Natural Ways to Treat Multiple Sclerosis

Proven MS Treatment By Dr Gary

Complete Method for Treating and Curing Multiple Sclerosis in an EASY TO Understand E-Book. You will never need to buy anything else from me to make this method work. You can download it and be reading within seconds. There is no medical speak in my e-book. I keep it simple and easy-to-grasp just like I'm talking with one of my patients. You will learn how to pull your body's chemical processes in line with a simple vitamin regimen and a nutrition method I found that works better than all the multiple sclerosis medicines combined. It's available everywhere. No more worrying about taking pills and/or injections on a daily basis or using other costly chemicals to take your MS away. More here...

Proven MS Treatment By Dr Gary Summary

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What is multiple sclerosis

In the classic sense, multiple sclerosis (MS) is a disease of the central nervous system (the brain and spinal cord) that most commonly affects young adults. Sclerosis means hardening MS means that there are multiple areas of hardened tissue in the brain and spinal cord. The word disease means a loss of a feeling of ease (i.e., dis-ease), or otherwise stated, a loss of a sense of well-being. This is a meaningful definition for MS patients faced with a bewildering variety of other specific symptoms. Often, patients afflicted with MS have difficulty describing just how they feel. Although the MS patient appreciates and understands this concept, many healthy persons, including physicians, unfortunately, often do not.

Multiple Sclerosis Like Syndrome

Clinical syndromes mimicking multiple sclerosis (MS), mainly in its relapsing-remitting pattern, are reported to occur in association with aPL. Laboratory findings and MRI studies are not often useful tools to distinguish APS from MS. With regard to the MRI, large size lesions and their atypical

Multiple Sclerosis Genetics

2 Major Histocompatibility Complex and Multiple Abstract Multiple sclerosis (MS) clusters with the so-called complex genetic diseases, a group of common disorders characterized by modest disease risk herit-ability and multifaceted gene-environment interactions. The major histocompatibility complex (MHC) is the only genomic region consistently associated with MS, and susceptible MHC haplotypes have been identified. Although the MHC does not account for all genetic contribution to MS, the other genetic contributors have been elusive. Microarray gene-expression studies, which also have not identified a major MS locus, have, however, been promising in elucidating some of the possible pathways involved in the disease. Yet, microarray studies thus far have been unable to separate the genetic causes of MS from the expression consequences of MS. The use of new methodologies and technologies to refine the phenotype, such as brain spectroscopy, PET and functional magnetic resonance imaging...

Major Histocompatibility Complex and Multiple Sclerosis

The only genomic region consistently shown to have a large effect on multiple sclerosis susceptibility across studies is the major histocompatibility complex (MHC human leukocyte antigen HLA in humans), which spans about 3.5 Mb on chromosome 6p21.3. The HLA contains a large array of highly polymorphic genes involved in immune response and self-recognition 78 . The major classes of the HLA genes are the class I and class II genes, located telomerically and centromeri-cally, respectively (Fig. 1). In an immune response, the cell surface HLA proteins present fragmented antigen proteins to T cells. The highly polymorphic regions of the class I and class II HLA genes correspond to the peptide-binding grove of the protein, which indicates that the polymorphisms likely developed to battle varying pathogenic challenges throughout evolution. Because of its role in antigen recognition, including self-antigens, the HLA system has been extensively studied in autoimmunity.

T2 Images of Multiple Sclerosis

While there is a single intensity value for each pixel in an image including the T2 time images just described, the intensity actually represents the weighted sum of many protons located within the pixel. For clinical brain imaging, water protons are the dominant source of signal. However, the signal from water is not uniform, and the local environment of each water proton affects the signal produced. Since the size of a pixel is much larger than a single molecule of water, its signal is a combination of all the water molecules within that pixel. Some have looked at these components of T2 signal in the context of multiple sclerosis 27 . Some components (like bulk water) have a relatively long T2 time (seconds). In other regions, the T2 time is much shorter (milliseconds). In regions where myelin wraps around an axon, it results in thin layers of water. In this case, water exchanges protons with non-water molecules, and the T2 time of these protons differs greatly from that of bulk...

Immunological Aspects of Axon Injury in Multiple Sclerosis

Abstract The role of immune-mediated axonal injury in the induction of nonre-mitting functional deficits associated with multiple sclerosis is an area of active research that promises to substantially alter our understanding of the pathogenesis of this disease and modify or change our therapeutic focus. This review summarizes the current state of research regarding changes in axonal function during demyelination, provides evidence of axonal dysmorphia and degeneration associated with demyelination, and identifies the cellular and molecular effectors of immune-mediated axonal injury. Finally, a unifying hypothesis that links neuronal stress associated with demyelination-induced axonal dysfunction to immune recognition and immunopathology is provided in an effort to shape future experimentation. M. Rodriguez (ed.), Advances in Multiple Sclerosis and Experimental Demyelinating Diseases. Current Topics in Microbiology and Immunology 318. Springer-Verlag Berlin Heidelberg 2008

Natalizumab Multiple Sclerosis [6874

The a4 family of integrins expressed on the surface of leukocytes are involved in cell adhesion processes. The a4 integrin can pair with either of two p subunits to generate a heterodimeric cell surface receptor known as a4pl (VLA4) or a4p7. Ligands for VLA4 include vascular cell adhesion molecule-l (VCAM-l), which is expressed on activated vascular endothelium, while a4p7 interacts predominantly with mucosal addressin cell adhesion molecule-l (MadCAM-l) existing on vascular endothelial cells of the gastrointestinal tract. By virtue of this a4-mediated interaction between leukocytes and vascular endothelial cells that leads to trans-end-othelial infiltration of various leukocytes (lymphocytes, monocytes, T-cells, etc.) at the site of inflammation, interference with the adhesion of the a4 integrin has been deemed a viable approach for disrupting the inflammatory cascade. As an antibody that binds to the a4 integrin subunit, natalizumab has been developed and launched for the treatment...

