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ABSTRACT: This pilot study used immunohistochemical techniques to investigate the advanced glycation end-product (AGE) Nepsilon-(carboxymethyl)lysine (CML) and its receptor (RAGE) in the brains of multiple sclerosis (MS) patients, comparing them with the brains of patients with Alzheimer's disease (AD) (positive controls) and with age-matched control subjects (negative controls). Postmortem slides derived from the hippocampi of MS patients, AD patients, and controls were stained with monoclonal antibodies for CML and human RAGE. Results showed increased AGE and RAGE immunostaining in the hippocampi of MS patients, similar to AD patients.
Immunological Investigations 11/2010; 40(2):197-205. · 1.47 Impact Factor
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ABSTRACT: Cognitive dysfunction is common in multiple sclerosis (MS), yet the magnitude of change on objective neuropsychological (NP) tests that is clinically meaningful is unclear. We endeavored to determine NP markers of the transition from employment to work disability in MS, as indicated by degree of decline on individual tests. Participants were 97 employed MS patients followed over 41.3 ± 17.6 months with a NP battery covering six domains of cognitive function. Deterioration at follow-up was designated as documented and paid disability benefits (conservative definition) or a reduction in hours/work responsibilities (liberal definition). Using the conservative definition, 28.9% reported deteriorated employment status and for the liberal definition, 45.4%. The Symbol Digit Modalities Test (SDMT) and California Verbal Learning Test, Total Learning (CVLT2-TL) measures distinguished employed and disabled patients at follow-up. Controlling for demographic and MS characteristics, the odds ratio of a deterioration based on a change of 2.0 on the CVLT2-TL was 3.7 (95% CI 1.2-11.4 and SDMT by 4.0 was 4.2 (95% CI 1.2-14.8), accounting for 86.7% of the area under the ROC curve. We conclude that decline on NP testing over time is predictive of deterioration in vocational status, establishing a magnitude of decline on NP tests that is clinically meaningful.
The Clinical Neuropsychologist 10/2010; 24(7):1131-45. · 2.12 Impact Factor
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ABSTRACT: This study compared the level of advanced glycation end products (AGEs), N-(Carboxymethyl)lysine (CML) and N-(Carboxyethyl)lysine (CEL), in patients with multiple sclerosis (MS) and healthy controls (HCs), correlating these markers with clinical indicators of MS disease severity.
CML and CEL plasma levels were analyzed in 99 MS patients and 43 HCs by tandem mass spectrometry (LC/MS/MS). Patients were stratified based on drug modifying therapies (DMTs) including interferon beta, glatiramer acetate and natalizumab.
The level of plasma CEL, but not CML, was significantly higher in DMT-naïve MS patients when compared to HCs (P < 0.001). Among MS patients, 91% had higher than mean plasma CEL observed in HCs. DMTs reduced CML and CEL plasma levels by approximately 13% and 40% respectively. CML and CEL plasma levels correlated with the rate of MS clinical relapse.
Our results suggest that AGEs in general and CEL in particular could be useful biomarkers in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma level of AGEs and MS disease pathology. These studies will pave the way for use of AGE inhibitors and AGE-breaking agents as new therapeutic modalities in MS.
Journal of Neuroinflammation 10/2010; 7:72. · 3.83 Impact Factor
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ABSTRACT: The chronic inflammation associated with multiple sclerosis (MS) may lead to the upregulation of pentosidine.
This cross-sectional study compares plasma pentosidine levels among healthy controls (HCs) and patients with MS at different disease stages. The study also determines pentosidine's usefulness as a biomarker of MS disease activity and/or severity via its correlation with a number of indicators of MS disease.
Pentosidine levels were analyzed in 98 MS patients and 43 HCs using reverse-phase high-pressure liquid chromatography with fluorescence detection.
Plasma pentosidine levels were significantly higher in MS patients when compared with HCs (p = 0.02). Patients on disease-modifying therapies (DMTs) had lower plasma pentosidine levels when compared with DMT-naïve patients (p = 0.01). Pentosidine plasma levels correlated with indicators of MS disease severity, including Extended Disability Status Scale (p = 0.03), MS Severity Scale (p = 0.01), and MS Functional Composite (p = 0.03). No correlation between pentosidine levels and age, rate of clinical relapse, and disease duration was observed.
