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Immune cells
Researchers solve MS 'puzzle'(18/05/15)
Evidence has long suggested multiple sclerosis is an autoimmune disease, but researchers have been puzzled because they found the same T cells that attack the myelin sheathing around nerve cells in MS patients are present in healthy subjects as well.
Now researchers from the Yale School of Medicine and colleagues at the Massachusetts Institute of Technology (MIT) report that auto-reactive T cells in MS patients produce different types of inflammatory hormones called cytokines than they do in healthy subjects.
"In most people, these T cells are acting to repair tissue, but in MS patients, they do damage to the nervous system," said Dr. David Hafler, the William S. and Lois Stiles Edgerly Professor of Neurology and senior author of the study, published May 14 in the journal Science Translational Medicine.
The Yale-led team analysed T cell populations from 23 MS patients and 22 healthy controls. Existing drugs target the MS-specific cytokines identified in the study and should be a promising new treatment for the disease, the authors say.
Hafler also noted the same sort of process might be found in other autoimmune diseases, such as rheumatoid arthritis and Type 1 diabetes.
Yonghao Cao of Yale and Brittany A. Goods of MIT are co-first authors of the paper.
The research was funded by the National Institutes of Health and the National Multiple Sclerosis Society.
Source: Bioscience Technology © Copyright 2015 Advantage Business Media (18/05/15)
Cytokines may play major role in MS(29/04/15)
Researchers say they have discovered the role of a major cytokine in multiple sclerosis that could be a target for new therapy against the disease.
MS is caused by immune cells that activate a cascade of chemicals in the brain, attacking and degrading the insulation that keeps neuronal signals moving. These chemicals, called cytokines, drive the inflammation in the brain, attracting more immune cells, and so causing the condition.
Researchers have long debated which cytokines drive the condition and which are merely accessory. Now a study published in the Journal of Immunology confirms the cytokine GM-CSF (Granulocyte macrophage colony-stimulating factor) likely plays an important role in human disease and offers a new explanation for why the MS treatment interferon-Beta is often so effective.
"After our animal studies showed GM-CSF was important in the development of an MS-like disease, we were excited to see these results confirmed using samples from MS patients in the current study," says Abdolmohamad Rostami, M.D., Ph.D., Chair of the Department of Neurology at Thomas Jefferson University and director of its neuroimmunology laboratory.
A few years ago, MS researchers were focused on a new type of immune cell called the Th-17 cell, which appeared to be a key player in driving the neuronal damage in MS. Because Th-17 cells produce the cytokine IL-17, researchers likewise thought this chemical was essential to the condition. IL-17, however, turned out to be something of a red herring.
In a paper published in Nature Immunology in 2011, Dr. Rostami and colleagues showed the Th-17 cells also produced another cytokine called GM-CSF, which created a chain reaction with another cell type ultimately increasing the GM-CSF levels in the brain of mouse models significantly. In addition, the researchers showed that in experimental models of MS, mice that were unable to produce GM-CSF never developed the condition, whereas mice lacking IL-17 did develop the disease, though generally developed a milder form.
In the new study, to test whether the same observation was true in humans, Dr. Rostami and colleagues tested blood samples of patients with MS who had not yet received therapy, and those currently being treated with interferon-Beta, a commonly used therapy. On average, untreated patients had two to three times as many immune cells producing GM-CSF as did patients being treated with interferon-Beta, or normal subjects. In addition, the researchers looked at brain samples of deceased patients with MS and found increased numbers of GM-CSF-producing cells in comparison to normal brain samples.
"The study demonstrates a new mechanism of action for interferon-Beta therapies," says Dr. Rostami.
In addition, a recent Phase 1 clinical trial of an antibody that blocks GM-CSF showed early signs of effect. Phase 1 trials are typically only designed to determine if a new drug is safe, and can't answer whether a new drug works. However, these results together with the work from the Rostami lab suggest that GM-CSF is a target worth pursuing for the treatment of MS.
"We hope that this research showing GM-CSF is an important target will lead us toward therapies that more effectively block the damaging immune reaction in the central nervous system of MS patients," says Dr. Rostami.
Source: EurekaAlert! Copyright © 2015 by the American Association for the Advancement of Science (AAAS) (29/04/15)
Scientists discover potential new treatment for MS(27/04/15)
Scientists from the Gladstone Institutes have discovered a way to prevent the development of multiple sclerosis in mice. Using a drug that blocks the production of a certain type of immune cell linked to inflammation and autoimmunity, the researchers successfully protected against the onset of MS in an animal model of the disease. The scientists say the next step is to test this strategy using other autoimmune disorders.
"We are very excited about these findings," says Eric Verdin, MD, a senior investigator at Gladstone and co-senior author on the study.
"In light of the significant effect the treatment had on inflammation, the implications of these results will likely extend beyond multiple sclerosis to other types of autoimmune disorders. We are particularly interested in testing this in type I diabetes given the similar pathways involved, and we are already seeing very promising results in preliminary experiments."
In the immune system, two kinds of T cells strike a delicate balance - T helper cells (Th17) activate the immune system, protecting against infections and cancers, while regulatory T cells (Tregs) suppress the system, keeping it in check. A disparity between these cell types, where there are too many Th17 and not enough Tregs, can lead to a hyperactive immune system, resulting in inflammation, tissue damage, and autoimmune disease.
In the current study, published in the Journal of Experimental Medicine, the researchers discovered that an important regulatory protein, sirtuin 1 (SIRT1), is involved in the production of Th17 cells. By blocking this protein, the scientists can protect against the onset of autoimmunity. SIRT1 also has a negative impact on Treg maturation and maintenance, so inhibiting its expression simultaneously enhances the production of Tregs and suppresses the creation of Th17.
To test this effect on disease, the researchers used a mouse model of MS and treated the animals with a drug that inhibits SIRT1. Typically, MS-model mice experience severe motor problems, eventually leading to paralysis, but when they were given the drug the mice behaved perfectly normally. Moreover, the treated animals showed no signs of inflammation or cell damage in their spines, classic markers for MS.
In contrast with the current research, SIRT1 is typically thought of as having anti-inflammatory properties, and compounds that increase SIRT1, like resveratrol, have been proposed as a way to delay aging. However, first author Hyungwook Lim, PhD, a postdoctoral fellow at Gladstone, says the new research suggests that the protein's effects are more complicated.
"The conventional theory has been that you should activate SIRT1 to improve health and longevity, but we show that this can have negative consequences," says Dr. Lim.
"Instead, we think the role of SIRT1 very much depends on the type of tissue being targeted. For instance, in immune cells, instead of being anti-inflammatory SIRT1 appears to have a pro-inflammatory role, which makes it a prime target to treat autoimmune disorders."
Other Gladstone investigators on the study include Jae Kyu Ryu, Mingjian Fei, Intelly Lee, Kotaro Shirakawa, Herbert Kasler, Hye-Sook Kwon, Katerina Akassoglou, and Melanie Ott, who was a co-senior author on the paper. Scientists from the University of California San Francisco, Scripps Research Institute, Buck Institute for Research on Aging, National Institute of Infectious Diseases Japan, German Cancer Research Center, New York University School of Medicine, and Howard Hughes Medical Institute also took part in the research. Funding was provided by the Kurtzig and Mulholland families, the National Center for Research Resources, and the National Center for Biotechnology Information.
Source: EurekaAlert Copyright © 2015 by the American Association for the Advancement of Science (AAAS)(27/04/15)
Immune system component found to be related to MS neurodegeneration(07/04/15)
A study published in PLOS ONE provides new insights into the relationship between the immune system and neurodegeneration and clinical disability in MS, reports Multiple Sclerosis News Today.
A team of researchers led by Dr. Shahin Aeinehband from the Neuroimmunology Unit at the Karolinska Institutet in Sweden looked at the association between a central component of the innate immune system, C3 protein, with the activity of cholinergic metabolism and neurodegeneration markers in both relapsing-remitting and primary progressive MS.
