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Biomedical subjects

Alireza Minagar

Publications and source records attributed to Alireza Minagar.

At least 19 recordsLinked to original sources
PubMed2006

Interferon-beta1a reduces plasma CD31+ endothelial microparticles (CD31+EMP) in multiple sclerosis.

BACKGROUND: A correlation between plasma CD31+ endothelial microparticles (CD31+EMP) levels and clinical, as well as brain MRI activity, in multiple sclerosis (MS) patients has been previously reported. However, the effect(s) of treatment with interferon-beta1a (IFN-beta1a) on plasma levels of CD31+EMP has not been assessed. In a prospective study, we measured plasma CD31+EMP levels in 30 patients with relapsing-remitting MS. METHODS: Using flow cytometry, in a blinded study, we measured plasma CD31+EMP in 30 consecutive patients with relapsing-remitting MS (RRMS) prior to and 4, 12, 24 and 52 weeks after initiation of intramuscular therapy with interferon-beta1a (IFN-beta1a), 30 micrograms weekly. At each visit, clinical examination was performed and expanded disability status scale (EDSS) scores were assessed. RESULTS: Plasma levels of CD31+EMP were significantly reduced from 24 through 52 weeks following initiation of treatment with IFN-beta1a. CONCLUSION: Our data suggest that serial measurement of plasma CD31+EMP levels may be used as a surrogate marker of response to therapy with INF-beta1a. In addition, the decline in plasma levels of CD31+EMP further supports the concept that IFN-beta1a exerts stabilizing effect on the cerebral endothelial cells in pathogenesis of MS.

Journal Article↗
PubMed2006

Gene chromosomal organization and expression in cultured human neurons exposed to cocaine and HIV-1 proteins gp120 and tat: drug abuse and NeuroAIDS.

As a model for Neuropsychiatric dysfunction in NeuroAIDS due to HIV-1 infection and drug abuse, we analyzed gene expression in human neurons treated with cocaine and HIV-1 proteins tat and envelope (env). One-way ANOVA showed statistically significant genes among the treatment groups (p < or = 0.0005). The identified genes were then subjected to a "stepwise" analysis using a repeated measures ANOVA to discover genes with parallel response group profiles across the treatment conditions. These groups were then analyzed using a repeated measures ANOVA to assess treatment main effects and gene-by-treatment interactions within groups. One-way ANOVA produced 35 genes that were significantly associated across all treatment conditions. Factorial analysis of each gene found statistically significant differences: 30--tat, 17--cocaine, 10--env, 6--tat/env, 6--coc/env, and 4--coc/tat. Analyses across genes found three sets of four genes, one set of three genes, and three sets of two genes with parallel profiles. Identified genes had functions included signaling, immune related, and transcription control. The genes were not stochastically arranged on the chromosomes, were in proximity to each other, and to other genes involved in neuropsychiatric diseases. We hypothesize that these genes fall in transcriptionally isolated groups and that abused drugs and HIV-1 proteins trigger transcription overload, coerced expression that may result in damage to the chromosome's control and organization of chromatin transcription machinery.

AIDS Dementia Complex↗
PubMed2006

Multiple sclerosis as a vascular disease.

Multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated disease with principal emphasis on the role of activated inflammatory cells, oligodendrocytes and astrocytes in its pathogenesis. Abnormalities of cerebral endothelial cells (CECs) is an under explored facet of MS pathogenesis and vascular abnormalities play a crucial role in formation of the MS lesions and disease progress, at least in the initial stages of disease. This review will focus on MS as a central nervous system (CNS) disease with a strong vascular constituent and examines abnormalities within CECs in MS and their role in the loss of blood-brain barrier and transendothelial migration of activated leukocytes into the CNS. One goal of this paper is to persuade and promote research on the endothelial abnormalities in pathogenesis of MS and to exploit existing knowledge on endothelial injury. A deeper understanding of endothelial pathophysiology in MS may help develop effective treatments through stabilization of endothelial function, translating into delay or arrest of MS disease onset and disability in MS patients.

Antibody Specificity↗
PubMed2006

Role of magnetic resonance spectroscopy in diagnosis and management of multiple sclerosis.

