Ms. There (ms + there)

Distribution by Scientific Domains

Selected Abstracts

Increased numbers of mononuclear cells from blood and CSF expressing interferon-gamma mRNA in multiple sclerosis are from both the CD4+ and the CD8+ subsets

E. Wallström
Activated, cytokine-producing lymphocytes may regulate central nervous system (CNS) inflammation in multiple sclerosis (MS). We utilize a novel combination of in situ hybridization (ISH) and immunocytochemical staining of peripheral blood lymphocytes (PBLs) to identify spontaneously interferon-gamma (IFN,) mRNA expressing cells as CD4+ or CD8+. A major proportion of the IFN, mRNA expressing lymphocytes belonged to the CD4+ lineage, which concords with the cellular composition of MS brain lesions, findings in experimental models and the HLA class II haplotype association in MS. There were also significantly more CD8+ IFN, mRNA expressing lymphocytes in the MS patients compared with healthy controls, further suggesting the contribution of activated cells from this lineage in the inflammatory response in MS. Both CD4+ and CD8+ IFN, mRNA expressing cells were enriched in the cerebrospinal fluid (CSF) as compared with the peripheral blood of the MS patients. Combined with emerging genetic data on HLA class I influences, our data argues for a joint role of activated CD8+ and CD4+ cells in the pathogenesis of MS. [source]

The challenge of multiple sclerosis: How do we cure a chronic heterogeneous disease?,,

Howard L. Weiner MD
Multiple sclerosis is (MS) a T-cell autoimmune disease characterized by a relapsing-remitting followed by a progressive phase. Relapses are driven by the adaptive immune system and involve waves of T helper cell 1 (Th1), Th17, and CD8 cells that infiltrate the nervous system and provoke a attack. These cells are modulated by regulatory T and B cells. Infiltration of T cells into the nervous system initiates a complex immunological cascade consisting of epitope spreading, which triggers new attacks, and activation of the innate immune system (microglia, dendritic cells, astrocytes, B cells), which leads to chronic inflammation. The secondary progressive phase is due to neurodegeneration triggered by inflammation and is driven by the innate immune system. Why a shift to the progressive stage occurs and how to prevent it is a central question in MS. Effective treatment of MS must affect multiple disease pathways: suppression of proinflammatory T cells, induction of regulatory T cells, altering traffic of cells into the nervous system, protecting axons and myelin, and controlling innate immune responses. Without biomarkers, the clinical and pathological heterogeneity of MS makes treatment difficult. Treatment is further hampered by untoward adverse effects caused by immune suppression. Nonetheless, major progress has been made in the understanding and treatment of MS. There are three definitions of cure as it applies to MS: (1) halt progression of disease, (2) reverse neurological deficits, and (3) prevent MS. Although the pathways to each of these cures are linked, each requires a unique strategy. Ann Neurol 2009;65:239,248 [source]

How to successfully apply animal studies in experimental allergic encephalomyelitis to research on multiple sclerosis

Lawrence Steinman MD
In their Point of View entitled "Experimental Allergic Encephalomyelitis: A Misleading Model of Multiple Sclerosis," Sriram and Steiner1 wrote, "The most disappointing aspect of EAE [experimental allergic encephalomyelitis] as a potential model for MS is its almost total inability to point toward a meaningful therapy or therapeutic approach for MS." Actually, EAE has led directly to the development of three therapies approved for use in multiple sclerosis (MS): glatiramer acetate, mitoxantrone, and natalizumab. Several new approaches to MS are in clinical trials based on positive indications in preclinical work relying on EAE. New clues to the pathogenesis of MS and new potential surrogate markers for MS are shown from research involving EAE when it is critically coupled with actual findings in MS. There are pitfalls in overreliance on the EAE model, or on any animal model for any human disease. Nevertheless, over the past 73 years, the EAE model has proved itself remarkably useful for aiding research on MS. Ann Neurol 2006;60:12,21 [source]