In the study Complement Component C3 And Butyrylcholinesterase Activity Are Associated With Neurodegeneration And Clinical Disability In Multiple Sclerosis, Dr. Shahin Aeinehband and his team analysed 48 samples of cerebrospinal fluid (CSF) from MS patients and compared them to 18 samples of CSF from healthy individuals. Levels of C3 protein; neurofilament-light (NFL), a marker for ongoing nerve injury; and activity of the two main acetylcholine degrading enzymes, acetylcholinesterase and butyrylcholinesterase (BuChE) were measured.
C3 protein levels were elevated in MS patients when compared to controls and were correlated both to disability and neurodegeneration (as showed by NFL levels). This finding supports the theory that the complement system influences MS and is compatible with previous findings in other neurodegenerative conditions. Additionally, the C3 protein levels were increased in patients with more cerebral lesions on magnetic resonance imaging and in patients with progressive disease. Finally, BuChE activity correlated with both C3 and NFL levels in individual samples.
In conclusion, the study found that C3 protein is a marker for ongoing nerve injury and degree of disease disability, with this relationship appearing to be especially important in late stage disease (i.e., with more cerebral lesions or clinically progressive disease). It also suggests a link between the expression of complement C3 and the cholinergic tone (BuChE activity).
Although further studies are needed to clearly establish the cause of these processes, these findings can offer future novel targets for MS therapy.
Source: Multiple Sclerosis News Today © BioNews Services 2015 (07/04/15)
Novel switch for autoimmune diseases could play role in MS(13/03/15)
Scientists at America's National Institutes of Health (NIH) say they may have discovered a critical immune system switch that could affect genes involved in autoimmune diseases. The ground-breaking work, published in the journal Nature, may be useful for developing treatments for autoimmune disorders such as multiple sclerosis (MS).
Finding autoimmune disease susceptibility genes, such as those involved in MS, is difficult due to environment-gene interactions that likely occur. Switches to control gene activities, known as enhancers, have been proposed to play a possible role.
Led by John J. O'Shea, M.D., the scientific director at NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases, the researchers decided to study a newly discovered type of enhancer called a super-enhancer (SE). SEs are powerful switches that control genes. Dr. O'Shea and his collaborators looked for SEs in T cells, immune cells that are important for contributing to the autoimmune disease rheumatoid arthritis.
"We now know more about the genetics of autoimmune diseases," stated NIAMS Director Stephen I. Katz, M.D., Ph.D. "Knowledge of the genetic risk factors helps us assess a person's susceptibility to disease. With further research on the associated biological mechanisms, it could eventually enable physicians to tailor treatments to each individual."
"Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach," remarked Dr. O'Shea. "From the locations of their super-enhancers, T cells are telling us where in the genome these cells invest their assets—their key proteins—and thereby where we are most likely to find genetic alterations that confer disease susceptibility."
The researchers searched the genetic material of T cells and found that many identified mutations associated with autoimmune diseases could be localized to T cell SEs. The scientists then treated human T cells with a drug used for rheumatoid arthritis, called tofacitinib. They discovered that genes controlled by SEs changed dramatically compared to other genes without SEs. They concluded that tofacitinib may work by acting on SEs to affect T cell genes.
"Three types of data — the genetics of rheumatoid arthritis, a genomic feature of T cells, and the pharmacological effects of a rheumatoid arthritis drug—are all pointing to the importance of super-enhancers," said lead author, Golnaz Vahedi, Ph.D. "These regions are where we plan to search for insights into the mechanisms that underlie rheumatoid arthritis and other autoimmune diseases, and for novel therapeutic targets for these conditions."
Source: Multiple Sclerosis News Today © BioNews-tx.com 2015 (13/03/15)
Study on immune response in MS targets new therapeutic approach(20/02/15)
A study published by a team of investigators at the University of Tokyo's Institute of Medical Science and Osaka University's Graduate School of Engineering has presented new evidence demonstrating how Toll-like receptor 9 (TLR9) binds to pathogenic DNA, turning on the functions of the innate immune system. This novel discovery is important for the design of new therapeutic drugs for autoimmune diseases, such as multiple sclerosis (MS), targeting TLR9. The study was published in the new issue of Nature.
Toll-Like Receptors (TLRs) play a critical role in the early innate immune (non-specific first line of defense against pathogens) response to invading bacteria, viruses, and other foreign agents and are also involved in sensing the body's internal alarm system to help activate other important components of its immune defenses. TLR9 detects the alarm system by recognizing a DNA sequence called Cytosine-phosphate-Guanine dinucleotide (CpG), a pattern that is specific to bacteria and viruses. This induces the release of interferon (IFN) and initiates the inflammatory response process. For autoimmune disease such as MS, studies have shown that TLRs and the release of IFN play a major role in the initiation of disease, triggering of relapses and regulation of damage.
Unfortunately, the exact structure of TLR9 and how it functions remained unknown, inhibiting advancement of treatments that specifically targeted these receptors. This study conducted by Professor Toshiyuki Shimizu PhD's research group used crystallographic (molecular structure) data to evaluate TLR9's ring-shaped form in three crucial states: as a free protein, bound to an inhibitor DNA, and bound to an agonist DNA. In the first two cases, TLR9 exists as a single ring, but when it binds to an agonist, like a DNA segment containing the CpG motif, two of its rings are bound together and form a dimer (chemical structure formed from two similar sub-units) that shares two DNA molecules.
In a statement explaining the importance of the study findings, Professor Shimizu said, "TLR9 is a promising drug target for treating viral infections, cancer, autoimmune diseases, and so on, so researchers have been trying to elucidate structurally how TLR9 recognizes pathogenic DNA ever since it was discovered more than a decade ago. This work represents a big step forward for drug development targeting TLR9, and also for our understanding of nucleic acid sensing by TLR9. TLRs have received significant attention due to their critical roles in the innate immune system, and our group has been focusing on the structural study of TLRs for many years. We believe that a precise understanding of TLR function should come from its visualization by structural analyses. Actually, we were quite surprised at the result of this study: the two DNA molecules, agonist and inhibitor, bound to completely different sites on TLR9, and the DNA molecules themselves had completely different structures, both of which we could never have predicted."
Source: Multiple Sclerosis News Today © BioNews-tx.com 2015 (20/02/15)
New molecule may improve treatments for inflammatory diseases(18/02/15)
A team of scientists have uncovered a molecule that fights one of the main causes of inflammatory diseases and could be the key to improved treatments for diseases like Alzheimer's, arthritis and multiple sclerosis. The research team, led by Trinity and the University of Queensland Australia, showed the molecule, MCC950, could suppress the key activator in inflammatory diseases, NLRP3. The finding also confirms that inflammatory diseases all share a common process, even though the part of the body becoming inflamed might differ.
Researcher Luke O'Neill said drugs like aspirin or steroids can work in several diseases, but can have side effects or be ineffective, and what they have found is a potentially transformative medicine, which targets what appears to be the common disease-causing process in a myriad of inflammatory diseases. There is huge interest in NLRP3, both among medical researchers and pharmaceutical companies, and they feel their work makes a significant contribution to the efforts to find new medicines to limit it. MCC950 can be administered orally and will be cheaper to produce than current protein-based treatments, which are given daily, weekly, or monthly by injection.
More importantly, the new molecule also remains in the body for a shorter duration, allowing clinicians to stop the anti-inflammatory action of the drug if the patient ever needed to switch their immune response back to 100 percent, in order to clear an infection. So far, the results have shown great promise for blocking multiple sclerosis in a model of the disease, as well as in sepsis where, in response to bacteria, potentially fatal blood poisoning occurs. However, the target for MCC950 is strongly implicated in diseases such as Alzheimer's disease, atherosclerosis, gout, Parkinson's disease and rheumatoid arthritis, which means it has the potential to treat all of these conditions. The study is published in medical journal Nature Medicine.
Source: dna © 2015 Diligent Media Corporation Ltd (18/02/15)
NUS researchers make breakthrough discovery that could lead to future treatment for multiple sclerosis(24/11/14)
The latest findings may provide an avenue for therapeutic intervention of multiple sclerosis. A multi-disciplinary research team from the National University of Singapore (NUS) has made a breakthrough discovery of a new type of immune cells that may help in the development of a future treatment for multiple sclerosis (MS).