Leptin in multiple sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated, inflammatory disorder of the central nervous system (CNS) myelin. The most studied model of multiple sclerosis in animals is the EAE that can be induced in susceptible strains of mice by immunization with self-antigens derived from myelin. The disease is characterized by autoreactive T-cells that traffic to the brain and the spinal cord and injury myelin, with the result of chronic or relapsing-remitting paralysis, depending on the antigen and the strain of mice used. It is known that myelin-reactive Th1 CD4+ cells induce and or transfer disease and that Th1 cytokines are present in inflammatory EAE lesions in the central nervous system. In contrast, Th2 cytokines are associated with recovery from EAE or protection from the disease.

Multiple sclerosis

The suggestion from this study is that atorvastatin has pleiotropic effects on the immune process to modify the auto-immune response to antigen in the development of EAE by intervening at many different steps of the process. In a similar study, lovastatin was found to reduce the severity and duration of EAE by acting on both T cells and on antigen presenting cells (APC) 96 . In an additional study, statins were shown to inhibit proliferation of PBMCs derived from patients with multiple sclerosis and to down-regulate MMP-9, chemokine receptors and adhesion molecules 97 . Curiously, in two separate studies in mice, statins promoted differentiation of Th0 lymphocytes towards a Th2 phenotype 95,98 . Plasma concentrations of statins were not measured in these studies. However, the findings were striking enough to stimulate a number of formal clinical trials for statin treatment in multiple sclerosis 99,100 . In one very recent report, simvastatin (80 mg) was given to 30 patients with...

Pathological Heterogeneity of Idiopathic Central Nervous System Inflammatory Demyelinating Disorders

2 Heterogeneity of Multiple Sclerosis White Matter 2.4 Evidence for Immunopathogenic Heterogeneity in Multiple Sclerosis 27 M. Rodriguez (ed.), Advances in Multiple Sclerosis and Experimental Demyelinating Diseases. Current Topics in Microbiology and Immunology 318. Springer-Verlag Berlin Heidelberg 2008

The Clinicopathologic Spectrum of CNS Idiopathic Inflammatory Demyelinating Disorders

Balo's concentric sclerosis) as well as the recurrent demyelinating disorders with a restricted topographical distribution (e.g., NMO). Although the clinical and pathological characteristics of these disorders are diverse, the presence in some cases of transitional forms suggests a spectrum of inflammatory demyelinating disorders that share a pathogenic relationship. A.B. Baker acknowledged this broad spectrum and stated, In all probability, what is generally known as multiple sclerosis is not a single disease but a group of diseases with certain clinical similarities. From the standpoint of clinical research, the present state of affairs is not satisfactory. In order to conduct clinical research in MS, it is imperative that very rigid criteria for diagnosing this disease be developed 6 . Advances based on recent systematic clinicopathologic-serologic correlative approaches have led to novel insights with respect to the classification of these disorders as well as a better...

Look into for additional help

The National Multiple Sclerosis Society (NMSS) chapters and other groups have played an important part in education of patients and their families about MS. The MS Society chapters have regularly supported educational lectures for MS patients and their families. These sessions sometimes double as group therapy. When supervised by a professional, they are of real value to participants. Certainly, meeting other patients and exchanging experiences can help put the disease in perspective. It is important to recognize that the clinical course of illness varies greatly from one person to another. Young people may be intimidated when they meet severely affected individuals, regardless of the age or duration of illness. Therefore, potential participants in these sessions may wish to get more information about who will be present at a particular group session they are considering attending and whether it will be led by a knowledgeable professional.

Imaging of Remyelination and Neuronal Health

2.2 T2 Images of Multiple Abstract Remyelination of axons that have been demyelinated due to multiple sclerosis (MS) may be a critical step in restoring the damaged axons and reversing the disease process. While it is possible to establish the presence of remyelination with microscopy of tissue samples, it is important to have noninvasive or minimally invasive methods to measure remyelination in living M. Rodriguez (ed.), Advances in Multiple Sclerosis and Experimental Demyelinating Diseases. Current Topics in Microbiology and Immunology 318. Springer-Verlag Berlin Heidelberg 2008

Can pregnancy in a woman with MS harm the unborn child

There is speculation that fertility is reduced in patients with MS and that the rate of spontaneous abortion is increased in the first trimester of pregnancy. There is no evidence or expectation that MS directly affects the unborn child. However, from the information collected in the North American Research Committee on Multiple Sclerosis (NARCOMS) database, the interferonbeta treatments for MS (Betaseron, Avonex, and Rebif) do pose an increased risk of birth defects in the unborn child.

Isoelectric Focusing of the CSF

Polyspecific Response Associated with CNS Autoimmune Diseases. The oligoclonal, intrathecally synthesized IgG contains numerous specific antibodies and autoantibodies. Antibodies are frequently found with specificities against measles, the rubella virus and the varicella-zoster virus, but seldom against the herpes simplex virus. The occurrence of one, two, or three of these antibodies is referred to as the MRZ reaction. The corresponding antigens are not present in these cases. The MRZ reaction is typical of multiple sclerosis as well as cerebral lupus erythematosus and is a chronically evolving immune process (F5, K10, S16). An increased IgG index is found in more than 80 of patients with multiple sclerosis. However, there seems to be no relationship in multiple sclerosis between the severity or the activity of the disease and the intrathecal production of IgG (F5, L1, S8, V1). The intrathecal IgA synthesis is found in only 12 of patients with multiple sclerosis (L1). An...