Our results suggest that pentosidine could be a novel, inflammatory biomarker in MS clinical practice. Longitudinal studies are warranted to determine any causal relationship between changes in plasma pentosidine levels and MS disease pathology. These studies may pave the way for use of advanced glycation end product (AGE) inhibitors and AGE-breaking agents as new therapeutic modalities in MS.
Multiple Sclerosis 10/2010; 17(2):157-63. · 4.26 Impact Factor
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ABSTRACT: The study is aimed to determine the role of luteolin (3',4',5,7-tetrahydroxyflavone), alone and in combination with human interferon-beta (IFN-beta), in modulating the immune response(s) of peripheral blood mononuclear cells (PBMCs) isolated from multiple sclerosis (MS) patients. PBMC proliferation in the presence or absence of these drugs was determined and the production of pro-inflammatory cytokines (IL-1beta, TNF-alpha), and the ratio of cell migration mediator MMP-9, and its inhibitor, TIMP-1 was assessed in the culture supernatants. Luteolin reduced, in a dose-dependent manner, the proliferation of PBMCs, and modulated the levels of IL-1beta and TNF-alpha released by PBMCs in the culture supernatants. Luteolin reduced the MMP-9/TIMP-1 ratio via lowering MMP-9 production. In the majority of cases, luteolin, when combined with IFN-beta, had additive effects in modulating cell proliferation, IL-1beta, TNF-alpha, MMP-9 and TIMP-1.
Journal of Neuroinflammation 10/2009; 6:28. · 3.83 Impact Factor
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Milena Stosic,
Julian Ambrus,
Neeta Garg,
Bianca Weinstock-Guttman,
Murali Ramanathan,
Bernadette Kalman,
Alireza Minagar, Frederick E Munschauer,
Timothy M Galey,
Sara Hussein,
Rohit Bakshi,
Robert Zivadinov
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ABSTRACT: MRI findings of primary anti-phospholipid antibody syndrome (PAPLS) are difficult to distinguish from those of multiple sclerosis (MS). Only a few previous studies have compared conventional and non-conventional MRI findings in MS and PAPLS patients. In addition, MRI differences between anti-phospholipid antibody (APLA) positive (+) and APLA negative (-) MS patients have not been reported. Therefore, the aim of this study was to investigate the differences in MRI measures among patients with PAPLS, MS and normal control (NC) subjects. We also explored non-conventional MRI measures in APLA+ and APLA- MS patients. Forty-nine (49) consecutive MS patients among whom 39 had relapsing-remitting (RR) and 10 secondary-progressive (SP) disease course, 30 patients with PAPLS and 49 NC were enrolled. Twenty-eight (28) MS patients were APLA+. MRI measures of T1- and T2-lesion volumes (LV) and brain atrophy, including fractions of whole brain (BPF), gray matter (GMF) and white matter (WMF), were evaluated. The magnetization transfer ratio (MTR) of T2- and T1-LVs and different normal-appearing brain tissue (NABT) compartments as well as diffusion-weighted imaging of whole brain mean parenchyma diffusivity (MPD) were obtained. MS patients differed significantly from NC in all MRI measures. PAPLS patients differed from NC in their T2-LV, in MTR measures and in MPD. When MS patients were compared to PAPLS patients, they showed significantly higher T2- and T1-LVs and T2-LV MTR, lower BPF and GMF and higher MPD. APLA+ RR and SPMS (all APLA+) patients showed significantly higher T2-LV, lower GMF, lower normal-appearing gray matter MTR and higher MPD when compared to APLA- patients. The results indicate that brain abnormalities can be detected in PAPLS patients with non-conventional MRI. MRI reveals more profound injury in patients with MS versus PAPLS. APLA mediates heterogeneous cerebral pathology that remains to be further investigated.