Led by Professor Xin-Yuan Fu, Senior Principal Investigator from CSI Singapore and Professor at the Department of Biochemistry at the NUS Yong Loo Lin School of Medicine, and Dr Wanqiang Sheng, post-doctoral fellow at CSI Singapore, the team found that a new type of immune T helper cells named TH-GM cells play a crucial role in the immune system and pathogenesis of neuronal inflammation. The findings shed light on a possible new avenue for therapeutic intervention, which can be used independently or in conjunction with other treatment options to improve outcomes in the treatment of MS.
Working with Dr Yong-Liang Zhang from the Department of Microbiology at the NUS Yong Loo Lin School of Medicine, Prof Fu and his team showed that STAT5, a member of the STAT family of proteins, programs TH-GM and initiates the immune response to an auto-antigen in responding to a signal from an interleukin, IL-7, causing neuro-inflammation, pathogenesis and damage in the central nervous system. Blocking IL-7 or STAT5 would provide a significant therapeutic benefit for this disease. The study was first published online on 21 November in the journal Cell Research by Nature Publishing Group.
MS is the most prevalent autoimmune disease of the central nervous system, affecting about 2.5 million people globally, with cases showing a higher prevalence in Northern Europe. Despite many years of research, the causes of MS are largely unclear and the disease remains incurable.
This study offers an important insight into the mechanisms behind MS. Dr Richard Flavell, Chair of the Department of Immunology at Yale University, USA, and a world leader in the immunology field, noted that the results from the study may now provide a mechanistic link between IL-7/STAT5-mediated signalling and T helper cell-mediated pathogenicity.
The STAT family of proteins and their signalling pathway (called JAK-STAT) were originally discovered by Prof Fu and his colleagues in 1992. Disturbance of this pathway was shown to be a major cause for many kinds of inflammatory diseases. Novel medicines interfering with JAK-STAT have since been approved in the United States, Europe, and Singapore for the treatment of numerous diseases, and annual sales of medicines involving JAK-STAT are expected to exceed US$1.6 billion in 2016. The newly discovered IL-7-STAT5 by Prof Fu and his team in neuro-inflammation significantly expands this line of medical research, development and therapeutic intervention in a number of major diseases.
Moving forward, Prof Fu and his team are researching the physiological function of TH-GM to further the development of therapy for various human autoimmune diseases.
Source: National University of Singapore (24/11/14)
Study unexpectedly blocks multiple sclerosis relapses in mice(12/11/14)
In multiple sclerosis, the immune system goes rogue, improperly attacking the body's own central nervous system. Mobility problems and cognitive impairments may arise as the nerve cells become damaged.
In a new study, researchers from the University of Pennsylvania and co-investigators have identified a key protein that is able to reduce the severity of a disease equivalent to MS in mice. This molecule, Del-1, is the same regulatory protein that has been found to prevent inflammation and bone loss in a mouse model of gum disease.
"We see that two completely different disease entities share a common pathogenic mechanism," said George Hajishengallis, a professor of microbiology in Penn's School of Dental Medicine and an author on the study. "And in this case that means that they can even share therapeutic targets, namely Del-1."
Because Del-1 has been found to be associated with susceptibility to not only multiple sclerosis, but also Alzheimer's, it's possible that a properly functioning version of this protein might help guard again that disease's effects as well.
Penn contributors to the study included Hajishengallis, Penn Dental Medicine postdoctoral researcher Kavita Hosur and Khalil Bdeir, a research associate professor at Penn's Perelman School of Medicine. They collaborated with senior author Triantafyllos Chavakis of Germany's Technical University Dresden and researchers from South Korea's University of Ulsan College of Medicine and other institutions. The work appears online in the journal Molecular Psychiatry.
In earlier studies, Hajishengallis, Chavakis and colleagues found that Del-1 acts as a gatekeeper that thwarts the movement and accumulation of immune cells like neutrophils, reducing inflammation. While neutrophils are needed to effectively respond to infection or injury, when too many of them accumulate in a tissue, the resulting inflammation can itself be damaging. Hajishengallis has found that gum tissue affected by periodontitis, a severe form of gum disease associated with inflammation and bone loss— had lower levels of Del-1 than healthy tissue.
While researching Del-1 in other tissues, such as gums and lungs, Hajishengallis and Chavakis found that Del-1 was also highly expressed in the brain. In addition, genome-wide screens indicate that the Del-1 gene may contribute to multiple sclerosis risk. For these reasons, the scientists hypothesized that Del-1 might prevent inflammation in the central nervous system just as it does in the gum tissue.
To test their theory, the researchers examined Del-1 expression in brain tissue from people who had died from MS. In MS patients with chronic active MS lesions, Del-1 was reduced compared to both healthy brain tissue and brain tissue from MS patients who were in remission at the time of their death. Similarly, Del-1 expression was reduced in the spinal cords of mice with the rodent equivalent of MS, experimental autoimmune encephalomyelitis (EAE).
Having confirmed this association between reduced Del-1 and MS and EAE, the scientists wanted to see if the reduction itself played a causal role in the disease.
Hajishengallis's and Chavakis's labs had previously utilized mice that lack Del-1 alone or Del-1 together with other molecules of the immune system. The researchers found that mutant mice lacking Del-1 had more severe attacks of the EAE than normal mice, with more damage to myelin, the fatty sheath that coats neurons and helps in the transmission of signals along the cell. Loss of this substance is the hallmark of MS and other neurodegenerative diseases.
Mice without Del-1 that had been induced to get EAE also had significantly higher numbers of inflammatory cells in their spinal cords at the disease's peak, a fact that further experiments revealed was due to increased levels of the signaling molecule IL-17.
Mice that were induced to get EAE that lacked both Del-1 and the receptor for IL-17 had a much milder form of the disease compared to mice that lacked only Del-1. These doubly depleted mice also had fewer neutrophils and inflammation in their spinal cords.
With a greater understanding of how Del-1 acts in EAE, the researchers were curious whether simply replacing Del-1 might act as a therapy for the disease. They waited until mice had had an EAE attack, akin to a flare-up of MS in human patients, and then administered Del-1. They were pleased to find that these mice did not experience further episodes of the disease.
"This treatment prevented further disease relapse," Chavakis said. "Thus, administration of soluble Del-1 may provide the platform for developing novel therapeutic approaches for neuroinflammatory and demyelinating diseases, especially multiple sclerosis."
The team is pursuing further work on Del-1 to see if they can identify a subunit of the protein that could have the same therapeutic effect.
"It's amazing that our work in periodontitis have found application in a central nervous system disease," Hajishengallis said. "This shows that periodontitis can be a paradigm for other medically important inflammatory diseases."
Source: Medical Xpress © Medical Xpress 2011-2014,Science X network (12/11/14)
Autoimmune disease progression appears to be reversed by naturally occurring molecule(08/10/14)
Type 1 diabetes, ulcerative colitis, and multiple sclerosis are among the more well-known autoimmune diseases. But according to the AARDA, there are more than 150 rare autoimmune diseases, which affect around 50 million Americans. Even with this large number, scientists are still in the dark regarding interventions that can help cure these diseases. But this might change with the discovery of a molecule called NAD+ that has the potential to reverse autoimmunity.
What is autoimmunity?
When an intruding pathogen, such as a virus or bacterium, enters our bodies, our innate immune system gets activated, immediately sending out its soldiers (antibodies and immune cells) to identify and eliminate the pathogen, thus protecting us. But sometimes something goes wrong with this innate immunity and it starts regarding the body's own tissues as foreign and repeatedly sends out soldier cells to attack them.
Autoimmune diseases can affect any part of the body, including the heart, brain, nerves, muscles, joints, lungs, kidneys, etc. There is still no established cause for autoimmunity, but genetic factors are considered to play a major role.