CD4 T cells play multiple roles in adaptive immunity

Th1 cells combat infection by intracellular pathogens by producing IFN-y and IL-2 to stimulate and sustain an effective cellular immune response. Th2 cells, on the other hand, produce the cytokines IL-4, IL-5, and IL-13 that promote clearance of infection by multicellular helminths. In mice, IL-4 and IL-5 secretion induces antibody (Ab) class switching in activated B cells from IgM and IgD to IgG1 and IgE and augments IgA production, respectively. IgG1 and IgA are functionally important for neutralization and targeting of extracellular pathogens for phagocytosis and killing by macrophages and neutrophils. IgE targets helminths for attack by eosinophils and triggers the activation of mast cells, thereby inducing mucus secretion, smooth muscle contraction, and vasodilatation to facilitate expulsion of helminths, while also playing a predominant role in asthma and allergy (Bischoff, 2007 Grimbaldeston et al, 2006). CD4 Th17 cells are thought to protect against...

Stress and the Naked Axon A Hypothesis

Simply stated, our current working hypothesis is that the stress of demyelination, manifested as retrograde transport defects, intra-axonal protein aggregation, retrograde trophic support withdrawal, mitochondrial dysfunction, and electrical dysregulation and silencing, results in the induction of aberrant neuronal and axonal expression of MHC class Ia and Ib molecules that serve as molecular recognition cues for the engagement of CTL- and NK cell-dependent attack, injury, transection, and killing of neurons and axons (Fig. 1). While much work remains to prove this model, our unifying hypothesis may help filter the currently available data and may provide a rationale for the construction of future experiments. Of note, it may also provide a basis for the rational design of new therapeutics aimed at thwarting the immune recognition of MHC molecules on demyelinated axons. Ultimately, any therapy that preserves axons will preserve neurologic function in demyelinated patients and will...

New Insights into Adaptive Immunity in Chronic Neuroinflammation

Introduction Multiple Sclerosis Is a Heterogeneous (CNS) is crucial for the development of new therapeutic concepts in chronic neuroinflammation, which differs considerably from other autoimmune diseases. Special immunologic properties of inflammatory processes in the CNS, which is often referred to as an immune privileged site, imply distinct features of CNS autoimmune disease in terms of disease initiation, perpetuation, and therapeutic accessibility. Furthermore, the CNS is a stress-sensitive organ with a low capacity for self-renewal and is highly prone to bystander damage caused by CNS inflammation. This leads to neuronal degeneration that contributes considerably to the phenotype of the disease. In this chapter, we discuss recent findings emphasizing the predominant role of the adaptive immune system in the pathogenesis of chronic neuroinflammation, that is, multiple sclerosis (MS) in patients and experimental autoimmune encephalomyelitis (EAE) in rodents. In...

Heterogeneous Inflammatory Disease Of The Nervous System

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS) in the western world, and leads to devastating disability in young adults with only limited treatment options available so far. Early in the disease course, most patients suffer from a relapsing-remitting course characterized by reversible neurological dysfunctions, such as impaired vision, paralysis, ataxia, and sensory deficits, and bladder, bowel, and sexual dysfunction. However, this phase of the disease is highly variable between different patients with regard to extent, duration, and clustering of the attacks. After ten years, about half of those patients will have entered a period of silent deterioration, less prominent attacks than in the first years after manifestation, and increasing cumulative disability. This gradual deterioration affects about 90 of MS patients after 20-25 years and typically comprises a decrease in lower extremity function and decline in...

What is a macrophage

Another drawing by Charcot showing loss of normal myelin around a small blood vessel. This blood vessel is a venule with five or six long, beanlike nuclei oriented more or less vertically in the middle of the drawing. Also seen are spaghetti-like axons without myelin, which appear smaller than the other axons with their myelin intact. This observation led to multiple sclerosis being termed a demyelinating disease. Figure 5. Another drawing by Charcot showing loss of normal myelin around a small blood vessel. This blood vessel is a venule with five or six long, beanlike nuclei oriented more or less vertically in the middle of the drawing. Also seen are spaghetti-like axons without myelin, which appear smaller than the other axons with their myelin intact. This observation led to multiple sclerosis being termed a demyelinating disease.

Organizations

The National Multiple Sclerosis Society (NMSS) Multiple Sclerosis International Federation Multiple Sclerosis Association of America (MSAA) Multiple Sclerosis Foundation Established in 1986, the MSF is a national, service-based, nonprofit organization. Their mission is to ensure quality of life through support, educational programs, research into the cause and cure, and investigation of medical and complementary treatment options. They offer a resource-rich web site, www.msfocus.org a peer counselor and caseworker staffed tollfree helpline, and a multimedia library in English and Spanish. Address Multiple Sclerosis Foundation 6350 North Andrews Avenue Fort Lauderdale, Florida 33309-2130 USA Toll-free Phone 888-MSFOCUS (673-6287) The Multiple Sclerosis Diet Book (Doubleday Publishers) By Multiple sclerosis A neurologic disease that is characterized by focal demyelination in the central nervous system, lymphocytic infiltration in the brain, with a variably progressive course. Pyramidal...

Parkinsonism With Atypical Postures

Tremor recording machine used by Charcot to separate cases of typical rest tremor from those with postural tremor and action-induced tremor. Early studies focused on the differentiation by tremor type of multiple sclerosis and Parkinson's disease, but this apparatus was later used to study the various formes frustes of Parkinson's disease as well. In the insert, tremor recordings are shown for resting posture (AB) and action (BC) in patients with different tremor patterns. From Dictionnaire Encyclop dique des Sciences M dicales, 1883. Fig. 1. Tremor recording machine used by Charcot to separate cases of typical rest tremor from those with postural tremor and action-induced tremor. Early studies focused on the differentiation by tremor type of multiple sclerosis and Parkinson's disease, but this apparatus was later used to study the various formes frustes of Parkinson's disease as well. In the insert, tremor recordings are shown for resting posture (AB) and action (BC) in...