Background: Identification of the responder candidates for multisite pacing is still difficult and severe heart failure, dilated left ventricle with reduced ejection fraction, prolonged QRS with left bundle branch block (LBBB) are still considered the principal indicators of ventricular desynchronization. The aim of the study was to assess if echographic ventricular desynchronization parameters measured in patients with dilated cardiomyopathy and severe heart failure are correlated with the duration of the QRS on surface electrocardiogram. Methods: This study included 51 patients aged 58.8 ± 7.4 years with idiopathic DCM. The following parameters were measured: QRS duration; effective contraction time (ECT) measured as the interval between QRS onset and closure of aortic valve, interventricular delay (IVD) measured as the time between onset of aortic and pulmonary flow, left ventricular mechanical delay (LVD) as the time from maximal interventricular septum contraction and posterior wall contraction, posterior (P), lateral (L), and posterolateral (PL) wall delays, as the time from QRS onset to maximal wall contraction. Regional post-systolic contraction was defined in a given wall as the difference (contraction delay , ECT)> 50 ms. Results: 29 patients presented complete LBBB, 22 patients had QRS duration < 120 ms. 39 patients had a post-systolic contraction of the PL wall (32 patients of the L wall and 26 patients of the P wall). 16 patients with QRS duration <120 had a post-systolic contraction of the PL wall (as for the LBBB the rest of 39 patients). In 40 patients the sequence of regional ventricular contraction was: P-L-PL wall (16 patients with QRS < 120). LVD was > 100 ms in 36 patients (26 patients with LBBB and 10 with QRS < 120). 27 patients with LBBB and 6 with QRS < 120 ms presented IVD > 30 ms. There was no correlation between the QRS duration and the parameters listed above. Conclusions: In a population of patients with severe heart failure and dilated cardiomyopathy there is no correlation between the duration of the QRS and echocardiographic parameters of ventricular desynchronization. These results show that mechanical ventricular desynchronization can be observed in patients with a QRS duration < 120 ms. Further studies are needed to evaluate if this population could beneficiate of multisite pacing therapy. [source]

Melatonin and its analogs potentiate the nifedipine-sensitive high-voltage-activated calcium current in the chick embryonic heart cells

Y.A. Mei
Effects of melatonin and its analogs on the voltage-activated calcium current of embryonic chick ventricular cardiomyocytes were investigated. Myocytes were dissociated from 14- to 16-day-old chicks (yellow Red Rob) embryonic hearts and cultured for 2,3 days. Calcium currents were studied by the patch-clamp technique. Whole-cell current recording showed nifedipine-sensitive, high-voltage-activated L-type calcium current inactivated in 70,100 ms during the voltage step period of 200 ms. There was no evidence of low-voltage-activated T-type calcium channels. Melatonin (ejected solution: 50 ,mol/L melatonin; concentration at the vicinity of recording cell: about 1,5 ,mol/L melatonin) and its analogs, 2-iodomelatonin and 2-iodo-n-butanol-5-methoxytryptamine, significantly increased the amplitude of the calcium current by 42,62%. The effect of melatonin on the L-type calcium current was not desensitised by repeated melatonin treatment. Our results suggest a specific melatonin receptor-mediated action on the calcium channel of the embryonic chick myocyte. The melatonin-induced increase in high-voltage calcium current may increase myocyte contractility and enhance cardiac output. A regulatory role of melatonin on the chick cardiac function should be further considered. [source]

Interhemispheric interaction between human dorsal premotor and contralateral primary motor cortex