This new research conducted by Brigham and Women's Hospital (BWH) has identified NAD+ (Nicotinamide adenine dinucleotide), a naturally occurring molecule in living cells, plants, and food that has the potential to turn "destructive" cells that attack healthy tissues into "protective" cells. The molecule has also been found to reverse disease progression by restoring tissue damaged by the autoimmunity process.
"Our study is the first to show that NAD+ can tune the immune response and restore tissue integrity by activating stem cells," said Abdallah ElKhal, senior author, in a statement. "These findings are very novel and may serve for the development of novel therapeutics." The study is published online Oct. 7, in Nature Communications.
NAD+ plays an essential role in several metabolic processes. To test the action of NAD+ in pre-clinical trials, the scientists used experimental autoimmune encephalomyelitis, a pre-clinical model for human multiple sclerosis. They found that NAD+ could regulate the differentiation of immune cells called CD4+ T cells that have an established role in many aspects of autoimmune inflammation. Mice having NAD+ were administered with CD4+ T cells. They showed a significant delayed onset of disease, as well as a less severe form, therefore demonstrating the molecule's protective properties.
"This is a universal molecule that can potentially treat not only autoimmune diseases, but other acute or chronic conditions such as allergy, chronic obstructive pulmonary disease, sepsis, and immunodeficiency," said coauthor Stefan G. Tullius.
The scientists also successfully demonstrated the tissue-restoring capability of NAD+. This, they say, can benefit patients with advanced tissue damage caused by autoimmune diseases. The scientists are now exploring the other medical benefits of NAD+.
"Since this is a natural molecule found in all living cells, including our body, we hope that it will be well-tolerated by patients," said ElKhal. "Thus, we hope that its potential as a powerful therapeutic agent for the treatment of autoimmune diseases will facilitate its use in future clinical trials."
Source: Medical Daily © 2014 IBT Media Inc (08/10/14)
To boost or supress autoimmunity, that is the question(11/09/14)
Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: Boosting autoimmunity to fight-off chronic neuroinflammation.
Schwartz M, Baruch K.
Immune cell infiltration to the brain's territory was considered for decades to reflect a pathological process in which immune cells attack the central nervous system (CNS); such a process is observed in the inflammatory autoimmune disease, multiple sclerosis (MS).
As neuroinflammatory processes within the CNS parenchyma are also common to other CNS pathologies, regardless of their etiology, including neurodegenerative disorders such as Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS), these pathologies have often been compared to MS, a disease that benefits from immunosuppressive therapy.
Yet, over the last decade, it became clear that autoimmunity has a bright side, and that it plays a pivotal role in CNS repair following damage. Specifically, autoimmune T cells were found to facilitate CNS healing processes, such as in the case of sterile mechanical injuries to the brain or the spinal cord, mental stress, or biochemical insults. Even more intriguingly, autoimmune T cells were found to be involved in supporting fundamental processes of brain functional integrity, such as in the maintenance of life-long brain plasticity, including spatial learning and memory, and neurogenesis.
Importantly, autoimmune T cells are part of a cellular network which, to operate efficiently and safely, requires tight regulation by other immune cell populations, such as regulatory T cells, which are indispensable for maintenance of immunological self-tolerance and homeostasis.
Here, we suggest that dysregulation of the balance between peripheral immune suppression, on one hand, and protective autoimmunity, on the other, is an underlying mechanism in the emergence and progression of the neuroinflammatory response associated with chronic neurodegenerative diseases and brain aging.
Mitigating chronic neuroinflammation under these conditions necessitates activation, rather than suppression, of the peripheral immune response directed against self.
Accordingly, we propose that fighting off acute and chronic neurodegenerative conditions requires breaking peripheral immune tolerance to CNS self-antigens, in order to boost protective autoimmunity. Nevertheless, the optimal approach to fine tune such immune response must be individually explored for each condition.
Source: J Autoimmun. 2014 Sep 5. pii: S0896-8411(14)00127-9. doi: 10.1016/j.jaut.2014.08.002 © 2014 Elsevier Ltd & Pubmed PMID: 25199710 (11/09/14)
Breakthrough hope for MS treatment(03/09/14)
Scientists say they have discovered how to "switch off" autoimmune diseases such as multiple sclerosis.
Researchers at the University of Bristol, who describe the work as an "important breakthrough", say it could improve the lives of millions around the world.
In their research, published today in Nature Communications, the team reveal how to stop cells from attacking healthy body tissue.
The team discovered how cells convert from being aggressive to protecting against disease, rather than the body's immune system destroying its own tissue by mistake.
It is hoped the insight will lead to the widespread use of antigen-specific immunotherapy as treatment for many autoimmune disorders.
Conditions which could be affected by the research include multiple sclerosis (MS), type 1 diabetes, Graves' disease and systemic lupus erythematosus.
MS alone affects around 100,000 people in the UK and 2.5 million people worldwide.
Professor David Wraith, of the university's School of Cellular and Molecular Medicine, led the "exciting" research - which was funded by the Wellcome Trust.
"Insight into the molecular basis of antigen-specific immunotherapy opens up exciting new opportunities to enhance the selectivity of the approach while providing valuable markers with which to measure effective treatment," Professor Wraith said.
"These findings have important implications for the many patients suffering from autoimmune conditions that are currently difficult to treat."
In the study, scientists were able to selectively target the cells that cause autoimmune disease by dampening down their aggression against the body's own tissue, while converting them into cells capable of protecting against disease.
This type of conversion has previously been applied to allergies, in a treatment known as "allergic desensitisation", but its application to autoimmune disorders has only recently been appreciated.
The researchers have now revealed how the administration of fragments of the proteins that are normally the target for the attack leads to correction of the autoimmune response.
Their work also shows that effective treatment can be achieved by gradually increasing the dose of antigenic fragment injected.
In order to analyse how this type of immunotherapy works, the scientists looked inside the immune cells themselves to see which genes and proteins were turned off by the treatment.
They found changes in gene expression that help explain how effective treatment leads to conversion of aggressor into protector cells.
The outcome is to reinstate self-tolerance, where an individual's immune system ignores its own tissues while remaining fully armed to protect against infection.
Researchers say that by specifically targeting the cells at fault, the immunotherapeutic approach avoids the need for immune suppressive drugs.
These drugs are often associated with side effects such as infections, development of tumours and disruption of natural regulatory mechanisms.
The treatment approach is currently undergoing clinical development through biotechnology company Apitope, a spin-out from the University of Bristol.
"Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy" is published in Nature Communications today.
Source: The Courier.co.uk © 2014 DC Thomson & Co, Ltd. (03/09/14)
Researchers discover neuroprotective role of immune cell(22/07/14)
A type of immune cell widely believed to exacerbate chronic adult brain diseases, such as Alzheimer's disease and multiple sclerosis (MS), can actually protect the brain from traumatic brain injury (TBI) and may slow the progression of neurodegenerative diseases, according to Cleveland Clinic research published today in the online journal Nature Communications.
The research team, led by Bruce Trapp, PhD, Chair of the Department of Neurosciences at Cleveland Clinic's Lerner Research Institute, found that microglia can help synchronize brain firing, which protects the brain from TBI and may help alleviate chronic neurological diseases. They provided the most detailed study and visual evidence of the mechanisms involved in that protection.
"Our findings suggest the innate immune system helps protect the brain after injury or during chronic disease, and this role should be further studied," Dr. Trapp said. "We could potentially harness the protective role of microglia to improve prognosis for patients with TBI and delay the progression of Alzheimer's disease, MS, and stroke. The methods we developed will help us further understand mechanisms of neuroprotection."
Microglias are primary responders to the brain after injury or during illness. While researchers have long believed that activated microglia cause harmful inflammation that destroys healthy brain cells, some speculate a more protective role. Dr. Trapp's team used an advanced technique called 3D electron microscopy to visualize the activation of microglia and subsequent events in animal models.
They found that when chemically activated, microglia migrate to inhibitory synapses, connections between brain cells that slow the firing of impulses. They dislodge the synapse (called "synaptic stripping"), thereby increasing neuronal firing and leading to a cascade of events that enhance survival of brain cells.