Journal of Neurology 08/2009; 257(1):63-71. · 3.47 Impact Factor
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ABSTRACT: Defects in processing speed and memory are common in multiple sclerosis (MS) patients. In other populations, amphetamines have been shown to enhance cognition, but their use is limited by adverse behavioral effects. The L-isomer may have equivalent cognition enhancement with less adverse effects due to decreased potency in subcortical areas. The aim of this study was to assess the safety and efficacy of L-amphetamine sulfate in the treatment of cognitive dysfunction in MS. This was a 2:1 randomized, placebo-controlled, double-blind trial, involving 33 MS clinics across the USA. One hundred and fifty-one clinically definite MS patients with documented cognitive dysfunction who were relapse free for >or=90 days, with an Expanded Disability Status Scale (EDSS) <or=6.5, and with no other medical/psychiatric condition that may cause psychological dysfunction were randomized to 30 mg of oral L-amphetamine sulfate or placebo for 29 days, including a dose escalation period. A history of cardiac disease, uncontrolled hypertension or electrocardiograph abnormalities resulted in exclusion. The primary outcomes were the Subject Global Assessment of Change and Symbol Digit Modalities Test (SDMT). Secondary outcomes were the results from the California Verbal Learning Test, second edition (CVLT2), Brief Visual Memory Test-Revised (BVMTR), and Paced Auditory Serial Addition Test (PASAT). One hundred and thirty-six subjects completed the study. No differences were found at baseline in demographics or in the results of the neuropsychological tests. After treatment, the active group performed significantly better for total learning (P = 0.041) and delayed recall (P < 0.01) on the BVMTR, and for delayed recall (P = 0.012) on the CVLT2. Five patients (four from the treatment group, one placebo) withdrew due to intolerable adverse events. L-amphetamine sulfate was associated with improved learning and memory and was well tolerated in this study. However, because the positive findings were observed on secondary outcome measures, the study requires replication before L: -amphetamine sulfate can be recommended for the treatment of cognitive impairment in MS.
Journal of Neurology 03/2009; 256(7):1095-102. · 3.47 Impact Factor
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ABSTRACT: Abstract
The study is aimed to determine the role of luteolin (3',4',5,7-tetrahydroxyflavone), alone and in combination with human interferon-beta (IFN-β), in modulating the immune response(s) of peripheral blood mononuclear cells (PBMCs) isolated from multiple sclerosis (MS) patients. PBMC proliferation in the presence or absence of these drugs was determined and the production of pro-inflammatory cytokines (IL-1β, TNF-α), and the ratio of cell migration mediator MMP-9, and its inhibitor, TIMP-1 was assessed in the culture supernatants. Luteolin reduced, in a dose-dependent manner, the proliferation of PBMCs, and modulated the levels of IL-1β and TNF-α released by PBMCs in the culture supernatants. Luteolin reduced the MMP-9/TIMP-1 ratio via lowering MMP-9 production. In the majority of cases, luteolin, when combined with IFN-β, had additive effects in modulating cell proliferation, IL-1β, TNF-α, MMP-9 and TIMP-1.
Journal of Neuroinflammation. 01/2009;
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ABSTRACT: The study is aimed to determine the role of quercetin (3,3'4',5,7-pentahydroxy flavone), alone and in combination with human interferon-beta (IFN-beta), in modulating the immune response(s) of peripheral blood mononuclear cells (PBMC) isolated from multiple sclerosis (MS) patients and from normal healthy subjects. PBMC proliferation in the presence or absence of these drugs was determined and the production of proinflammatory cytokines (IL-1beta, TNF-alpha), and the ratio of cell migration mediator MMP-9, and its inhibitor, TIMP-1 were assessed in the culture supernatants. Quercetin reduced, in a dose-dependent manner, the proliferation of PBMC and modulated the level of IL-1beta and TNF-alpha released by PBMC in the culture supernatants. Quercetin reduced the MMP-9/TIMP-1 ratio via lowering MMP-9 production. Quercetin, when combined with IFN-beta, had additive effects in modulating TNF-alpha and MMP-9. These immunomodulatory responses to quercetin were similar between MS patients and healthy control (HC) subjects.