Prevalence of PSP and MSA

Despite the various different diagnostic criteria, the rates for PSP and MSA across all studies are not too dissimilar. One obvious observation is that studies with very large populations, e.g., New Jersey (6) or United Kingdom (15), produce lower prevalence estimates whereas very small populations produce high rates. The effect of varying population size and hence intensity of case finding is most elegantly demonstrated by the Russian Doll Method method employed by Nath and colleagues (15). This general pattern is also well noted with prevalence studies for multiple sclerosis

Caprine respiratory syncytial virus

Carp virus A transmissible virus obtained from cases of human multiple sclerosis. Depresses the number of circulating poly-morphonuclear neutrophils within 16-48 h of inoculation into adult mice. The effect lasts at least 11 months during which time the mice remain normal. The virus passed through membranes of 50nm average pore diameter but not of 25nm. Replicates in PAM cells, a line of mouse fibroblasts. The effect in mice was neutralized by serum from patients with multiple sclerosis. However, the mouse test has proved difficult to reproduce and is unreliable. It is possible that these results are an artifact and the virus does not exist.

Bcells in autoimmuneinflammatory disease

Autoimmune and inflammatory diseases remain an area of significant unmet medical need. B-cells are critical regulators of immune responses and are implicated in the pathogenesis of conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and immune thrombocytic purpura (ITP) 1-4 . Principal among

Clinical Box 21 Graft Versus Host Disease

A main reason for the shortage of transplant organs is the fact that the tissues of the donor and the recipient need to match for successful transplantation. Tissues are matched when they have a similar pattern of cell surface proteins. Cell surface proteins are in fact glycoproteins due to the carbohydrates (sugars) attached to their surface. The carbohydrate acts as a flag designating the cell as belonging to the individual. The cellular gly-coprotein pattern may specify an individual within a species or specify a species. If a particular sugar is missing from the surface of a cell, the immune system may recognize this cell as foreign and try to kill it. An attack on self tissue may lead to autoimmune diseases, where the autoimmune reaction can be directed against a specific tissue such as the brain in multiple sclerosis or the digestive tube in Crohn disease. In other cases, the overly active immune system may attack many cells and tissues so that various organs are affected such...

Key advances in preclinical validation

Studies of pre-clinical models of other autoimmune diseases have also been reported recently. In a model of systemic lupus erythematosus, CCR2_ _ mice exhibited prolonged survival and reduced renal disease relative to their WT counterparts 20 . Importantly, reduced macrophage and T-cell accumulation in the renal lesion sites was noted. Overall, these data are consistent with other recent studies on genetic deletion of MCP-1 21 or administration of a peptide antagonist of CCR2 22 in models of lupus. The recent data with experimental autoimmune encephalomyelitis (EAE, a rodent model of human multiple sclerosis) are more complex, in that different outcomes were observed depending on the system studied. Administration of a small molecule antagonist blunted EAE disease progression in C57BL 6 mice 15 . Likewise, genetic deletion of CCR2 in the C57BL 6 background also reduced EAE disease score, particularly in the early stages of disease 23 . However, CCR2_ _ mice on a Balb C background...

Experimental autoimmune encephalomyelitis

In this preclinical animal model for multiple sclerosis (MS), two key sets of data lend support for a potential role for CB2 agonists in treatment. First, experimental autoimmune encephalomyelitis (EAE) is exacerbated in CB2 knockout mice upon disease induction compared to wild-type littermates 19,20 . Second, therapeutic treatment of mice at the peak of disease with the CB2 agonist HU-308 (7, K, human CB2 22.7+3.9 nM human CB K,- 10 p.M K,- for rodent CB2 not reported) 21 show a significant reduction in disease score compared to the vehicle-treated

Neurodegenerative Disease

MMP inhibitors have also been considered a treatment for neurodegenerative or neuroinflammatory diseases. Interest has focused on multiple sclerosis (NS) in which the active phase of the disease is characterized by degradation of the blood-brain barrier, demyelination, and axonal loss. Studies have shown elevated levels of MMPs in the cerebrospinal fluid of MS patients, in particular gelatinase B (36), and MMPs have been shown to degrade myelin basic protein, releasing encephalogenic fragments (37,113).

Therapeutic significance

1.1.2 Clinical data of FTY720 in multiple sclerosis and transplantation randomized, Phase III study in 668 de novo renal transplant patients, FTY720 given at a daily dose of 2.5 mg or 5mg per patient was directly compared to mycophenolate mofetil for the potential to synergize with cyclosporine A to prevent rejection of the renal allografts. FTY720 (2.5 mg) was equipotent to my-cophenolate mofetil in providing rejection prophylaxis, however, a two fold higher dose of FTY720 (5 mg) did not support a 50 reduction in cyclosporine A exposure, indicating insufficient immunosuppressive activity of FTY720 58,59 . A proof-of-concept Phase II clinical trial was conducted in 281 patients with relapsing-remitting multiple sclerosis. The median total number of gadolinium-enhanced lesions on MRI was lower with FTY720 1.25 mg (1 lesion p 0.001) and FTY720 5mg (3 lesions p 0.006) than with placebo (5 lesions). The annualized relapse rate was 0.77 with placebo, 0.35 with FTY720 1.25 mg (p 0.009) and...

Further Clinical Opportunities For Hdac Inhibitors

In addition to their application in cancer, HDAC inhibitors also show promise in neurological and immunological disorders 64 . HDAC inhibitors alone or in combination with other drugs were claimed to be useful for the treatment of multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer's disease 65 . HDAC inhibitors were found to be beneficial in treating neurodegenerative diseases caused by polyglutamine toxicity, such as Huntington's disease 66,67 . Recently, this was confirmed in a mouse model of Huntington's disease in which the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was found to improve motor deficits 68 .

The Neurovascular Unit

In July 2001, the National Institutes of Neurological Disorders and Stroke convened the Stroke Program Review Group (SPRG) 87 to advise on directions for basic and clinical stroke research for the following decade. Although much progress had been made in dissecting the molecular pathways of ischemic cell death, focusing therapy to a single intracellular pathway or cell type had not yielded clinically effective stroke treatment. Integrative approaches were felt to be mandatory for successful stroke therapy. This meeting emphasized the relevance of dynamic interactions between endothelial cells, vascular smooth muscle, astro- and microglia, neurons, and associated tissue matrix proteins, and gave rise to the concept of the neurovascular unit. This modular concept emphasized the dynamics of vascular, cellular, and matrix signaling in maintaining the integrity of brain tissue within both the gray and white matter, and its importance to the pathophysiology of conditions such as stroke,...