Application of magnetic resonance spectroscopy (MRS) to study the nature, pathogenesis, tissue injury and therapeutic response of MS patients has altered our view of multiple sclerosis (MS) fundamentally. By offering biochemical analysis of demyelinating lesions and axonal injury, MRS generates objective and quantifiable data on central nervous system tissue and metabolism during pathogenesis of MS. Of these biochemical markers, N-acetylaspartate, which serves as an indicator of neuronal and axonal injury and choline (Cho) peaks which demonstrate cell membrane metabolism, provide a plethora of data on the neuropathology of MS. Based on these findings, MRS provides neuroscientists with a unique diagnostic and prognostic tool to follow MS patients and assess their response to treatment with immunomodulators. MRS findings are so significant that consideration should be given to their routine inclusion as secondary outcome measures in clinical trials of MS patients.

Animals↗
PubMed2006

Neurosurgical treatment of multiple sclerosis.

OBJECTIVES: To describe the role of neurosurgical techniques in treatment of symptoms of multiple sclerosis (MS). METHODS: A review of the existing world literature searching (using PubMed, August 22, 2005) for key words 'multiple sclerosis' and multiple symptoms associated with MS including trigeminal neuralgia, pain (pump and rhizotomy), spasticity, intrathecal pump, hydrocephalus and stimulation (brain and spinal). RESULTS: In total, 1,404 articles met selection criteria. These were narrowed based upon uniqueness of technique described, nature of information provided and avoidance of redundancy. Further, the methods listed were classified into groups of cranial and spinal techniques. Indications, brief description of technique and outcome/side effects were noted for each technique. DISCUSSION: A vast, growing body of literature exists for various neurosurgical applications for MS treatment. Older techniques such as rhizolysis for neuralgia and rhizotomy for spasticity have been modified using stereotactic radiosurgery and deep brain stimulation, along with central nervous system stimulation and intrathecal pumps. Other applications continue to be found with varying degrees of success. CONCLUSIONS: Neurosurgical techniques, based upon proper selection criteria, can significantly improve MS-related symptoms with low procedure-associated risk and therefore can substantially improve patients' quality of life.

Deep Brain Stimulation↗
PubMed2005

Presenilin-1 detection in brain neurons and FOXp3 in peripheral blood mononuclear cells: normalizer gene selection for real time reverse transcriptase pcr using the DeltaDeltaCt method

Quantification of gene expression is important to confirm changes in levels of gene expression in disease. Prior quantification methods include standard curves, absolute quantification, and relative quantification. This paper describes an analytic method for the relative quantification of Presenilin-1 (PS-1) in neurons and Forkhead-box (FOX) p3 in PBMNCs using real-time PCR analytic techniques. A comparative Ct method (deltadelatCt) is described in which the quantity of target normalized to a normalizer gene reference is given by 2-deltadelatCt where deltadelatCt = [Ct of the gene of interest in the unknown specimen - Ct normalizer gene in the unknown specimen] - [Ct of the gene of interest in the calibrator specimen - Ct normalizer gene in the calibrator specimen]. The calibrator specimen is ideally from a non-treated control specimen and is analyzed on every assay plate with the unknown specimens of interest. The use of the deltadelatCt methodology allows for a higher throughput and a more economical approach to investigate gene expression. We applied this methodology to the quantification of PS-1 and FOXp3 genes and compare the levels of expression by normalizing to different normalizer genes using the deltadelatCt methodology. We find that use of GAPDH is the optimum normalizer gene for the genes analyzed in neurons from human brain and in PBMNCs.

Animals↗
PubMed2005

Soluble HLA measurement in saliva and cerebrospinal fluid in Caucasian patients with multiple sclerosis: a preliminary study.