Journal of Neuroimmunology 11/2008; 205(1-2):142-7. · 2.96 Impact Factor
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ABSTRACT: To characterize gene expression in multiple sclerosis (MS) patients after the first dose and chronic dosing of 30 microg, once weekly, intramuscular interferon-beta1a (IFN-beta) and to delineate the pharmacogenomic differences between Good Responders and Partial Responders to IFN-beta therapy.
The treatment responses after the first IFN-beta dose and chronic IFN-beta dosing were assessed in 22 relapsing MS patients (17 females, 5 males; average age: 41.5+/-SD 10.4 years). Gene expression profiles in peripheral blood mononuclear cells were obtained prior to treatment and at 1, 2, 4, 8, 24, 48, 120, 168 h after the first IFN-beta dose and at 1, 6 and 12 months after chronic dosing with once-weekly 30 microg IFN-beta-1a intramuscularly. Repeated measures statistics with false discovery rate control were used. The functional characteristics, biological pathways and transcription factor sites were analyzed.
Of the 1000 genes modulated following the first dose and upon chronic dosing of IFN-beta in MS patients, approximately 35% were up-regulated and 65% were down- regulated; the percentage of modulated genes in common was approximately 50%. The expression of the pharmacodynamic mRNA markers of IFN-beta effect showed differences in time profiles for the Good Responder and Partial Responders to IFN-beta therapy and the Jak-STAT, TNFRSF10B, IL6, TGFbeta, retinoic acid and CDC42 pathways were differentially modulated. The patients with side effects to therapy showed differences in the TGFbeta1, IFNG/STAT3 and TNF pathways.
Gene expression is a valuable tool for understanding the molecular mechanisms of IFN-beta action in MS patients.
Journal of Neuroimmunology 11/2008; 205(1-2):113-25. · 2.96 Impact Factor
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ABSTRACT: MRI research in multiple sclerosis (MS) samples reveals pathology in both the cerebral cortex and deep grey matter (DGM). The classical subcortical dementia hypothesis has been ascribed to MS and is supported by studies highlighting the role of thalamic atrophy in neuropsychological outcomes. However, the importance of mesial temporal lobe (MTL) atrophy in MS is largely untested and poorly understood. New structural imaging techniques permit volumetric measures of multiple regions within the MTL lobe and DGM.
To determine the relative importance of MTL and DGM structures in predicting MS performance on memory tests presented in the auditory/verbal and visual/spatial spheres.
Cross sectional analysis of 50 patients with MS undergoing structural brain MRI and neuropsychological testing. Using Freesurfer software, the volumes of the MTL (hippocampus, amygdala) and DGM (thalamus, caudate) structures were calculated and compared with control values. Neuropsychological testing contributed measures of new learning, delayed recall and recognition memory, in the auditory/verbal and visual/spatial memory modalities.
Significant correlations between lower regional volume and poorer test performance were observed across all memory tests. For measures of free recall or new learning, DGM volumes were most strongly predictive of outcomes. In contrast, measures of recognition memory were predicted only by MTL volumetric measures.
For the first time, the predictive validity of MTL and DGM atrophy were simultaneously compared with MS using reliable and validated neuropsychological measures. This study found that both compartments play significant but different roles in the amnesia of MS.
