Uric acid: a novel treatment strategy for multiple sclerosis.
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Biomedical subjects
Publications and source records attributed to Alireza Minagar.
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Egas Moniz is generally remembered for having discovered cerebral angiography in 1927, and having introduced lobotomy as a form of treatment for mental illness in 1935. Less well known is his pioneering research on occlusive cerebrovascular disease, namely internal carotid artery (ICA) occlusion, as documented by cerebral angiography. It is our contention that the medical community has, until recently, largely overlooked this research. His neglected observations on ICA occlusion and the important diagnostic role played by angiography are reviewed. We propose to show how our paper differs from previous publications regarding Moniz's ICA occlusion contributions. Whereas most previous reviews have focused on either the role played by cerebral angiography in the diagnosis of ICA occlusion, or on the importance of Moniz's internal carotid occlusion observations, our review attempts to integrate both topics. We will tie Moniz's ICA occlusion research to his documented use of angiography.
Cardioembolic stroke accounts for approximately 15% of all strokes and is thought to be one of the more preventable types of strokes. Features that have been reported to support cardioembolism as a mechanism for ischemic stroke have included documented cardiac source of embolism, maximal neurologic deficit at onset, multiple cerebrovascular territories involved, enhanced tendency toward hemorrhagic transformation, enhanced risk of syncope or seizure associated with presentation, and lower likelihood of premonitory transient ischemic attacks. Features that tend to make cardioembolic stroke less likely include significant cerebral atherosclerosis, step-wise progression of the neurologic deficit within a finite period of time, vascular distribution such as entire internal carotid artery territory with combined middle cerebral artery and anterior cerebral artery involvement or watershed distribution, and premonitory transient ischemic attacks. A number of cardiac conditions can promote thromboembolism, and there is risk stratification reflective of the specific condition or coexistent conditions. Anticoagulant therapy generally has been found to be the most effective means of preventing cardiogenic brain embolism, but the intensity of anticoagulation needs to be optimized to reflect the risk-to-benefit ratio for the particular patient.
The Edwin Smith surgical papyrus, which dates back nearly five millennia, is the oldest known medical text and contains the first written example of the word "brain", as well as the earliest known descriptions of the meninges and the cerebrospinal fluid. The papyrus describes 48 cases and gives the first accounts of several forms of brain injury and their associated complications. The Egyptian author presents an analytical approach to the reported cases and classifies them as favourable, uncertain or intractable, depending on prognosis. The authors believe that case 20 of the papyrus presents the first possible case of aphasia, which occurred following head trauma. The patient, frustrated by his inability to speak, developed nuchal stiffness, which might have been due to meningeal irritation. The case concludes with the advice that a patient with such a grave condition should only be comforted, not treated.
Disruption of the blood brain barrier (BBB) and transendothelial migration of inflammatory cells are crucial steps in the development of demyelinating lesions in multiple sclerosis (MS). Occludin and vascular endothelial-cadherin (VE-cadherin) are two major components of the tight junctions (TJs) in the brain microvasculature that help to create the BBB. In the present study, we investigated the effect of serum from MS patients on the expression of these two junctional markers and on the endothelial integrity. Serum from six MS patients in exacerbation, six in remission, and six normal controls (10% by volume) was incubated with cultured endothelial cells, and the expression of occludin and VE-cadherin was measured by immunoblotting. Serum from MS patients in exacerbation significantly reduced the expression of occludin and VE-cadherin compared with patients in remission and normal controls. This disintegrating effect was more pronounced for occludin than for VE-cadherin. We assume that the elevation in cytokines or other serum-soluble factors in MS patients in exacerbation likely provokes downregulation of occludin and VE-cadherin. This downregulation of TJs proteins may, therefore, contribute to the disruption of the BBB in this condition.
Cortical speech disorders rarely occur in multiple sclerosis (MS). We report a patient with relapsing-remitting MS, who presented with acute verbal dyspraxia. Magnetic resonance imaging (MRI) demonstrated an acute T2/Flair hyperintense, primarily white matter lesion underlying the middle third of the inferior frontal gyrus. The verbal dyspraxia cleared beginning 48 hours after the initiation of iv dexamethasone. Follow-up MRI demonstrated qualitative and quantitative diminution of the hyperintensity. This is the first report of a clinically definite MS patient with acute verbal dyspraxia. Moreover, there was a suggestive localization of verbal praxis to Brodmann areas 44/45.