BACKGROUND: Measurement of soluble HLA in body fluids has a potential role in assessing disease activity in autoimmune disorders. METHODS: We applied a solid phase, enzyme-linked immunoassay to measure soluble HLA class I (sHLA-I) and class II (sHLA-II) molecules in the saliva and cerebrospinal fluid (CSF) in 13 untreated patients with relapsing-remitting form of multiple sclerosis (MS). For comparison purposes, we also studied saliva from 53 healthy subjects. RESULTS: Saliva from normal controls had detectable sHLA-I levels in 41 of 53 individuals studied, with values ranging from 9-100 ng/ml (mean = 41 +/- 2.8 ng/ml). sHLA-I was undetectable in the saliva in 11 of 13 MS patients, and in none of the CSF specimens. In contrast, mean sHLA-II concentration in the saliva of MS patients was significantly increased compared to controls (386 +/- 52 unit/ml vs. 222 +/- 18.4 unit/ml, t = 8.68, P < 0.005). The mean CSF sHLA-II level (369 +/- 16 unit/ml) was equivalent to the mean sHLA-II concentration measured in saliva (mean = 386 +/- 52 unit/ml) (P = 0.7). In patients with brain magnetic resonance imaging (MRI) enhancing lesions (n = 5), reflective of more active disease, CSF sHLA-II averaged 356 +/- 26 unit/ml compared to 380 +/- 51 in saliva. Similarly, in patients with non-enhancing lesions (n = 8), CSF sHLA-II averaged 377 +/- 18 unit/ml compared to 390 +/- 77 unit/ml in saliva. Thus, the mean sHLA-II concentration in saliva and CSF was essentially equivalent for MS patients with or without enhancing plaques. CONCLUSION: Our data suggest that the measurement of soluble HLA in saliva, specifically sHLA-II, correlates with the level found in the CSF. Therefore, if sHLA correlates with disease activity in MS, as has been proposed, saliva measurements provide a noninvasive correlate of CSF measurement.

Journal Article↗
PubMed2005

Differential RNA expression of hepatic tissue in lean and obese mice after LPS-induced systemic inflammation.

Mortality of obese patients with sepsis has been reported to be significantly higher than lean patients. The underlying basis for this difference is not currently known. However, it has been suggested that obesity is associated with an altered immune response to a septic or inflammatory insult. Since obesity is based on exclusion in many sepsis trials, little is known about how obesity affects mortality or whether obese individuals respond differently to therapeutic interventions. In this study, obese and non-obese mice were given intra-peritoneal injection of saline or LPS and the livers were harvested 2 hours later. RNA from these livers were subjected to DNA microarray. Analysis showed distinct differences in gene expression between lean and obese animals. The expression of one hundred and seventeen genes was found to be different among the groups. In the obese animals treated with LPS, the expression of 20 genes showed a significant change. Ontology analysis revealed increased expression of 15 genes and significant decrease in expression of 5 genes. This study shows different gene expression of liver in response to LPS in lean versus obese animals. These genes might play a role in the outcome of sepsis.

Animals↗
PubMed2005

Troglitazone, a PPAR-gamma activator prevents endothelial cell adhesion molecule expression and lymphocyte adhesion mediated by TNF-alpha.

BACKGROUND: Cytokine mediated induction of the mucosal addressin cell adhesion molecule-1(MAdCAM-1) expression is associated with the onset and progression of inflammatory bowel disease (IBD). RESULTS: Using western blotting and cell-based ELISA, we show in this study that troglitazone, an activator of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), widely used in the treatment of diabetes, has as well recently been highlighted as protective in models of inflammation and cancer. We found that troglitazone (10-40 microM), significantly reduced the TNF-alpha (1 ng/ml) mediated induction of endothelial MAdCAM-1 in a dose-dependent manner, achieving a 34.7% to 98.4% reduction in induced MAdCAM-1. Trogliazone (20 microM) reduced TNF-alpha induced VCAM-1, ICAM-1 and E-selectin expression. Moreover, troglitazone significantly reduced alpha4beta7-integrin dependent lymphocyte adhesion to TNF-alpha cultured endothelial cells. CONCLUSIONS: These results suggest that PPAR-gamma agonists like troglitazone may be useful in the clinical treatment of IBD.

Animals↗
PubMed2005

Elevated endothelial microparticle-monocyte complexes induced by multiple sclerosis plasma and the inhibitory effects of interferon-beta 1b on release of endothelial microparticles, formation and transendothelial migration of monocyte-endothelial microparticle complexes.

