly toxic to dopamine cells in the brain — into less toxic agents, thereby contributing to the risk of Parkinson’s.
For the current study, UCLA researchers tested a number of additional pesticides and found 11 that also inhibit ALDH and increase the risk of Parkinson’s — and at levels much lower than they are currently being used, said the study’s lead author, Jeff Bronstein, a professor of neurology and director of the movement disorders program at UCLA.
Bronstein said the team also found that people with a common genetic variant of the ALDH2 gene are particularly sensitive to the effects of ALDH-inhibiting pesticides and are two to six times more likely to develop Parkinson’s when exposed to these pesticides than those without the variant.
The results of the new epidemiological study appear Feb. 5 in the online issue of Neurology, the medical journal of the American Academy of Neurology.
"We were very surprised that so many pesticides inhibited ALDH and at quite low concentrations — concentrations that were way below what was needed for the pesticides to do their job," Bronstein said. "These pesticides are pretty ubiquitous and can be found on our food supply. They are used in parks and golf courses and in pest control inside buildings and homes. So this significantly broadens the number of people at risk."
The study compared 360 patients with Parkinson’s disease in three agriculture-heavy Central California counties and 816 people from the same area who did not have Parkinson’s. The researchers focused their analyses on individuals with ambient exposures to pesticides at work and at home, using information from the California Department of Pesticide Regulation.
In the previous PNAS study, Bronstein and his team had determined the mechanism that leads to increased risk. Exposure to pesticides starts a cascade of cellular events, preventing ALDH from keeping a lid on the aldehyde DOPAL, a toxin that naturally occurs in the brain. When ALDH does not detoxify DOPAL sufficiently, it accumulates, damages neurons and increases an individual’s risk of developing Parkinson’s.
"ALDH inhibition appears to be an important mechanism by which these environmental toxins contribute to Parkinson’s pathogenesis, especially in genetically vulnerable individuals," said study author Beate Ritz, a professor of epidemiology at UCLA’s Fielding School of Public Health. "This suggests several potential interventions to reduce Parkinson’s occurrence or to slow its progression."
In the current study, the research team developed a lab test to determine which pesticides inhibited ALDH. They then found that those participants in the epidemiologic study who had a genetic variant in the ALDH gene were at increased risk of Parkinson’s when exposed to these pesticides. Just having the variant alone, however, did not increase risk of the disease, Bronstein noted.
"This report provides evidence for the relevance of ALDH inhibition in Parkinson’s disease pathogenesis, identifies pesticides that should be avoided to reduce the risk of developing Parkinson’s disease and suggests that therapies modulating ALDH enzyme activity or otherwise eliminating toxic aldehydes should be developed and tested to potentially reduce Parkinson’s disease occurrence or slow its progression, particularly for patients exposed to pesticides," the study states.
(Source: newsroom.ucla.edu)
Impaired cell division leads to neuronal disorder
Prof. Erich Nigg and his research group at the Biozentrum of the University of Basel have discovered an amino acid signal essential for error-free cell division. This signal regulates the number of centrosomes in the cell, and its absence results in the development of pathologically altered cells. Remarkably, such altered cells are found in people with a neurodevelopmental disorder, called autosomal recessive primary microcephaly. The results of these investigations have been published in the current issue of the US journal “Current Biology”.
Cell division is the basis of all life. Of central importance is the error-free segregation of genetic material, the chromosomes. A flawless division process is a prerequisite for the development of healthy, new cells, whilst errors in cell division can cause illnesses such as cancer. The centrosome, a tiny cell organelle, plays a decisive role in this process.
Prof. Erich Nigg’s research group at the Biozentrum of the University of Basel has investigated an important step in cell division: the duplication of the centrosome and its role in the correct segregation of the chromosomes into two daughter cells. The protein STIL has an essential function in this process. It ensures that centrosome duplicate before one half of the genetic material is transported into each of the two daughter cells.
KEN-Box important for protein breakdown
During cell division, the protein STIL is degraded. If this does not occur, the protein accumulates in the cell, which then causes an overproduction of centrosomes. As a consequence, mis-segregated chromosomes are incorporated into the daughter cells, which then represent cells with faulty genetic material. The scientists discovered an amino acid signal on the STIL protein, a so-called KEN-Box, and showed that this is critical for the breakdown of the protein: “The Ken-Box is the signal that orders the protein degradation machinery to break down the STIL protein,” explains Christian Arquint, the first author of this publication. In the absence of the KEN-Box, the protein is not degraded.
Absence of the KEN-Box causes microcephaly
In some patients with microcephaly, a neuronal disorder that leads to a reduced number of nerve cells being produced and, therefore, a smaller brain, the KEN-box is lacking from the STIL protein. The scientists were thus able to demonstrate a tantalizing connection between the absence of this particular amino acid signal and an illness. “When during our investigations of cell division and centrosome duplication we came across a connection to the disorder microcephaly, we were particularly pleased, as this helps us to better understand how this disorder develops“, says Christian Arquint.
In the future, the research group led by Erich Nigg plans to uncover other connections between errors of cell division and the illness microcephaly. They also want to focus on the investigation of other proteins that play important roles in the process of cell division, in particular those involved in centrosome duplication.