Key Points Degenerative Neurologic Diseases y

Spinal anesthesia should be avoided in patients with multiple sclerosis. 7. With the exception of spinal anesthesia in multiple sclerosis, neither general nor regional anesthesia exacerbates the course of disease in the neuropathies described. 2. Koff MD, Cohen JA, McIntyre JJ, et al. Severe brachial plexopathy after a ultrasound-guided single-injection nerve block for total shoulder arthroplasty in a patient with multiple sclerosis. Anesthesiology 108 325-328, 2008. 3. Perlas A, Chan VW Neuraxial anesthesia and multiple sclerosis. Can J Anaesth 52 454-458, 2005.

Results of Sacral Neuromodulation

The first publications showed an improvement in bladder hyperactivity among spinal cord lesion patients 63, 154 . Bosch and Groen 20 showed that treatment of refractory urge incontinence by chronic S3 nerve stimulation was feasible in selected multiple sclerosis patients. The fact that no irreversible changes to the bladder or nerves occur is an advantage of this treatment option over destructive alternatives. However, the unpredictable evolution of the disease and particularly cognitive alterations are con-treindicated in case of rapid evolution. In a case series, Chartier-Kastler et al. 41 reported 9 women with spinal diseases (including vascular myelitis, multiple sclerosis and traumatic spinal cord injury) undergoing neuromodulation. All patients reported an improvement of 75 in their visual analog scale at last follow-up (mean follow-up 43 months). In another case series, Hohenfellner et al. 83 evaluated patients with neurogenic bladder (complete or incomplete spinal cord...

Cytokine Measurements in Disease

And immunoreactive IL-1 are detectable in rheumatoid arthritis, osteoarthritis, and other arthritides, and inhibitory activity in biological assays is present in many cases (F22, H30, N13, S43, W30). In a study of synovial fluid from various arthritides, 49 of 111 fluids contained immunoreactive IL-1 of these 74 were from RA and 15 from seronegative arthritides, whereas 11 were from patients with noninflammatory arthritis (W19). Syntheses of IL-ip mRNA (B66) and the IL-1 (3 molecule have been demonstrated in synovia (D29). Raised ventricular fluid IL-1 levels have been found in head injury (M18). IL-1 has been detected in the CSF of patients with multiple sclerosis (H9). TNF was also found to be present in some cases, but IL-6 was found very rarely. It is interesting that no correlation between plasma IL-1 levels and acute phase proteins has been found and there is, as yet, little evidence to suggest that IL-1 measurements will find a place in clinical practice. In patients with...

Are There Apcs In The Retina

Stream into the neural parenchymal tissue (79) it was believed for many years that these barriers naturally extend to blood-borne cells. However, inflammatory processes do occur in the brain and retina and there is evidence that the normal central nervous system (CNS) is subject to regular patrol by lymphocytes, most likely of the activated or blast form since resting T cells do not normally enter the CNS parenchyma (80). This is supported by evidence that in autoimmune conditions, such as multiple sclerosis or uveitis, autoreactive T cells do indeed enter the CNS or eye, respectively. A paradigm has emerged that low numbers of lymphocytes, albeit activated, access and patrol the CNS parenchyma for potential pathogens (81). If, as evidence to date would indicate, DCs are excluded from the normal neural retina (and brain parenchyma), which cell type within the neural retina acts to present Ag to patrolling activated T cells If, as outlined earlier, it is accepted that DCs act as the...

Other Unusual Causes Of Secondary Parkinsonism

Parkinsonism was reported after a wasp sting resulting in a progressive syndrome of frequent freezing, rigidity, and bradykinesia, in addition to dystonia in the left arm (98). The patient was reported to have had emotional lability and bilateral frontal release signs. The brain MRI showed marked destruction of the striatum and pallidum bilaterally, and enlargement of the lateral and third ventricles. There were circulating antibodies against the basal ganglia and cerebral cortex. The patient responded to immunosuppressive therapy with plasma exchange and intravenous immunoglobulin. Multiple sclerosis (MS) has also been reported to cause parkinsonism (99). One patient presented mainly with gait difficulty, with slowness, short steps, and unsteadiness. She also developed rest tremor, hypomimia, and hypophonia. There were other features suggestive of multiple sclerosis in the form of diplopia, brisk reflexes, and sensory loss. The patient improved with steroids. So far in the literature...

Peptide Vaccine Induced Anaphylaxis in the NOD Mouse

The identification of autoantigens in autoimmune diseases such as type 1 diabetes or multiple sclerosis has made peptide immunotherapy possible. In fact, peptide vaccine trials are currently underway in type 1 diabetes for an altered peptide ligand of insulin peptide B 9-23 (20), for GAD peptides, and for heat shock protein 60 (HSP60) (p277) (21). However, in mouse studies of peptide vaccination, anaphylaxis has been reported in diabetes experiments using the B 9-23 peptide (22) and GAD peptides (23) and in multiple sclerosis studies (experimental autoimmune encephalitis) using proteolipid protein (PLP) (139-151) and myelin oligodendrocyte glycoprotein (MOG) (35-55) peptides (24). Even more concerning is the report of systemic hypersensitivity reactions in humans during phase II trials with an altered peptide ligand for myelin basic protein (MBP) (83-99) (25,26), which led to the premature discontinuation of therapy in some patients. More research into peptide-induced anaphylaxis,...