Hitoshi Mochizuki
We used transcranial magnetic stimulation (TMS) in a paired pulse protocol to investigate interhemispheric interactions between the right dorsal premotor (dPM) and left primary motor cortex (M1) using interstimulus intervals of 4, 6, 8, 10, 12, 16 and 20 ms in ten healthy subjects. A conditioning stimulus over right dPM at an intensity of either 90 or 110% resting motor threshold (RMT) suppressed motor-evoked potentials (MEPs) evoked in the first dorsal interosseous (FDI) muscle by stimulation of left M1. Maximum effects occurred for interstimulus intervals (ISIs) of 8,10 ms. There was no effect if the conditioning stimulus was applied 2.5 cm lateral, anterior or medial to dPM. The effect differed from previously described M1 interhemispheric inhibition in that the threshold for the latter was greater than 90% RMT, whereas stimulation of the dPM at the same intensity led to significant inhibition. In addition, voluntary contraction of the left FDI (i.e. contralateral to the conditioning TMS) enhanced interhemispheric inhibition from right M1 but had no effect on the inhibition from right dPM. Finally, conditioning to right dPM at 90% RMT reduced short-interval intracortical inhibition (SICI; at ISI = 2 ms) in left M1 whilst there was no effect if the conditioning stimulus was applied to right M1. We conclude that conditioning TMS over dPM has effects that differ from the previous pattern of interhemispheric inhibition described between bilateral M1s. This may reflect the existence of commissural fibres between dPM and contralateral M1 that may play a role in bimanual coordination. [source]

Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects

John D. Davis
AIMS To assess the effect of a single dose of maraviroc on the QTc interval in healthy subjects and to evaluate the QTc interval,concentration relationship. METHODS A single-dose, placebo- and active-controlled, five-way crossover study was conducted to investigate the effects of maraviroc (100, 300, 900 mg) on QTc in healthy subjects. Moxifloxacin (400 mg) was used as the active comparator. The study was double-blind with respect to maraviroc/placebo and open label for moxifloxacin. There was a 7-day wash-out period between each dose. QT interval measurements obtained directly from the electrocardiogram (ECG) recorder were corrected for heart rate using Fridericia's correction (QTcF). A placebo run-in day was conducted before period 3, when ECGs were collected at intervals while subjects were resting or during exercise. These ECGs plus other predose ECGs were used to evaluate the QT/RR relationship for each subject to enable calculation of an individual's heart rate correction for their QT measurements (QTcI). ECGs were taken at various intervals pre- and postdose in each study period. Pharmacokinetic parameters were determined for each maraviroc dose. The end-points that were evaluated were QTcF at median time to maximum concentration (Tmax) based on the machine readings and QTcI at median Tmax based on manual over-reads of the QT/RR data. A separate analysis of variance was used for each of the pair-wise comparisons for each end-point. The relationship between QTc interval and plasma concentration was also investigated using a mixed-effects modelling approach, as implemented by the NONMEM software system. A one-stage model was employed in which the relationship between QT and RR and the effects of maraviroc plasma concentration on QT were estimated simultaneously. RESULTS The mean difference from placebo in machine-read QTcF at median Tmax for maraviroc 900 mg was 3.6 ms [90% confidence interval (CI) 1.5, 5.8]. For the active comparator, moxifloxacin, the mean difference from placebo in machine-read QTcF was 13.7 ms. The changes from placebo for each of the end-points were similar for men and women. No subjects receiving maraviroc or placebo had a QTcF ,,450 ms (men) or QTcF ,,470 ms (women), nor did any subject experience a QTcF increase ,,60 ms from baseline at any time point. Analysis based on the QTcI data obtained from the manual over-readings of the ECGs gave numerically very similar results. The QT:RR relationship was similar pre- and postdose and was not related to maraviroc concentration. The population estimate of the QT:RR correction factor was 0.324 (95% CI 0.309, 0.338). The population estimate of the slope describing the QT,concentration relationship was 0.97 ,s ml ng,1 (95% CI ,0.571, 2.48), equivalent to an increase of 0.97 ms in QT per 1000 ng maraviroc plasma concentration. Most adverse events were mild to moderate in severity. CONCLUSIONS Single doses of maraviroc, up to and including 900 mg, had no clinically relevant effect on QTcF or QTcI. At all maraviroc doses and for both end-points, the mean difference from placebo for QTc was <4 ms. There was no apparent relationship between QT interval and maraviroc plasma concentration up to 2363 ng ml,1. This conclusion held in both male and female subjects, and there was no evidence of a change in the QT/RR relationship with concentration. [source]