The blood-brain barrier (BBB) is a complex organization of cerebral endothelial cells (CEC), pericytes and their basal lamina, which are surrounded and supported by astrocytes and perivascular macrophages. Collectively these cells separate and form the compartments of the cerebral vascular space and the cerebral interstitium under normal conditions. Without the BBB, the 'interior milieu' of the central nervous system (CNS) would be flooded by humoral neurotransmitters and formed blood elements that upset normal CNS functions and lead to vascular/neural injury. Dysregulation of the BBB and transendothelial migration of activated leukocytes are among the earliest cerebrovascular abnormalities seen in multiple sclerosis (MS) brains and parallel the release of inflammatory cytokines/chemokines. Mechanisms for breakdown of the BBB in MS are incompletely understood, but appear to involve direct effects of these cytokines/ chemokines on endothelial regulation of BBB components, as well as indirect cytokine/chemokine-dependent leukocyte mediated injury. Unique endothelial structural features of the BBB include highly organized endothelial tight junctions, the absence of class II major histocompatibility complex, abundant mitochondria and a highly developed transport system in CEC. Exposure of endothelium to proinflammatory cytokines (IFN-gamma, TNF-alpha and IL-1beta) interrupts the BBB by disorganizing cell-cell junctions, decreases the brain solute barrier, enhances leukocyte endothelial adhesion and migration as well as increases expression of class II MHC and promotes shedding of endothelial 'microparticles' (EMP). In this review we examine interactions between cytokines/chemokines, activated leukocytes, adhesion molecules and activated CEC in the pathogenesis of BBB failure in MS.
Meningovascular syphilis is now quite uncommon, but there have been increasing reports in patients immunocompromised with human immunodeficiency virus. The response of syphilis affecting the central nervous system to antibiotic therapy remains a challenge. This is an even greater challenge in patients who have underlying compromise of the immune system. The authors present a 46-year-old male with recurrent stroke who was found to have cerebrospinal fluid compatible with syphilitic involvement of the central nervous system and a cerebral arteriogram, which revealed focal narrowing of the right middle cerebral artery. The baseline transcranial Doppler study demonstrated increased mean and peak flow velocity within the right middle cerebral artery. Despite a 10-day course of intravenous penicillin, with substantial improvement in the cerebrospinal fluid results, this flow velocity elevation persisted, in a remarkably consistent pattern, over a 4-month follow-up period. Thus, the involved vessel remained patent following treatment, but no clear resolution of the stenotic lesion was observed.
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Macrophage/microglia (M phi) are the principal immune cells in the central nervous system (CNS) concomitant with inflammatory brain disease and play a significant role in the host defense against invading microorganisms. Astrocytes, as a significant component of the blood-brain barrier, behave as one of the immune effector cells in the CNS as well. However, both cell types may play a dual role, amplifying the effects of inflammation and mediating cellular damage as well as protecting the CNS. Interactions of the immune system, M phi, and astrocytes result in altered production of neurotoxins and neurotrophins by these cells. These effects alter the neuronal structure and function during pathogenesis of HIV-1-associated dementia (HAD), Alzheimer disease (AD), and multiple sclerosis (MS). HAD primarily involves subcortical gray matter, and both HAD and MS affect sub-cortical white matter. AD is a cortical disease. The process of M phi and astrocytes activation leading to neurotoxicity share similarities among the three diseases. Human Immunodeficiency Virus (HIV)-1-infected M phi are involved in the pathogenesis of HAD and produce toxic molecules including cytokines, chemokines, and nitric oxide (NO). In AD, M phis produce these molecules and are activated by beta-amyloid proteins and related oligopeptides. Demyelination in MS involves M phi that become lipid laden, spurred by several possible antigens. In these three diseases, cytokine/chemokine communications between M phi and astrocytes occur and are involved in the balance of protective and destructive actions by these cells. This review describes the role of M phi and astrocytes in the pathogenesis of these three progressive neurological diseases, examining both beneficent and deleterious effects in each disease.
BACKGROUND: Endothelial MAdCAM-1 (mucosal addressin cell adhesion molecule-1) expression is associated with the oxidant-dependent induction and progress of inflammatory bowel disease (IBD). Melatonin, a relatively safe, potent antioxidant, has shown efficacy in several chronic injury models may limit MAdCAM-1 expression and therefore have a therapeutic use in IBD. METHODS: We examined how different doses of melatonin reduced endothelial MAdCAM-1 induced by TNF-a in an in vitro model of lymphatic endothelium. Endothelial monolayers were pretreated with melatonin prior to, and during an exposure, to TNF-a (1 ng/ml, 24 h), and MAdCAM-1 expression measured by immunoblotting. RESULTS: MAdCAM-1 was induced by TNF-a. Melatonin at concentrations over 100 microm (10(-4) M) significantly attenuated MAdCAM-1 expression and was maximal at 1 mM. CONCLUSIONS: Our data indicate that melatonin may exert therapeutic activity in IBD through its ability to inhibit NF-kappaB dependent induction of MAdCAM-1.