Monocyte migration through the disrupted cerebral endothelial cell (EC) junctions plays an essential role in formation of multiple sclerosis (MS) demyelinating lesions. During pathogenesis of MS, activated ECs release endothelial microparticles (EMP), which possibly facilitate transendothelial migration (TEMIG) of monocytes. To assess functional roles of EMP in MS, specifically, their (i) interaction with monocytes, (ii) effect on monocyte TEMIG in an in vitro model of the brain microvascular endothelial cells (BMVEC), (iii) phenotypic profiles of EMP elicited by MS plasma and (iv) the effects of IFN-beta 1b on release of EMP and on TEMIG of monocytes (mono) and monocytes:EMP complexes (mono:EMP) through the BMVEC. The effect of IFN-beta 1b on the release of EMP and the TEMIG of mono and mono:EMP was assessed by preincubating BMVEC cultures of IFN-beta 1b prior to addition of plasma. Three EMP phenotypes, CD54, CD62E and CD31 were assayed. Plasma specimens from 20 patients with relapsing remitting MS (11 in exacerbation, MS-E, and 9 in remission, ME-R) and 10 healthy controls were studied. Incubation of BMVEC with MS-E plasma yielded elevated levels of EMPCD54, EMP62E and EMPCD31 relative to MS-R and control plasmas. MS-E but not MS-R or control plasma also augmented TEMIG of monocytes, respectively. Mono:EMP complexes further augmented TEMIG relative to mono alone, but only in the presence of MS-E plasma; there was no significant effect with MS-R or control plasmas. The presence of IFN-beta 1b inhibited TEMIG of mono and mono:EMP by 20% and 30%, respectively. MS-E but not MS-R plasma elicited release of activation-derived EMP and enhanced TEMIG of mono and mono:EMP. IFN-beta 1b inhibited TEMIG and release of EMP, suggesting a role of EMP and a novel therapeutic mechanism for IFN-beta 1b in MS.

Adjuvants, Immunologic↗
PubMed2005

Soluble HLA class I and class II molecules in relapsing-remitting multiple sclerosis: acute response to interferon-beta1a treatment and their use as markers of disease activity.

During relapses in relapsing-remitting multiple sclerosis (RRMS), serum soluble HLA class I surface antigen (sHLA-I) levels are reported to either decrease or remain unchanged, whereas serum sHLA-II levels increase. Interferon-beta1b therapy was recently reported to increase serum sHLA-I in RRMS. In the present prospective study, solid-phase enzyme-linked immunosorbent assay was used to measure sHLA-I and sHLA-II in the sera of 21 RRMS patients during a clinical exacerbation, and then six weeks after treatment with high-dose interferon-beta1a (IFN-beta1a). Pretreatment serum sHLA-I was significantly lower in patients than in normal controls (P < 0.0005). Pretreatment sHLA-II was also significantly lower than in normal controls (P = .003) unless enhancing MRI lesions (objectified relapse) were present; then sHLA-II levels were similar to normal controls (relative increase). Six weeks after initiation of IFN-beta1a treatment, a significant increase in serum sHLA-I was observed in all 21 RRMS patients (P < .0005). Conversely, serum sHLA-II decreased significantly after treatment in the entire patient group (P < .0005). The acute effect of IFN-beta1a on serum sHLA-I and sHLA-II was observed to be the opposite of that occurring during RRMS relapses. Monitoring of both sHLA-I and sHLA-II appears necessary if these molecules are to be developed as RRMS activity markers.

Adult↗
PubMed2005

Imaging of multiple sclerosis: role in neurotherapeutics.