Data Interpretation

Monoclonal expansion of T-cells may be indicative for antigen-driven process either in blood or in tissue. Since each monoclonal TCR can be molecularly defined (see above), a molecular probe specific for the respective CDR3 region can be designed and the individual T-cell clone can either be traced in different compartments or longitudinally over time in a patient. This methodology has been used to tag clonal T-cell populations in autoimmune myositis (25), or in patients with multiple sclerosis (MS) suggesting that expansion of certain TCR VB families may be associated with disease onset or progression (26, 27). Similarly, if a monoclonal T-cell response can be linked to MHC peptide recognition, it allows to visualize monoclonal TCRs with defined specificity in situ, e.g. in a patient with melanoma responding to peptide vaccination An TCR VB16+ Melan-A MART-1 reactive T-cell clone could be demonstrated in a vitiligo lesion associated with destruction of melanin-positive cells (i.e....

Applications of Arrays to Neurological Disorders

Initial gene expression studies in neurology focused on using tissue homo-genates from affected regions of the brain to gain further insights into the pathogenic mechanisms responsible for neuronal cell death. More recently, the application of LCM and linear amplification has interrogated the gene expression of the vulnerable neuronal cell type, without the dilution effect from supporting cells of the central nervous system (CNS). Illustrative examples from Huntington's disease (HD), Alzheimer's disease (AD), multiple sclerosis (MS), and motor neuron disease (MND) demonstrate how micro-array technology has been used to advance the knowledge of these diseases. 5.2. Multiple Sclerosis

Conclusions and future challenges

Despite over 20 years of research, much about the regulation and function of L-selectin remains unknown. For example, while many different ligands that can be recognized by L-selectin have been described, definitive evidence demonstrating any of these molecules to be the physiological ligand for L-selectin is lacking. Furthermore, the PSGL-1-independent L-selectin ligands expressed by leukocytes remain to be identified. Important to L-selectin function is the generation of transmembrane signals through L-selectin following ligation. These signals, described following binding of ligands and L-selectin-specific mAbs, result in increased leukocyte effector functions such as enhancement in leukocyte binding activity and subsequent chemotaxis. However, it is unclear how such a short cytoplasmic tail, lacking known binding domains for signaling molecules, mediates such a variety of functions. Much of the differences observed in the migration of lymphocyte subsets can be explained by...

Diseases of the Myelin Sheath

Multiple sclerosis and Tay-Sachs disease are degenerative disorders of the myelin sheath. In multiple sclerosis (MS), the oligodendrocytes and myelin sheaths of the CNS deteriorate and are replaced by hardened scar tissue, especially between the ages of 20 and 40. Nerve conduction is disrupted with effects that depend on what part of the CNS is involved double vision, blindness, speech defects, neurosis, tremors, and numbness. Patients experience variable cycles of milder and worse symptoms until they eventually become bedridden. Most die from 7 to 32 years after the onset of the disease. The cause of MS remains uncertain most theories suggest that it results from an immune disorder triggered by a virus in genetically susceptible individuals. There is no cure.

Hemiparkinsonismhemiatrophy

Parkinsonism owing to multiple sclerosis Tremor-dominant parkinsonism following injury Parkinsonism following some insult in utero, or immediate postnatal period in association with tremor, cognitive dysfuncion, behavioral abnormalities, headaches, and strabismus Hemiatrophy in association with hemiparkinsonism dystonia, but without postural instability Tends to remain unilateral for 535 yr after onset of parkinsonian symptoms Early age at onset, history of birth injury, slow progression of the disease are very typical features. Parkinsonism in presence of tumors, hemorrhage typically contralateral to the lesion and sometimes ipsilateral to the lesion Parkinsonian features in presence of other symptoms of multiple sclerosis

Association of Kallikreins with Human Diseases

Many kallikreins seem to play important physiological roles in the CNS. In mouse, neuropsin appears to have an important role in neural plasticity, and the amount of neuropsin mRNA is related to memory retention after a chemically induced ischemic insult 191 . The human neuropsin gene (hK8) was first isolated from the hippocampus. Recent reports describe the association of hK8 expression with diseases of the CNS, including epilepsy 192, 193 . In addition, an 11.5-fold increase in KLK8 mRNA levels in Alzheimer's disease (AD) hippocampus compared to controls was recently reported 194 . The same study showed that KLK1, KLK4, KLK5, KLK6, KLK7, KLK8, KLK10, KLK11, KLK13, and KLK14 are expressed in both the cerebral cortex and hippocampus, whereas KLK9 is expressed in the cortex but not the hippocampus 194 . Another kallikrein, KLK6, was shown to have amyloidogenic activity in the AD brain 107, 195 , indicating that it may play a role in AD development (107). KLK6 was also found to be...

Osteonecrosis Avascular Necrosis or Aseptic Necrosis

Asherson Syndrome

Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC et al (2003) Catastrophic antiphospholipid syndrome international consensus statement on classification criteria and treatment guidelines. Lupus 12(7) 530-534 Asherson RA, Frances C, Iaccarino L, Khamashta MA, Malacarne F, Piette JC et al (2006) The antiphospholipid antibody syndrome diagnosis, skin manifestations and current therapy. Clin Exp Rheumatol 24(1 Suppl 40) S46-S51 Branch DW, Khamashta MA (2003) Antiphospholipid syndrome obstetric diagnosis, management and controversies. Obstet Gynecol 101(6) 1333-1344 Cabral AR, Cabiedes J, Alarcon-Segovia D (1990) Hemolytic anemia related to an IgM autoantibody to phosphatidylcholine that binds in vitro to stored and to bromelain-treated human eryth-rocytes. J Autoimmun 3(6) 773-787 Castanon C, Amigo MC, Banales JL, Nava A, Reyes PA (1995) Ocular vaso-occlusive disease in primary antiphospholipid syndrome. Ophthalmology 102 256-262 Cervera R, Khamashta MA, Font J, Reyes PA,...