Interest in alternative medical treatments, including acupuncture, is increasing. Alternative treatments must be subjected to the same objective standards as all medical treatments. A non-blinded pilot study of the safety, tolerability, and efficacy of acupuncture (ACUPX) for the symptoms of (PD) was performed. Twenty PD patients (mean age, 68 years; disease duration, 8.5 years; Hoehn and Yahr [H&Y] stage, 2.2; Unified Parkinson's Disease Rating Scale score [UPDRS], 38.7) each received acupuncture treatments by a licensed acupuncturist. All patients were treated with two acupuncture treatment sessions per week. The first seven patients received 10 treatments and the last 13 patients 16 treatments. Patients were evaluated before and after ACUPX with the Sickness Impact Profile (SIP); UPDRS; H & Y; Schwab and England (S & E); Beck Anxiety Inventory (BAI); Beck Depression Inventory (BDI); quantitative motor tests, including timed evaluations of arm pronation supination movements, finger dexterity, finger movements between two fixed measured points, and the stand-walk-sit test; and a patient questionnaire designed for the study. Following ACUPX, there were no significant changes in the UPDRS, H&Y, S&E, BAI, BDI, quantitative motor tests, total SIP or the two SIP Dimension scores. Analysis of the 12 SIP categories not corrected for multiple comparisons revealed a post-ACUPX improvement in the sleep and rest category only (P = 0.03). On the patient questionnaire, 85% of patients reported subjective improvement of individual symptoms including tremor, walking, handwriting, slowness, pain, sleep, depression, and anxiety. There were no adverse effects. ACUPX therapy is safe and well tolerated in PD patients. A range of PD and behavioral scales failed to show improvement following ACUPX other than sleep benefit, although patients reported other discrete symptomatic improvements. A broad battery of tests in PD patients suggested that ACUPX resulted in improvement of sleep and rest only. This finding needs to be verified using more in-depth and controlled evaluation of ACUPX for PD-related sleep disturbance.
Devic disease is characterized by an attack or attacks of optic neuritis and necrotizing myelitis without clinical or magnetic resonance imaging (MRI) evidence of brain involvement or presence of oligoclonal bands in the cerebrospinal fluid (CSF). More than a century after its first systematic study by the French physician, Eugene Devic, its cause as well as its pathogenesis, remains unknown. Devic disease is both a diagnostic and therapeutic challenge to clinicians. The authors present the latest review on the nature, course, possible mechanisms, and therapeutic options of Devic disease.
PURPOSE: A literature review was performed of the three principal subpopulations most commonly associated with human T-cell lymphotropic virus type II (HTLV-II) with the view of identifying the prevalence and transmission routes of HTLV-II. These included blood donors (BDs), intravenous drug users (IVDUs), and Amerindians (Indian populations from the Americas). We used the major criterion of serological and molecular distinction between human T-cell lymphotropic virus types I (HTLV-I) and II (HTLV-II). Three questions were formulated in addressing the possibility that HTLV-II might be responsible for the reported prevalence and transmission of this virus in these groups. Question One: Which population groups have the highest HTLV-II seroprevalence rates? Question Two: Are worldwide HTLV infection rates among the three sub-populations associated predominantly with the HTLV-II retrovirus type? Question three: What are the principal modes of transmission of HTLV-II? METHODS: Since earlier epidemiologic studies did not routinely use assays capable of distinguishing between HTLV-I and HTLV-II antibodies, their findings are necessarily inaccurate. However, with the more recent development of enhanced serologic assays, using recombinant antigens that are capable of accurately making this differentiation, it is now possible to more precisely define the epidemiology of HTLV-II. We reviewed only those studies where serological and molecular methods of accurately distinguishing between the two retroviruses were utilized. Initially, we located 36 studies, which met this particular review criterion. Of the five different assays we identified, the most prevalent were the polymerase chain reaction (PCR) (n = 14) and the synthetic peptide-based enzyme-linked immunoassay (Synth EIA) (n = 13). Our BD, IVDU, and Amerindian groups were also evaluated according to this differentiation schema. We were able to locate over 100 prevalence studies where focus was on some aspect of analysis of at least one or more of these three groups. By using many search terms - such as HTLV-II endemic population, seroepidemiological, as well as case control and cohort studies - we were able to create a comprehensive bibliographic database. RESULTS: The two groups identified with high HTLV-II prevalence rates are the IVDUs and Amerindian population. The importance of breast-feeding, IVDU, and contaminated blood products in the HTLV-II transmission process is confirmed. Sexual intercourse, however, as a mode of HTLV-II transmission remains problematic. CONCLUSIONS: By confining our evaluation to only those studies that used serological and/or molecular methods capable of distinguishing between the two retroviruses, we have been able to establish with confidence that there are consistent emerging patterns of HTLV-II infection in these populations.
Movement disorders associated with multiple sclerosis (MS) are uncommon, except for tremor. We report two patients with relapsing-remitting MS, who developed either dystonia or chorea during clinical exacerbation of their MS. The movement disorders resolved during treatment with adrenocorticotropin hormone (ACTH). Acute exacerbations of MS may be associated with transient movement disorders, which are responsive to ACTH.
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