Trapp is internationally known for his work on mechanisms of neurodegeneration and repair in multiple sclerosis. His past research has included investigation of the cause of neurological disability in MS patients, cellular mechanisms of brain repair in neurodegenerative diseases, and the molecular biology of myelination in the central and peripheral nervous systems.
Source: Medical Xpress © Medical Xpress 2011-2014 (22/07/14)
Tolerance-directed immunotherapy: Future of MS treatment?(30/05/14)
It may take some time and require overcoming certain hurdles, but the future of multiple sclerosis (MS) management may lie in delivering therapies that make immune cells tolerant of specific antigens.
These "tolerance-directed" immunotherapies could eventually provide a safe, cost-effective, and highly efficient alternative to current approaches to MS treatments that suppress the immune system and inevitably lead to patients becoming more susceptible to infections, cancer, and other disorders.
Stephan D. Miller, PhD, Judy Guggenheim Research Professor of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, elaborated on the development of these precisely targeted immunotherapies in his opening lecture at the 6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS).
He is also a cofounder and member of COUR Pharmaceutical Development Company Inc, a nanobiotechnology company focused on the development of novel immune therapies using nanotechnologies based on the Immune Modifying nanoParticle platform.
As Dr. Miller explained, targeted tolerance-directed immunotherapies intervene in the autoimmune response, affecting only the pathogenic autoreactive T cells that react to a specific antigen. Such therapies reset those particular cells to actually avoid an immune response, rather than suppressing a response.
In the future, such new therapies may allow clinicians to shut down the underlying disease process instead of just controlling MS symptoms, said Dr. Miller, who has more than 30 years of experience in the field of autoimmune research.
New Way to Treat MS?
"We hope that our tolerance-directed therapy offers a new way to treat newly diagnosed MS patients to halt their disease in a safe and efficient manner by treating the root causes of the disease without the need to take a lifetime of immunosuppressive drugs and in a way that will avoid potential side effects, such as infections and increased rate of cancer," Dr. Miller told Medscape Medical News.
He and his colleagues have already proven the tolerance-directed approach to be safe and effective in a mouse model and, with a group of German researchers, have shown it to be effective in humans. The results of that published study of 9 patients with MS found that the tolerance-directed immunotherapy reduced the patients' immune system reactivity by 50% to 75% (Sci Transl Med. 2013;5:188ra75).
The drawback in that study, though, was that it used a method that involved extracting white blood cells, processing them to deliver myelin antigens so that the body would develop tolerance for them, and then reinfusing these treated white blood cells into the patients.
Dr. Miller and his colleagues are planning another trial of tolerance-directed immunotherapy. However, rather than using the relatively complicated and pricey extraction-processing approach, they hope to be able to deliver the therapy via biodegradable polymer-based nanoparticles: poly (D,L-lactide-co-glycolide) or PLG. It's the same technology used in absorbable sutures that dissolve after tissue heals.
"We are currently in the planning stages of this phase 1 trial using myelin antigen containing PLG nanoparticles in newly diagnosed MS patients," confirmed Dr. Miller, adding that his team hopes to carry out the study in collaboration with neurologists at the Multiple Sclerosis Center at Rush University Medical Center in Chicago.
If all goes well, the study should begin within the next 6 months to a year, said Dr. Miller.
This novel treatment approach has broad implications not only for the treatment of MS but also for a variety of other immune-mediated diseases, including type 1 diabetes and rheumatoid arthritis, and other conditions for which physicians want to manipulate the immune system, such as asthma, food allergies, and islet transplantation in diabetes. Immunologic tolerance, said Dr. Miller, is the "holy grail" for autoimmune diseases.
Broad Implications
Asked to comment on this approach, Corey Ford, MD, director, MS Clinic, and professor, neurology, University of New Mexico, Albuquerque, who introduced Dr. Miller's lecture, told Medscape Medical News that the idea of "tolerizing" the immune system has been around for a long time and that this is the mechanism by which the drug glatiramer acetate (Copaxone, Teva Pharmaceuticals) may be working.
"We have thought for a long time that MS may be triggered by antigens of some sort — we don't know what they are; maybe they're viruses or other environmental triggers — and that desensitizing the immune system to those could play a role in treatment."
Dr. Ford used the example of a patient who is allergic to penicillin. "You can desensitize that person to penicillin by giving him very small doses and gradually increasing the amount so his immune system becomes tolerant," he said.
Dr. Miller's tolerance-directed immunotherapy would in essence be "a more targeted way to desensitize a person with an autoimmune disease to the antigens" that might be triggering their disease, said Dr. Ford.
Dr. Ford agreed that there's still a lot of research needed to determine which antigens and what sequence of antigens are important.
The "good news," he said, is that the nanoparticles "are safe, can be given to humans, and are approved." And the fact that the framework or platform the antigen attaches to is biodegradable removes the worry about toxicity, he added.
"If you can make educated guesses about the right ones to use, maybe you have a treatment for a disease like MS and for many other conditions. This is a strategy that's a framework; it's not just a single disease-targeted approach."
Dr. Miller is cofounder and member of COUR PharmaceuticalDevelopment Company Inc, a nanobiotechnology company focused on the development of novel immune therapies using nanotechnologies based on the Immune Modifying nanoParticle (IMP) platform. The IMP particles are derived from Food and Drug Administration–approved, biodegradable polymer poly(lactic-co-glycolic-acid) that, when modified and built using proprietary IMPtechnology, provide therapeutic relief in numerous inflammatory conditions.
6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS). Opening Lecture. Presented May 28, 2014.
Source: Medscape Multispeciality Copyright © 1994-2014 by WebMD LLC (30/05/14)
Genome study identifies three possible drug candidates for autoimmune diseases(02/05/14)
New pharmaceuticals to fight autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and psoriasis, may be identified more effectively by adding genome analysis to standard drug screening, according to a new study by a research team led by UC San Francisco and Harvard researchers, in collaboration with Tempero and GlaxoSmithKlein.
In a study reported online April 17, 2014 in the journal Immunity, the scientists combined drug screening with state-of-the-art techniques for analyzing the genome, leading to three small molecules that improved symptoms in a mouse form of multiple sclerosis.
The three potential drug candidates, selected from a large library of screened chemicals, each knocked down the response of Th17 cells, a type of immune cell that drives many autoimmune diseases by attacking normal cells in the body. More specifically, the drugs homed in on an essential molecule within the Th17 cells.
"We examined what makes Th17 cells – which play a crucial role in multiple autoimmune diseases – distinct from other closely related T cells within the immune system," said Alexander Marson, MD, PhD, a leading T cell expert and member of the UCSF Diabetes Center. "Then we investigated several small molecules that inhibit the development and function of these cells. When the Th17 cells were hit by these molecules we saw less severe multiple-sclerosis-like symptoms in the mice."
The research team, led by Marson and Vijay K. Kuchroo, PhD, an immunologist at Brigham and Women's Hospital in Boston and Harvard Medical School, combined powerful techniques to shed light on a class of protein molecules within cells known as transcription factors.
Drug designers have rarely targeted transcription factors. Each transcription factor binds to DNA at a unique set of locations along the 23 pairs of chromosomes, and thereby influences which genes are turned on and off to trigger the protein production that drives cell development and function.
Different transcription factors shape the development of different types of T cells within the immune system, Marson and others are discovering. In their new study, Marson found that the transcription factor called ROR gamma t has a unique role in guiding development of Th17 cells, while inhibiting the development of other immune cells.
Preventing Th17 cells from developing by inhibiting the function of ROR gamma t appears to be an effective strategy for fighting autoimmune diseases, Marson said. "There already are drugs in clinical trials for autoimmune diseases – including psoriasis and rheumatoid arthritis – that are antibodies for IL-17 or IL-17 receptors," Marson said, referring to signaling molecules secreted by Th17 cells that can help trigger an attack our own healthy tissue, and the receptors that receive those signals. "This is an entirely different and promising approach to fight autoimmune disease," he said.
"Our studies map a path to targeting transcription factors and provide both insight into how transcriptional regulators shape the identity and affect the development of Th17 cells, and also into how different drug molecules might affect these regulatory circuits in the cells," he said.