Therapeutic Potential

Bronchial asthma is an inflammatory airway disease. Upon stimulation, adhesion molecules are expressed on the endothelial cells of the airways, which recruit leukocytes, primarily eosinophils, into the airways. Eosinophil accumulation eventually leads to airway edema, bronchoconstriction, airway wall remodeling and hyperresponsiveness. These events further induce the expression of inflammatory cytokines and adhesion molecules. Elevated expression of VCAM-1 has been detected in the lungs of asthmatic patients and anti-asthmatic treatment reduced the expression of VCAM-1 33-35 . In animal models, VCAM-1 antibodies significantly protected against allergen-induced airway inflammation, inhibiting T-cell migration into the lungs and eosinophil accumulation in bronchoalve-olar lavage fluid 36 . VCAM-1 is also implicated in other diseases such as multiple sclerosis 37-39 , chronic transplant rejection 40-43 , and diabetes 44,45 .

Chemokines Targets for Novel Therapeutics

Arthritis (RA), multiple sclerosis (MS) (29-34), atherosclerosis (35), asthma (36, 37), chronic obstructive pulmonary disorder (COPD) (38), and allergic disease (39). Taken together, this information has provided a very strong rationale for the implementation of chemokine antagonist programs. In the remainder of this review we will focus on the progress made towards identifying low molecular weight antagonists for CCR1, one of the receptors for MIP-1a and RANTES, CXCR2, one of the IL-8 receptors, and CCR2, the MCP-1 receptor (CCR2).

Antagonists of VLA4

Recent Biology - Over the last ten years, monoclonal antibodies to the a4 subunit as well as inhibitory peptides based on VLA-4 ligands have been used in animal models to implicate the integrin in several inflammatory diseases including asthma (11), contact hypersensitivity, multiple sclerosis, diabetes, inflammatory bowel disease, arthritis and allograft rejection (11-19). Early studies identified the VLA-4 ligand VCAM-1 as a homing receptor for monocytes in an animal model of atherosclerosis (20). More recently, gene disruption techniques were used to generate mice that express less than 10 of the VCAM-1 found in normal wild-type mice (21). When crossed with mice deficient for the LDL receptor, the resulting offspring showed a significant reduction in atherosclerotic lesion size as compared to those mice that were deficient in the LDL receptor alone. Interestingly, mice deficient for both the ICAM-1 and the LDL receptor genes did not show a reduction in lesion area relative to the...

The Overactive Bladder

Pathophysiology Oab

1) Neurologic illness or injury, most commonly traumatic or medical spinal cord injury, demyelinating disease including multiple sclerosis, supraspinal disease such as stroke, Parkinson disease, tumor, degenerative disease or dementia. The neurogenic mechanism of OAB may be related to various changes in both peripheral and central neural pathways, such as

Clinical trials of antagonists of MCP1CCR2

Other clinical trials with CCR2 antagonists are underway 1 , but no reports have been forthcoming. Both MLN-1202, a humanized anti-CCR2 antibody, and MK-0812, a small molecule antagonist, were examined in rheumatoid arthritis (vide supra) and are also being examined in multiple sclerosis. Two additional small molecules - CCX-915 and INCB-8696 - have entered phase 1 trials with multiple sclerosis as a projected phase 2 trial. An intention to study INCB-8696 in systemic lupus erythematosus has also been declared. Finally, phase 2 clinical

Clinical Application of Sacral Neuromodulation

The work-up for treatment by sacral neuromodulation must include careful assessment of past history with special emphasis on drugs influencing bladder function. A physical examination may be given to assess neurologic status, togther with a perineal examination with urodynamic investigation to assess bladder and sphincter function. To rule out any other lower urinary tract pathological conditions, urine culture can be performed to exclude urinary tract infection. Cytology and cystoscopy are helpful in ruling out carcinoma cystitis, and when indicated, imaging of the upper tract may be performed. It is recommended to perform MRI of the entire spinal cord to screen for neurologic diseases such as multiple sclerosis, a neoplasm, syringomyela, lipoma, etc.

SSAOVAP1 and inflammatory diseases

Inflammation is the first response of the immune system to infection or irritation. Leukocyte migration from the circulation into tissues is essential for this process. An inappropriate inflammatory response to a normally innocuous stimulus or to a false signal can result in local inflammation of an otherwise healthy tissue which can lead to disorders such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and respiratory diseases. In order to pass through the walls of the blood vessels, the leukocytes first adhere to the endothelium via binding to adhesion molecules (reviewed in 42 ). Membrane bound SSAO VAP-1 is abundantly expressed in vascular endothelial cells such as high venule endothelial cells (HVE) of lymphatic organs and is also expressed in hepatic sinusoidal endothelial cells (HSEC), smooth muscle cells and adipocytes. Although SSAO VAP-1 reveals no similarity to any known adhesion molecule and the leukocyte ligand for SSAO VAP-1 has not been...

Selective iNOS inhibitors

Inducible NOS has been implicated in a number of inflammatory diseases such as septic shock, multiple sclerosis, rheumatoid and osteoarthritis, ulcerative colitis, and asthma. Not surprisingly, many research institutions have developed programs to design inhibitors of iNOS. In addition to

Tube Removal

Abnormalities in gastric motility occur in a variety of disorders including diabetes and certain neurologic disorders such as Parkinson's and multiple sclerosis. Enteral feeding through a jejunostomy tube allows delivery of nutrients beyond the malfunctioning stomach (Table 4).

Future Directions

Fifth, certain kallikreins, such as human kallikrein 6, are highly expressed in the central nervous system. It has previously been shown that hK6, and possibly some other kallikreins, are implicated in inflammatory reactions within the central nervous system that lead to demyelination. The association of hK6 and some other kallikreins with AD and multiple sclerosis points to the possibility that some of these enzymes may play important roles within the central nervous system. In addition, many of these enzymes have been found in endocrine tissues such as the islets of Langerhans, thyroid, pituitary, and others, pointing to the possibility that they may participate in prohormone or hormone processing.