Journal of neurology, neurosurgery, and psychiatry 11/2008; 80(2):201-6. · 4.87 Impact Factor
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Robert Zivadinov,
Niels Bergsland,
Milena Stosic,
Jitendra Sharma,
Fernando Nussenbaum,
Jacqueline Durfee,
Nima Hani,
Nadir Abdelrahman,
Zeenat Jaisani,
Alireza Minagar,
Romy Hoque, Frederick Munschauer,
Michael Dwyer
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ABSTRACT: Objective: To investigate differences in lesions and surrounding normal appearing white matter (NAWM) by perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) in patients with acute and chronic ischemic stroke and multiple sclerosis (MS).Methods: Study subjects included 45 MS patients, 22 patients with acute ischemic stroke and 20 patients with chronic ischemic stroke. All subjects underwent T2-weighted imaging (WI), flair attenuated inversion recovery (FLAIR), DWI and dynamic contrast enhanced PWI. Apparent diffusion coefficient (ADC) and mean transit time (MTT) maps were generated and values were calculated in the acute and chronic ischemic and demyelinating lesions, and in NAWM for distances of 5, 10 and 15 mm. Fifty-three acute ischemic and 33 acute demyelinating lesions, and 775 chronic ischemic and 998 chronic demyelinating lesions, were examined. Univariate, multivariate and data mining analyses were used to examine the feasibility of a prediction model between different lesion types. Correctly and incorrectly classified lesions, true positive (TP), false positive (FP) and precision rates were calculated.Results: Patients with acute ischemic lesions presented more prolonged mean MTT values in lesions (p=0.002) and surrounding NAWM for distances of 5, 10 and 15 mm (all p
Neurological Research 09/2008; 30(8):816-826. · 1.52 Impact Factor
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Ayda Tekok-Kilic,
Ralph H B Benedict,
Bianca Weinstock-Guttman,
Michael G Dwyer,
Dominic Carone,
Bhooma Srinivasaraghavan,
Viritha Yella,
Nadir Abdelrahman, Frederick Munschauer,
Rohit Bakshi,
Robert Zivadinov
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ABSTRACT: The primary goal of this study was to investigate associations between regional gray matter (GM) atrophy and neuropsychological function in multiple sclerosis (MS), while accounting for the influence of central brain atrophy (i.e. third ventricle enlargement). Using a cross-sectional design, we studied 59 MS patients with brain MRI and neuropsychological testing. Regional gray matter fractions (rGMFs) were calculated from MRI images for 11 homologous brain areas using the semiautomatic brain region extraction (SABRE) technique. Neuropsychological testing followed consensus panel guidelines and included tests emphasizing episodic memory, working memory and processing speed. The analytic approach was stepwise linear regression, with forward selection and p<0.05 threshold for significance. Consistent with previous research, there were significant correlations between third ventricle width and neuropsychological tests. Stepwise linear regression analyses controlling for third ventricle width retained rGMFs obtained from specific regions within the prefrontal cortex. Left frontal atrophy was associated with tests emphasizing auditory/verbal memory. Right frontal atrophy was associated with impairment in visual episodic and working memory. For the first time, we show an independent relationship between cortical atrophy and cognitive impairment after accounting for the effects of central atrophy.
NeuroImage 08/2007; 36(4):1294-300. · 5.89 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a disease of the central nervous system that causes cognitive impairment with a frequency of roughly 50%. While processing speed and memory defects are most commonly observed, a substantial number of patients also have deficiency in higher executive ability. Two tests, the Wisconsin Card Sorting Test (WCST) and the Sorting Test from the Delis-Kaplan Executive Function System (DKEFS), have been recommended for evaluation of neuropsychological impairment in MS. We investigated the validity of these tests in 111 MS patients and 46 age- and education-matched controls. MS patients performed more poorly on both measures, but only the DKEFS discriminated the groups after controlling for depression. Both tests were modestly or strongly correlated with MRI indices of brain atrophy or lesion burden and discriminated between employed and disabled patients. While both tests appear to have good validity in the MS population, the availability of alternative forms makes the DKEFS an attractive alternative to the WCST, as was suggested by a consensus panel.
Journal of Clinical and Experimental Neuropsychology 03/2007; 29(2):215-23. · 2.13 Impact Factor
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Kailash Chadha,
Bianca Weinstock-Guttman,
Robert Zivadinov,
Kavitha Bhasi,
Jason Muhitch,
Joan Feichter,
Miriam Tamaño-Blanco,
Nadir Abdelrahman,
Julian Ambrus, Frederick Munschauer,
Murali Ramanathan
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ABSTRACT: Interferon inhibitory activity (IIA) is a logical candidate for explaining neutralizing antibody-negative partial responsiveness to interferon beta in multiple sclerosis (MS), but its role has not been evaluated.