To reveal the distinct and sometimes subtle effects of the drug candidates, the researchers studied the entire genome to see where ROR gamma t attached to DNA, which genes were activated or turned off as a result, and how these effects were altered by the drug candidates.
"Not only did we look at which genes are turned on and off, but we also systematically looked at DNA-binding sites across this genome," Marson said. "This pushes the boundary of what's typically done."
In addition to attaching to DNA, ROR gamma t has a pocket that looks like it should bind a hormone, Marson said. But what this hormone might be, and its effects, are unknown. The different drug candidates that inhibited Th17 development had different effects on ROR gamma t and resultant DNA binding and gene activation, possibly because of distinct interactions with the hormone-binding pocket, Marson said.
Analyzing the large data sets generated through such experiments could help pharmaceutical companies wading into development of drugs that target transcription factors to test the waters, Marson said, enabling drug developers to better understand mechanisms of drug action and to more easily see gene activity that could trigger side effects. According to Marson, "This is a new, broadly applicable approach for systematically evaluating leading drug candidates for autoimmune diseases."
Source: MedicalXpress © Medical Xpress 2011-2014 (02/05/14)
OSU scientists discover possible treatment for MS and other autoimmune diseases(21/03/14)
Researchers tested the compound in mice that had a condition in which the immune system tries to eliminate foreign cells.
Oregon State University scientists have discovered a chemical compound that could be a safer alternative to treating autoimmune diseases, possibly bringing hope to people suffering from conditions caused by their immune system attacking their bodies.
Studies are still needed in humans, however. Autoimmune diseases can affect almost any part of the body and result in such diseases as colitis, multiple sclerosis and psoriasis.
"We mostly treat autoimmune diseases with high-dose corticosteroids or cytotoxic drugs to suppress the immune response, and the side effects can be very difficult to deal with," lead researcher Nancy Kerkvliet said in a statement. "But if this chemical works in clinical studies, it could result in a safer alternative to conventional drugs."
Kerkvliet and OSU professor Siva Kumar Kolluri tested thousands of chemical compounds and found that one of them, 10-CI-BBQ, binds to a protein inside T cells. The chemical and protein pass into the nucleus and change the cells into regulatory T cells, which shut down the immune response.
Researchers tested the compound in mice that had a condition in which the immune system tries to eliminate foreign cells. The disease can occur in humans when they receive stem cell or bone marrow transplants.
Daily injections completely suppressed the disease. The compound was rapidly metabolized and not toxic.
The research was published in the journal PLOS ONE.
Source © 2014 American City Business Journals. All rights reserved. (21/03/14)
New insights into immune response could lead to development of new treatments(19/03/14)
A team of biologists and engineers at the University of California, San Diego has discovered that white blood cells, which repair damaged tissue as part of the body's immune response, move to inflamed sites by walking in a stepwise manner. The cells periodically form and break adhesions mainly under two "feet," and generate the traction forces that propel them forward by the coordinated action of contractile proteins. Their discovery, published in the Journal of Cell Biology, is an important advance toward developing new pharmacological strategies to treat chronic inflammatory diseases such as arthritis, irritable bowel syndrome, Type 1 diabetes, and multiple sclerosis.
"The immune system requires the migration of white blood cells to the point of infection and inflammation to clear invaders and begin the process of digesting and repairing tissue. However, when the body fails to properly regulate the recruitment of these cells, the inflammation can become chronic resulting in irreversible tissue injury and loss of functionality," said Juan C. Lasheras, a professor in the departments of Mechanical and Aerospace Engineering and Bioengineering, and in the Institute for Engineering in Medicine. "Understanding the way in which these cells generate the necessary forces to move from the blood stream to the site of inflammation will guide the design of new strategies that could target specific mechanical processes to control their migration," Lasheras said.
Figuring out how white blood cells move required an interdisciplinary approach involving engineering and biological sciences. The lead author of the study is Effie Bastounis, a member of a team led by UC San Diego Jacobs School of Engineering professors Lasheras and Juan Carlos del Alamo, of the Department of Mechanical and Aerospace Engineering, and Richard A. Firtel, a professor of Cell and Developmental Biology in the Division of Biological Sciences. "This work was made possible through interdisciplinary approaches that applied mathematical tools to a basic question in cell biology about how cells move," stated Richard Firtel. "By first applying novel methodologies to study the amoeba Dictyostelium, an experimental system often used by cell biologists, we were able to discover the basic mechanisms that control amoeboid movement, which we then applied to understanding white blood cells."
The team used new analytical tools to measure, with a high degree of accuracy and resolution, the forces the cells exert to move forward. The novel methodology, which they have been refining during the last several years supported by grants from the National Institutes of Health (R01-GM084227 and R01-GM037830), is called Fourier Traction Force Microscopy. Before their study, scientists thought white blood cells did not move in a highly coordinated manner. Furthermore, their work discovered that cells move by not only extending themselves at their front and contracting their backs, but also by squeezing inwardly along their lateral sides pushing the front of the cell forward. These findings establish a new paradigm as to how cell move. The research team is currently extending their techniques, which they have used to study leukocytes and other types of amoeboid cells, to investigate the mechanics of cancer cell migration and invasion.
Source: MNT © 2004-2014 MediLexicon International Ltd (19/03/14)


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Senators quiz defense companies on sequestration
Letter, sent to 15 large vendors, asks for estimated impacts of sequestration on defense contractors.
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Inquiry hears of wider Secret Service misbehavior
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Twenty senators all Democrats have signed on in support of the Domestic Partnership Benefits and Obligations Act, which would extend health-care benefits to same-sex, domestic partners of federal employees.
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CBO: House postal reform bill to save $20B in decade
The bill introduced last summer by Rep. Darrell Issa (R-Calif.) would eliminate Saturday mail delivery, close mail processing facilities, require postal employees to pay the same percentage in their health and life insurance premiums as federal employees do, and allow the Postal Service to use nearly $11 billion in surplus retirement contributions.
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View Diary: BREAKING: White House Advisor Drops Bombshell (minor updates) (321 comments)
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- Details of the settlement are expected today, but somehow a cop standing on the hood of a car emptying a magazine through the windshield stands in stark contrast to any sense of justice. Is 600 ...7 comments 5 Recs
- Today is Memorial Day (well, at least it still is where I live), and I have done a lot of thought today. About my own time in the service, about the people I knew who perished, and the people who ...11 comments 17 Recs
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- Yep, another milestone. And timely too. I'm all 3-day-weekended out. (Not complaining, you understand, just explaining.) Tuesday! A day to have a slice of IAN cake and sip a beverage.15 comments 9 Recs
- This is a oddly humorous movie about a car jumper. It's worth a watch.1 comments 0 Recs
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text:
The Senate has passed a bill to give the Department of Transportation more flexibility in how it makes the mandatory cuts of the sequester. Hundreds of flights were delayed this week after the FAA furloughed air traffic controllers, setting off a political storm.
Source: NPR
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Hotels/Motels near The Vault are shown below in the order of their distance. Browse our hotels to find accommodations near The Vault (in Desert CA) for your upcoming travels.
We sell the best lodging close to The Vault so you can review the discounted Desert CA lodging below and securely book your ideal hotel.
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text:
Lawmaker linked to 'pork' scam threatens to file raps vs Napoles
MANILA, Philippines — A congressman linked to the alleged pork barrel scam on Thursday threatened to file charges against Janet Lim-Napoles following the discovery that P3.5 million of his allocation had gone to a fake nongovernment organization.
Cagayan de Oro Representative Rufus Rodriguez said he would not take sitting down the findings that part of his Priority Development Assistance Fund in 2007 did not go to its intended beneficiary.
"I won't stop at simply defending myself which I will do at the proper forum. Definitely, I will also press charges," he told the Philippine Daily Inquirer.
Rodriguez maintained that his signatures were forged and documents were faked, allowing the bogus NGO to get hold of his PDAF, informally know as pork barrel fund.
"I was really shocked when I learned about it," he recalled, noting that the amount was earmarked for the Technology and Livelihood Resource Center.