Role in inflammation

CSF-1 deficiency also conferred resistance to peripheral demyelinating disease 44 , and a FMS kinase inhibitor reduced markedly the loss of motor function in a MOG peptide-induced model of multiple sclerosis 45 . However, dinitrobenzene sulfonic acid-induced colitis was exacerbated in CSF-1-deficient mice 46 . In some settings, CSF-1-dependent macrophages may be a source of antiinflammatory molecules and may mediate tissue repair 2 . Although much remains to be learned regarding the long-term consequences of FMS inhibition in man, FMS inhibition in rats is well tolerated 20 , and FMS provides a tractable and exciting target to control the macrophage lineage across a spectrum of human disease.

GAmino butyramides

Compound 5 has recently been identified as MK-0812 81 , a potent CCR2 antagonist (CCR2 Bnd IC50 5.0 nM chemotaxis IC50 0.2 nM) that has advanced into human clinical trials for the treatment of rheumatoid arthritis and multiple sclerosis (vide supra). It has been described in several applications and claimed as a specific salt form 65,75-78 . Benzoxazine 7 has also been specifically described as a CCR2 antagonist with possible application in combination with statins for the treatment of inflammatory conditions 67,79,80 .

Conclusion

A significant investment has been made in the discovery of a richly diverse set of oral small molecule FMS inhibitors. It can be anticipated that at least some of these compounds will advance to clinical trials and reveal the human pharmacology of selective FMS inhibition. The association of CSF-1 expression and macrophage numbers with diverse human diseases, and the preclinical efficacy of FMS inhibitors in models of cancer, arthritis, and multiple sclerosis, presage a broad range of potential therapeutic applications for these compounds.

Antibodies To Cxcr3

Several research groups have discussed in the patent literature the potential utilities of CXCR3 antibodies for treatment of human diseases 46-48 . Investigators have presented data suggesting that immunization of SJL mice with an oligopeptide containing amino acid sequences from the first and fourth extracellular domains of CXCR3 prevents development of disease symptoms when the mice are subsequently immunized with an encephalitogenic peptide (PLP139 151) 47 . Furthermore, investigators have also claimed that treatment of SJL mice with a monoclonal antibody generated against the first 37 amino acids of human CXCR3 reduces incidence of disease in response to immunization with the same encephalitogenic peptide 48 . These data suggest that CXCR3-directed antibodies could potentially be useful in the treatment of multiple sclerosis.

Hydrazines

A group from La Jolla Pharmaceuticals has released data on their novel hydrazines in recent scientific 20,59,60 and patent literature 61,62 . A series of arylallyl hydrazines (e.g., 8 and 9) were shown to be potent, irreversible inhibitors of rat and human SSAO VAP-1 59 . LJP-1207 (8, IC50 2nM, human) was evaluated in a series of in vivo inflammation models. Significant efficacy was observed in a mouse ulcerative colitis, mouse LPS-induced septic shock, and the rat carrageenan foot models 20 , in a mouse model that resembles human multiple sclerosis 63 , and in a transient forebrain ischemia model in estrogen-treated ovariectomized female rats 60 .

Other Compounds

The cannabinoid receptor agonist, R-( + )-WIN-55,212-2 (12), has shown efficacy in controlling disease progression in animal models of multiple sclerosis (MS). This effect has been attributed to its ability to reduce migration of leukocytes into the central nervous system 90 , in which adhesion molecules are believed to be involved. Compound 12, but not its enantiomer, S-(-)-WIN-55,212-2, strongly inhibited IL-1-induced expression of VCAM-1 on astrocytoma and A-172 glioblastoma cells. Interestingly, S-(-)-WIN-55,212-2 showed no efficacy in models of MS. The inhibitory effect of 12 on VCAM-1 expression is not believed to be mediated via cannabinoid receptors, since both selective cannabinoid receptor antagonists and pertussis toxin failed to affect it. Experimental data suggest that 12 blocks IL-1 signaling by inhibiting the transactivation potential of nuclear factor-kB (NF-kB) 91 .

Conclusions

The discovery of FTY720 and the unique role of S1P receptors in the trafficking of lymphocytes have catalysed intensive research in this area. Two different hypotheses have been proposed to explain the mechanism by which S1P receptor agonists reduce the levels of peripheral lymphocytes. The first hypothesis suggests that agonism of S1P receptors on lymphocytes induces internalization of the receptor, resulting in a blockade of S1P-directed migration of the lymphocytes from the lymph nodes. The second hypothesis suggests that agonism of S1P receptors on the lymphatic endothelium leads to an increase in barrier function and a reduction in lymphocyte transmigration. Further mechanistic studies are needed to determine whether one of these mechanisms is predominant or whether both mechanisms are important. Significant progress has been achieved towards S1P subtype-selective agonists and antagonists with suitable pharmaco-kinetic properties for in vivo studies and these compounds will help...

Human Retroviruses

HTLV retroviruses are endemic in Japan and the Caribbean but relatively uncommon in the United States. They cause adult T-cell leukemia lymphoma and a neurological disorder similar to multiple sclerosis. The infection can persist for a lifetime but rarely causes major illnesses in most people who are infected. In rare instances, the virus may, after many years of infection, cause nervous system disease or an unusual type of leukemia. HTLV-II infections are usually associated with intravenous drug usage, especially among people who share needles or syringes. Disease associations with HTLV-II have been hard to confirm, but the virus may cause subtle abnormalities of immunity that lead to frequent infections, or rare cases of neurological disease.

Retinal Microglia

In recent years it has become apparent that DCs, though absent from the CNS parenchyma (including retina), can infiltrate these tissues during inflammation such as multiple sclerosis or experimental autoimmune encephalomyelitis (97,98), and a similar situation appears to exist in the retina during inflammation (99). There is also some evidence that in vitro MG can differentiate into DCs in the prolonged presence of GM-CSF (98) however, whether this can occur in vivo is presently unclear.

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