Magnetic resonance imaging (MRI) plays an ever-expanding role in the evaluation of multiple sclerosis (MS). This includes its sensitivity for the diagnosis of the disease and its role in identifying patients at high risk for conversion to MS after a first presentation with selected clinically isolated syndromes. In addition, MRI is a key tool in providing primary therapeutic outcome measures for phase I/II trials and secondary outcome measures in phase III trials. The utility of MRI stems from its sensitivity to longitudinal changes including those in overt lesions and, with advanced MRI techniques, in areas affected by diffuse occult disease (the so-called normal-appearing brain tissue). However, all current MRI methodology suffers from limited specificity for the underlying histopathology. Conventional MRI techniques, including lesion detection and measurement of atrophy from T1- or T2-weighted images, have been the mainstay for monitoring disease activity in clinical trials, in which the use of gadolinium with T1-weighted images adds additional sensitivity and specificity for areas of acute inflammation. Advanced imaging methods including magnetization transfer, fluid attenuated inversion recovery, diffusion, magnetic resonance spectroscopy, functional MRI, and nuclear imaging techniques have added to our understanding of the pathogenesis of MS and may provide methods to monitor therapies more sensitively in the future. However, these advanced methods are limited by their cost, availability, complexity, and lack of validation. In this article, we review the role of conventional and advanced imaging techniques with an emphasis on neurotherapeutics.

Animals↗
PubMed2005

The role of alpha-4 integrin in the aetiology of multiple sclerosis: current knowledge and therapeutic implications.

Multiple sclerosis (MS) has been recognised as a disease since the mid-19th century. The delineation of its CNS pathology, revealing the presence of inflammatory demyelination and relative sparing of axons, was originally interpreted as evidence of infection. Despite many studies, a primary infectious aetiology of MS has not been found. However, the occurrence of acute demyelinating disease following a variety of infections and vaccinations, leading to MS in about a third of cases, provides evidence for the existence of an auto-allergic pathogenesis for the disease. Improved understanding of the role of the blood-brain barrier in protecting the CNS, and the mechanisms by which cells gain entry into the brain and spinal cord has advanced the understanding of MS. Evidence of the central role of the adhesion molecule alpha4beta1-integrin (very late activation antigen-4 [VLA-4]) for lymphocytes in endothelial transmigration into the CNS specifically, has provided a major insight into the pathogenesis of human demyelinating disease and its experimental model, experimental autoimmune encephalomyelitis (EAE). This finding has led to a new window of therapeutic opportunity in MS. Monoclonal antibodies to VLA-4 abrogate the development of EAE in sensitised animals and may actually reverse its clinical and pathological findings in manifest disease. Natalizumab, one such monoclonal antibody, which is administered intravenously, has been found to be a promising agent in the treatment of MS. Although single doses produced no improvement in the speed or quality of recovery from acute exacerbations of MS in a phase II trial, long-term administration (in phase II and phase III trials) have produced significant benefits with results showing both a marked reduction in the risk of new magnetic resonance imaging lesions and a significant reduction in the risk of exacerbations within 2 months of the initiation of therapy. Phase III double-blinded controlled trials have provided additional evidence of safety and a favourable impact on exacerbation rates over the 1 year of administration. Unfortunately, the success of natalizumab has been curtailed by three cases of progressive multifocal leukoencephalopathy, which have prompted the manufacturer to voluntary withdraw the drug from the market. An independent review board is currently investigating the safety of the drug to determine whether it should return to the market. The demonstration that selective modulation (blocking) of the adhesion molecule VLA-4 by natalizumab in MS, resembling that observed in experimental disease, represents a major advance in rational therapy.

Animals↗
PubMed2005

Hereditary ataxia and behavior.

Recognizing cognitive deficits and psychiatric disorders in patients with autosomal dominant ataxias is relatively new. At this time, the percentage of patients with these disorders who experience changes in cognition or psychiatric symptoms is unknown. Cognitive impairment, when seen, is often found on tests of executive function, probably reflecting disruption of afferent and efferent pathways of the prefrontal cortex and subcortical structures, including the cerebellum. Widespread global dysfunction does occur in some cases, especially later in the disease course. Psychiatric symptoms including depression, aggression, irritability, and psychosis have all been reported. As these behavioral changes receive further study, one hopes that guidelines for treating these symptoms will emerge. Clinicians should be mindful of the psychosocial effects that genetic testing for the hereditary ataxias may have, especially in cases of predictive testing for those who are asymptomatic but at risk because of family history. Guidelines established for genetic testing in HD may be helpful when approaching these cases.

Behavior↗