To investigate the role of IIA and soluble interferon-alpha/beta receptor (sIFNR) in determining response of patients with MS to interferon beta therapy.
Parallel-group, open-label study.
Baird Multiple Sclerosis Center, Buffalo, NY. Patients Blood was obtained before and 24 hours after injection of interferon beta-1a from 38 anti-interferon beta neutralizing antibody-negative patients with relapsing-remitting MS and 16 untreated healthy controls. On the basis of clinical parameters of response to interferon beta therapy, the patients were divided into stable or good-responder (n = 20) and active or partial-responder (n = 18) groups.
Quantitative analyses of magnetic resonance imaging were obtained; the IIA and sIFNR levels were measured using bioassay and enzyme-linked immunosorbent assay, respectively.
The IIA and sIFNR levels were elevated in MS patients compared with controls (P<.001). The IIA levels were higher in active or partial responders compared with stable or good responders (P<.001); the sIFNR levels were not different between groups. The Extended Disability Status Score and T2 lesion volumes were higher in the active or partial-responder group compared with the stable or good-responder group. Interferon beta-1a did not have short-term effects on the IIA and sIFNR levels. In univariate general linear model and stepwise regression analyses, IIA levels were associated with T2 lesion volume.
The levels of IIA are associated with increased MS disease activity and with responsiveness to interferon beta therapy in anti-interferon beta neutralizing antibody-negative MS patients.
Archives of Neurology 12/2006; 63(11):1579-84. · 7.58 Impact Factor
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ABSTRACT: Cognitive dysfunction is common in multiple sclerosis (MS). Correlations are reported between atrophy and neuropsychological test results.
To determine if neocortical volume would supplant or supplement third ventricular width and other magnetic resonance imaging measures when predicting neuropsychological impairment.
Cross-sectional study.
University MS clinic.
Seventy-seven patients with relapsing-remitting MS, 42 patients with secondary progressive MS, and 27 healthy control subjects.
Brain atrophy and lesion burden measures were obtained in all patients. A subset of 82 patients and all controls underwent neuropsychological testing.
Patients with secondary progressive MS had more atrophy than patients with relapsing-remitting MS and controls. Neocortical volume was significantly correlated with all neuropsychological measures, with r values ranging from 0.29 to 0.58. Third ventricular width was retained in most stepwise regression analyses predicting cognitive impairment in patients with MS and distinguishing secondary progressive from relapsing-remitting courses of MS.
We confirm an association between neocortical volume and multiple cognitive domains in MS, although neocortical volume did not explain significantly more variance than other magnetic resonance imaging measures. Of the magnetic resonance imaging variables studied, third ventricular width was retained in most regression models.
Archives of Neurology 10/2006; 63(9):1301-6. · 7.58 Impact Factor
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ABSTRACT: Cognitive impairment occurs in roughly 50% of patients with multiple sclerosis (MS). It is well known that processing speed and episodic memory deficits are the most common neuropsychological (NP) sequelae in this illness. Consensus has emerged about the specific tests that prove most helpful for routine monitoring of MS associated cognitive impairment. The purpose of this study was to examine the validity of the Minimal Assessment of Cognitive Function in MS (MACFIMS), a recommended battery based on the findings of an international conference held in 2001. We tested 291 MS patients and 56 healthy controls. Frequencies of impairment paralleled those reported in previous work for both individual cognitive domains and general impairment. All tests were impaired in the MS group, and distinguished relapsing-remitting (RR) from secondary progressive (SP) course. Principle components analysis showed a distinct episodic memory component. Most of the MACFIMS tests discriminated disabled from employed patients. However, in regression models accounting for all NP tests, those emphasizing verbal memory and executive function were most predictive of vocational status. We conclude that the MACFIMS is a valid approach to routine NP assessment of MS patients. Future work is planned to determine its psychometric properties in a longitudinal study.