"It's a legitimate agency and I had no reason to believe that the PDAF would not be spent properly."
Rodriguez said he would wait for the official findings of the National Bureau of Investigation before he filed charges.
The third-term congressman was put on the spot after his name surfaced as among the legislators whose PDAF allocations had supposedly gone to fake NGOs put up by Napoles, who is now the subject of an arrest warrant for a separate case.
Like Davao City Representative Isidro Ungab, he said he had prepared all documents purportedly showing that transactions were all above board.
In his case, Rodriguez said his signatures were faked to allow the fake NGO to secure part of his PDAF, which was in fact allocated for the TLRC.
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text:
1330 Larpenteur Ave W ( )
St Paul, MN 55113-6342View Hours
1330 Larpenteur Ave W ( )
St Paul, MN 55113-6342View Hours
December 29, 20094.0
Mac's fish and chips looks like a small shack from the outside but their food is the real deal. It's the closest you can get to real british fish and chips that I have found. They serve fresh haddock and also fried shrimp and oysters. You order you food in baskets which comes with a side of coleslaw and fries.
I usually order for take out because the inside can get a bit crowded. The interior is nothing to marvel over, but it's the food that counts.
June 30, 20134.0
Personally, I never ate at the old Mac's, but I did eat there a few years ago and it was awful. New owners have changed that. The fish was wonderful. The clams were tasty. The Salt Water taffy was sticky, but delicious. There was a debate at our table about the fries. They are skin on and fresh cut. It was decided that they were tasty, but some did not like the skin on the fries.
So, if you have been avoiding Mac's, it is time to go back!
October 29, 2011
I was just at MAC'S fish&chips and for 27$ the fish was cooked but the out side crust was under cooked the cole slaw was really bad and the chips where french fries and they sucked too . The tarter sauce was too sweet. I would not…
March 18, 2011
I used my Groupon on a Tuesday after it had expired. When I explained the misprint on the Groupon said open Mon-Sat, but they were closed on Mondays, the owner said "no problem." Friendly service. The food was delicious, crispy cod with…
These dishes from the Mac's Fish & Chips menu are contributed by Menuism users directly, as part of a restaurant review, or as part of an image upload.


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Read more: Click here to read a longer version of this story
A WOMAN with two missing fingers has grown them back - albeit as part of a phantom limb.
The woman was born missing two fingers on her right hand. Aged 18, she had the hand amputated after a car accident. She later began to feel that her missing limb was still present, and that the phantom hand had short versions of the missing fingers.
Paul McGeoch and colleagues at the University of California, San Diego, slowly trained her to feel that all five phantom digits were full size (Neurocase, DOI: 10.1080/13554794.2011.556128).
"The deformed hand was suppressing the brain's innate representation of her fingers," he says. The innate representation kicked in again after the accident.
- New Scientist
- Not just a website!
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Rescue helicopters and ships completed more than two days of fruitless search for the Malaysia Airlines jet that disappeared over the sea with 239 people on board en route Beijing from here on Saturday.
On Monday, search teams rushed to investigate a yellow object that looked like a life raft floating in the ocean, but it turned out to be moss-covered trash. With no confirmation that the Boeing 777 crashed, hundreds of distraught relatives waited anxiously for news. Thai police and Interpol questioned the proprietors of a travel agency in the resort town of Pattaya that sold one-way tickets to two men who boarded flight MH370 using stolen passports.
Malaysia's police chief was quoted by local media as saying that one of the men had been identified. Civil aviation chief Azharuddin Abdul Rahman declined to confirm this, but said they were of "non-Asian" appearance, adding that the authorities were looking at the possibility the men were connected to a stolen passport syndicate.
Experts say possible causes of the apparent crash include an explosion, catastrophic engine failure, terrorist attack, extreme turbulence, pilot error or even suicide.
On Sunday afternoon, a Vietnamese plane spotted a rectangular object that was thought to be one of the missing plane's doors, but ships working through the night could not locate it. Malaysian maritime officials found oil slick in the South China Sea and sent a sample to a lab to see if it came from the plane. Tests showed the oil was not from an aircraft, Mr. Rahman said.
Keywords: Malaysia Airlines, Interpol, MH 370, missing Malaysian jet, Vietnam search and rescue team


text:
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Recommended Just For You
Customer Raves & Reviews
Great Magnet
Awesome product, only wished that our company logo could have been bigger. There was only a certain amount of space alloted for it.
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we use Magnet Street every year, very professional, calenders show up on time and never have had a problem in the last 10 years
Quick processing and delivery of a great advertising magnet clients will use.
Magnet will be use to advertise my business and football schedules. Fast processing and delivery.


text:
Man dies in hospital from recent shooting
A 24-year-old man died Thursday afternoon at a local hospital from injuries related to a shooting May 13, Police Cmdr. Mike Walsh said.
Nueces County Medical Examiner Dr. Ray Fernandez said Reynaldo Ybarra Jr. died as a result of multiple gunshot wounds.
Ybarra, the driver of a Pontiac Grand Am, was shot once in the arm and twice in the chest by a man driving a Ford Expedition while stopped at a traffic light about 9 p.m. in the 4200 block of Violet Road, police said.
Ybarra's passenger, 29-year-old Juan Hernandez, was shot once in the upper leg. The driver of the Expedition then headed west on Leopard Street while the injured men turned into a nearby store parking lot, from where they were both taken to Christus Spohn Hospital Memorial, police said.
No arrests have been made but Walsh said Hernandez identified 24-year-old Gabriel Barboza as the shooter.
Hernandez's condition was unavailable late Friday.
A warrant issued for Barboza's arrest Monday in connection with the shooting remained in effect late Friday.
Walsh said a judge issued a bond of $100,000 for Barboza on two counts of aggravated assault but that police asked the district attorney's office Friday to elevate one of the charges to murder.
Contact Mary Ann Cavazos
at 886-3623
or cavazosm@ caller.com
Subscribe to the Caller-Times
Need Help? Call us at 1-800-566-8098.
Monday-Friday: 5am-8pm / Saturday: 7am-12pm / Sunday: 6am-1pm


text:
Elizabeth Brooks
Her birth date is confirmed by her gravestone.
John Hindley Company (1855)Age at departure: 54
- Andrus, Milo, Autobiography, in Library of Congress, Collection of Mormon Diaries [1935-1938], reel 8, item 26, 1:7.
- Source Location
- Church History Library, Salt Lake City, Utah
Find A Grave
- Source Location
- Internet Web Site
Ship Passenger and Manifest Lists/Mormon Migration
- Trail Excerpt
- Source Location
- Family History Library, Salt Lake City, Utah


text:
Arsenal Traveling Roster
Wed, 23-07-2014 16:06 — ssandalow
Wenger names 20-man squad ahead of Saturday's match
Short Title:
Arsenal Roster Announced
Primary Image:
Is Video:
No overlay
New York Red Bulls | 600 Cape May St. | Harrison, NJ 07029 | 877.RB.SOCCER © 2014 MLS. All Major League Soccer trademarks and copyrights used by permission. All rights reserved. Made by MLS Digital


text:
Buy Ben's Diary
So you love Ben Stein's stuff online. Who doesn't? Now you can have the beloved Ben Stein's Diary, his monthly column from the print magazine, delivered to your e-mail inbox for the very affordable $1.95 per month. You probably spent more on a cup of coffee this morning, but Ben will put an even greater hop in your step. Subscribe now.


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In my mind, it's no coincidence that the tradition of giving flowers at Valentine's Day coincides with the dreary winter weather that pummels much of the country in February. While battling the cold and snow, flowers are a colorful and necessary reminder that if we can just make it through the snowstorms and chilly temperatures, the warmth of spring will be our reward.
And while this floral shot in the arm can be had at many florists from state to state, I have yet to find a florist shop as jaw-droppingly dramatic in its midcentury glamour than Stein Your Florist in the Mayfair neighborhood of Philadelphia.... Read More →
The National Trust for Historic Preservation works to save America's historic places. Join us today to help protect the places that matter to you.