Journal of the International Neuropsychological Society 08/2006; 12(4):549-58. · 2.76 Impact Factor
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ABSTRACT: The objective of this study was to evaluate multiple interferon (IFN) specific mRNA biomarkers in multiple sclerosis (MS) patients with anti-IFN-beta neutralizing antibodies (NAB) using a pharmacodynamic study design. Thirty patients were enrolled. Blood samples were drawn at pre-treatment, 4-, 8-h time points following the intramuscular dose of IFN-beta-1a. Total RNA was obtained from peripheral blood cells, processed to cDNA and analyzed using quantitative real-time polymerase chain reaction. Pre-treatment serum samples were analyzed for anti-IFN-beta binding and neutralizing antibodies: 22 patients were NAB negative; equal numbers of the eight remaining patients were either NAB positive or had borderline NAB status. The results showed that early assessment (at 4 h after IFN-beta injection) of mRNAs for Stat-1, MxA, MxB and TRAIL was more sensitive than the later measurements. Furthermore, the NAB positive patients had strongly attenuated gene expression responses on all the mRNAs. Patients with borderline NAB had average responses that appear to be lower than NAB negative patients on several genes, notably Stat-1, TRAIL and beta2 microglobulin.
Journal of Neuroimmunology 08/2006; 176(1-2):125-33. · 2.96 Impact Factor
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ABSTRACT: Hyperglycemia is associated with increased mortality and morbidity in acute ischemic stroke.
Hyperglycemia induces a pro-oxidative and proinflammatory state that can cause direct neuronal toxicity. Hyperglycemia-mediated increase in matrix metalloproteinase-9 can cause neuronal damage by an increase in cerebral edema. Moreover, hyperglycemia may be responsible for a procoagulant state that can further compromise blood supply to the penumbral areas in acute ischemic stroke. Insulin infusion has an effect that is opposite to that of hyperglycemia. It not only lowers blood glucose levels but also exerts an antioxidant and anti-inflammatory effect. Insulin also improves NO production and results in improved blood circulation to the ischemic areas. This article focuses on the potential mechanisms underlying the injurious effects of glucose and the beneficial effects of insulin.
In the absence of other potential beneficial therapies, there is an urgency to institute trials with insulin infusion in acute ischemic stroke.
Stroke 02/2006; 37(1):267-73. · 5.73 Impact Factor
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Bianca Weinstock-Guttman,
Monika Baier,
Youngmin Park,
Joan Feichter,
Peterkin Lee-Kwen,
Eileen Gallagher,
Jaya Venkatraman,
Kulwara Meksawan,
Suzanne Deinehert,
David Pendergast,
Atif B Awad,
Murali Ramanathan, Frederick Munschauer,
Richard Rudick
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ABSTRACT: OBJECTIVES: To determine whether a low fat diet supplemented with omega-3 positively affects quality of life (QOL) in relapsing-remitting MS (RRMS) patients. In this 1-year long double-blind, randomized trial, patients were randomized to two dietary interventions: the "Fish Oil" (FO) group received a low fat diet (15% fat) with omega-3 FOs and the "Olive Oil" (OO) group received the AHA Step I diet (fat 30%) with OO supplements. The primary outcome measure was the Physical Components Summary Scale (PCS) of the Short Health Status Questionnaire (SF-36). Additional measures using MS specific QOL questionnaires, neurological status and relapse rate were obtained. RESULTS: 31 RRMS patients were enrolled, with mean follow up over 11 +/- SD 2.9 months. Clinical benefits favoring the FO group were observed on PCS/SF-36 (P = 0.050) and MHI (P = 0.050) at 6 months. Reduced fatigue was seen on the OO diet at 6 months (P = 0.035). The relapse rate decreased in both groups relative to the rates during the 1 year preceding the study: mean change in relapse rate in the FO group: -0.79 +/- SD 1.12 relapses/year (P = 0.021) vs. -0.69 +/- SD 1.11 (P = 0.044) in the OO group. This study suggests that a low fat diet supplemented with omega-3 PUFA can have moderate benefits in RRMS patients on concurrent disease modifying therapies.
Prostaglandins Leukotrienes and Essential Fatty Acids 12/2005; 73(5):397-404. · 3.37 Impact Factor