Beth Lennon
Beth Lennon is the creator of the website RetroRoadmap.com. As "Mod Betty," she delights as the retro travel "hostess with the mostess," scouting out cool vintage places and sharing them with the world.


text: Little Known Fact #174 4 Arch Duke Maxyenko, ಠ_ಠProfileFollowUnfollow Arch Duke Maxyenko, ಠ_ಠFiled to: little known facts 5/07/14 4:17pmEditDelete InviteInvite manuallyPromoteXDismissXUndismissBlock for oppositelockHideShare to KinjaShare to FacebookShare to PinterestShare to TwitterGo to permalink Vladimir Putin always keeps his good luck charm in his back pocket. It's a golden Ritz cracker. 4 7Reply 7Discuss


text:
When we were in our early teens, 'stickers' were much in vogue and my elder brother was an avid collector. Our home was filled with stickers and that was our pride. Once, our uncle had brought his friend home and that friend conversed to us about his collection of stickers. He promised to send us a bunch through post after he got back to Chennai and took down our postal address. We were excited. Those days, snail mail was delivered twice a day. At home for our summer break, each day we waited eagerly for the postman and the stickers. With each passing day, our disappointment increased; enthusiasm waned and turned to gloom. After a week, our mother noticed we were sulking. Getting to know the background, she smiled the issue away. We were made to realize that the guest may have just mentioned it in the passing and may not have meant it seriously. Having already boasted about the expected addition to our collection amongst friends, we felt 'let down'. Hence, to us it was plain and simple 'deceit'. Personally, it was the first instance when it dawned that people may not mean what they say.
That insight was part of 'growing up' to understand 'face value' needn't be 'meant value'. Having been in an atmosphere where the elders at home were clear either way in handling our requests, it took time to comprehend that not all promises are made seriously. Real world has instances aplenty where words are not kept, sowing the seeds of distrust and suspicion. This invariably takes its toll on the quality of relationships. Trust is not a 'given' and the earnestness of intent is gauged by sincerity in execution. Such action leads to the unswerving belief that assurances are indeed authentic. Trust then springs forth as a bona fide outcome.
Faith in a superpower, whichever way a person conceives it, could be certitude without proof. On the other hand, 'trust' is certitude that needs affirmation on an ongoing basis. Trust is built in trickles over time. Consistency displayed in thoughts, words and action fortifies trust. Be it amongst family members at home, peers in social groups or across levels in organizations, trust cannot be taken for granted. It needs to be actively and consciously cultivated and nurtured.
Assurances may be given on the spur of the moment to take care of the situation on hand, to postpone a problem, merely to project an image, to clinch a deal, to extract a favour or to reconcile differences. These may fool some people for some time but integrity would be called to question sooner than later. It is no surprise that a politician's promise has become a joke today. Reactions to a broken promise may range from simple disappointment to a strong sense of betrayal. This could well spell the end of a relationship as it is trust that decides and defines bonds.
It is trustworthiness of character that bestows credibility to leadership. An effective leader clarifies expectations at the outset, clears mismatches, promises pragmatically and delivers reliably. He would be transparent and ensure that justice is not only done but it is also seen to be done. He would apprise people who are affected by a decision on how it has been made, the thought process and the constraints associated with the situation. This would display legitimacy of the decision and make parties involved own it up together. A leader would then be able to empower his team in an atmosphere of trust with an air of confidence.
Unfortunately, a few persons have a yawning gap between the 'aspirational self' from which they talk and the 'real self' from which they act. Their impression management strategies not backed by real character lack authenticity. Their political games and power play involve flattery, back biting and twisted tales. It is a matter of time before they fall a victim to the demon of distrust they've created themselves.
The magic ingredient that can make us move from conscious to unconscious competence on trust building is 'genuineness'. Poetic talk of 'woods that are lovely, dark and deep and promises to keep' may suffice for initial inspiration. However, this needs to be followed up consistently and transparently with sincere action. This would attest our genuineness irrespective of consequences, chiselling a trustworthy smile that flows, connects and bonds…
(The writer may be contacted at email@example.com)
Keywords: Stickers collection, trust, bonding, leadership, genuineness


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8 oz. Seafood Stuffing for
whole Lobsters or Lobster Tails
I just want to thank you for the lobster and clam shipment. I'll certainly recommend you to anyone out here who understands that lobsters only grow in Maine.
One 8 oz. package of our delicious Seafood Stuffing will generously stuff up to four medium Lobsters or four 6-8 ounce Lobster Tails.
This moist Stuffing is ready to serve and is packed with Maine Scallops and Shrimp, butter and bread crumbs!


text:
Case of P.E.I. man accused of terrorism link returns to court in...
Details on the Huntsville portion of the upcoming Pan Am Games torch relay...
Amber Rose's new boyfriend Machine Gun Kelly struggles to cope "every day"...
Monday, euchre: first lone hand, Mike Burgess; second lone hand, Rene...
Cold temps cause more premature deaths than heat, international study shows
The North Muskoka Lightning Minor Hockey Association held a very successful fundraiser in the form of a fishing derby on Monday, Feb. 20.
This was on Misquito Lake behind the MacTier Legion. Many hockey parents and children were trying for the big one. The MacTier Legion was rented out for the day at the event.
Also the North Muskoka Lightning Minor Hockey Association will be holding its annual general meeting at the MacTier arena hall on Monday, March 5, starting at 7 p.m. Parents take note.
The MacTier-Foot's Bay United Church held a pancake supper on February 21. This was at the MacTier Church hall from 5 to 7 p.m. and it was good attendance and delicious.
This past holiday family weekend had great sunny weather, good for ice fishing, snowshoeing, cross-country skiing or any other outdoor activity.
This is probably the last good weekend of the winter as we are only one month until spring.
The Diabetes Education Centre of Parry Sound area will be hosting a Label Reading Class to help you make informed food choices for healthy living with diabetes.
Heather Fisher, registered dietician and certified diabetes educator is the host. This is on Wednesday, Feb. 29, at the MacTier Medical Centre from 10:30 a.m. to 12 noon.
Call Dian Norrie at 705-375-5200 if you wish to attend.
Coming up on Saturday, Feb. 25, from 10 a.m. to noon is a public meeting at the Community Policing Office.
This is held to discuss ideas for recreation in Georgian Bay Township, specifically those in the MacTier area. Plan to attend.
MacTier Food Bank dates for March are as follows: Thursday, March 8, 7 p.m. to 8 p.m.; Monday, March 12, 10 a.m. to 11 a.m.; and Thursday, March 22, from 7 p.m. to 8 p.m. The food bank is located at the back of MacTier Legion.
Don't forget this Friday, Feb. 24, the MacTier Figure Skating Club is holding a wine and cheese evening at the MacTier arena hall from 5 to 10 p.m.
Included in that are booths displaying Tupperware, Avon, the Pampered Chef, Passion Party, Jockey Clothing and more. Come and check this out.
This just in from the Township of Georgian Bay council chambers, the council passed an anti-idling by-law, generally vehicles are not to be left idling for more that three minutes or face fines of up to $75.
Also, the septic inspection program for Stewart Lake will commence this summer, including 102 properties on Stewart Lake, excluding those properties in Township of Muskoka Lakes.
Northern Georgian Bay Community Policing meets the second Thursday of the month at 7:30 p.m. at the community policing office in MacTier. They are canvassing for new members.
Congratulations to our MacTier school elementary curling team as they were entered in an elementary bonspiel at Parry Sound Curling Club the past week. They won two games and lost one game. They are entered in All Ontario Elementary Championship playdowns at Parry Sound in April. Best to all.
MacTier Curling Club Night League
February 15
Team Points
Patenaude ... 196
Watkinson ...167.5
Kelly ...154
Macgregor ... 132.5
MacTier Curling Club Stick Curling
February 16
Player Score
Bill ...101
Heidi ... 99.5
Ed ... 98
Earl ... 88
Murray... 80.5
Joan ...79.5
Jamie ...74
Carol ...63
Dave ...60
Dwight 59.5
Gail 58
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