Clinicians treating multiple sclerosis (MS) patients need biomarkers in order to predict an individualized prognosis for every patient, that is, characteristics that can be measured in an objective manner, and that give information over normal or pathological processes, or about the response to a given therapeutic intervention. Pharmacogenetics/Genomics in the fields of MS by now can be considered a promise. In the meanwhile, clinicians should use the information provided by the many clinical epidemiological studies performed by now, telling us that there are some clinical markers of good prognosis (female sex, young age of onset, optic neuritis or isolated sensory symptoms at debut, long interval between initial and second relapse, no accumulation of disability after five years of disease evolution, normal or near normal magnetic resonance imaging (MRI) at onset). Some markers in biological samples are considered as potential prognostic markers like IgM and neurofilaments in CSF or antimyelin and chitinase 3-like 1 in blood (plasma/sera). Baseline MRI lesion number, lesion load and location have been closely associated with a worse evolution, as well as MRI measures related to axonal damage (black holes in T1, brain atrophy, grey matter atrophy (GMA) and white matter atrophy (WMA), magnetization transfer measures and intracortical lesions). Functional measures (OCT, evoked potentials) have a potential role in measuring neurodegeneration in MS and could be very useful tools for prognosis. Several mathematical approaches to estimate the risk of short term use early clinical and paraclinical biomarkers to predict the evolution of the disease.

Synaptic plasticity is important for functional recovery after cerebral ischemic injury. In the present study, we investigated chronological change in the immunoreactivity of PSD-95, a kind of postsynaptic density protein, in the hippocampus proper (CA1-3 regions) after 5min of transient cerebral ischemia in gerbils. PSD-95 immunoreactivity was observed in MAP-2-immunoreactive dendrites in the CA1-3 regions of the sham group. The PSD-95 immunoreactivity was shown as beaded structure in the MAP-2-immunoreactive dendrites. However, PSD-95 immunoreactivity began to be dramatically decreased in MAP-2-immunoreactive dendrites in the CA1 region, not CA2-3 region, at early time after ischemia-reperfusion. At 5days after ischemia-reperfusion, MAP-2 immunoreactivity almost disappeared in the ischemic CA1 region, and PSD-95 immunoreactivity was much lower than that in the sham group. In brief, PSD-95 immunoreactivity in the CA1 dendrites was markedly decreased at early time after ischemia-reperfusion. We suggest that decreased PSD-95 immunoreactivity in the ischemic CA1 region may lead to a deficit of postsynaptic plasticity in the brain.

Recently, increasing studies have been focused on the association between the p22phox gene C242T polymorphism and ischemic stroke (IS). However, the results were controversial. As far as we know, there is no previous systematic review or meta-analysis concerning this association. Thus, we conducted this meta-analysis to evaluate this association. The strength of association was evaluated by the odds ratio (OR) with the corresponding 95% confidence intervals (CIs). Heterogeneity was assessed by Q-test and the I(2) statistic. Publication bias was tested using funnel plots and Egger's regression test. Cumulative meta-analysis was performed to assess the trend in pooled OR over time. There was no significant association of the p22phox gene C242T polymorphism with IS in the overall analysis and subgroup analysis by ethnicity and subtypes of IS. However, statistical significance was found in the dominant model (OR: 1.57, 95%CI: 1.18-2.09), codominant model (OR: 1.62, 95%CI: 1.20-2.17) and allelic model (OR: 1.44, 95%CI: 1.11-1.87) among the hospital-based studies. The cumulative meta-analysis also suggested no trend of association between this polymorphism and IS from 2007 to 2011 as more data accumulated over time. Our meta-analysis indicated that the p22phox gene C242T polymorphism is unrelated to the risk of IS in the overall analysis and subgroup analysis by ethnicity and subtypes of IS. However, statistical significance was found in the subgroup analysis by source of controls among the hospital-based studies.

Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, motor developmental delay, ataxia, and progressive spasticity. The gap junction protein gamma-2 gene (GJC2), encoding the gap junction protein connexin 47, is one of the genes responsible for this condition. In this study, a novel homozygous mutation in GJC2 (c.746C>G; p.P249R) was identified in a 21-year-old female patient with PMLD. Although her mother was a carrier of this mutation, the Mendelian inheritance pattern could not be determined because the paternal sample was unavailable. Alternatively, chromosomal microarray testing together with single nucleotide polymorphism typing (CGH+SNP) was performed to determine the gene copy number and analyze the haplotype in the 1q42.13 region in which GJC2 is located. The result showed no deletion, but the GJC2 region was involved in the loss-of-heterozygosity region. Furthermore, haplotype of chromosome 1, in which GJC2 is located, revealed that both copies of chromosome 1 were derived from the patient's mother, indicating maternal uniparental disomy of chromosome 1. This study showed the advantage of the SNP genotyping microarray for detecting the origin of the mutation.

OBJECTIVE:

To investigate in a single-center randomized control trial whether a single IVIg course improves short-term outcome in patients with postpolio syndrome (PPS).

METHODS:

Fifty-one patients with PPS were randomly allocated to receive 2g/kg IVIg body weight or placebo infused over 5 consecutive days. The primary endpoint was health-related quality of life (HRQoL) limited to the physical component score (PCS) in the Short-Form-36 (SF-36). Secondary endpoints included the SF-36 mental component score (MCS), 6-minute walk test, visual analog scale, 101-numeric rating, and fatigue severity scale. Muscle strength was graded according to the Medical Research Council scale and by dynamometer. Primary and secondary outcome variables were tested double-blind at baseline, 2months, and 4months.

RESULTS:

At two months, although SF-36 PCS scores were similar in both arms, the role physical (RP) domain improved significantly in the treatment arm (p=0.05) and so did the composite MCS (p=0.015), and role emotional (RE) subscale (p=0.02). No differences were found in the remaining outcome measures. At 4months, none of the outcome variables differed significantly between groups.

CONCLUSIONS:

Although the study did not reach the primary endpoint, we showed that a single IVIg course improves HRQoL related to mental activity, as measured by the SF-36 composite MCS, and role limitations including RP and RE SF-36 subscales at 2months, in patients with PPS. A single IVIg course leaves, gait, muscle strength, fatigue and bodily pain unchanged in patients with PPS. CLASSIFICATION OF

EVIDENCE:

Class I evidence indicates that IVIg did not change SF-36 PCS, and Class II evidence indicates that IVIg improved scores on the SF-36 MCS, RP, and RE.

Multiple sclerosis (MS) is a debilitating disease of the central nervous system. Its etiology is still an unanswered enigma; its symptoms are varied and unpredictable; and there is no cure for it. Genetics has been introduced as a contributing factor to MS. Not only may MS stem from nuclear gene variations/mutations, but also it may arise from mitochondrial gene variations/mutations. The association of mitochondrial DNA variations/mutations with the pathogenesis of MS has, so far, been analyzed by several studies. This paper reviews the literature with regard to MS and corresponding mitochondrial DNA variations.

Neural stem cells (NSCs) possess immunosuppressive characteristics, but effects of NSCs on human dendritic cells (DCs), the most important antigen presenting cells, are less well studied. We used an in vitro approach to evaluate the effects of human NSCs on differentiation of human blood CD14(+) monocytes into DCs. NSCs derived from H1 human embryonic stem cells (hESC-NSCs) and human ReNcell NSC line, as well as human bone marrow derived mesenchymal stem cells (MSCs), were tested. We observed that in response to treatment with interleukin-4 and granulocyte macrophage colony-stimulating factor CD14(+) monocytes co-cultured with NSCs were able to down-regulate CD14 and up-regulate the differentiation marker CD1a, whereas MSC co-culture strongly inhibited CD1a expression and supported prolonged expression of CD14. A similar difference between NSCs and MSCs was noted when lipopolysaccharides were included to induce maturation of monocyte-derived DCs. However, when effects on the function of derived DCs were investigated, NSCs suppressed the elevation of the DC maturation marker CD83, although not the up-regulation of costimulatory molecules CD80, CD86 and CD40, and impaired the functional capacity of the derived DCs to stimulate alloreactive T cells. We did not observe any obvious difference between hESC-NSCs and ReNcell NSCs in inhibiting DC maturation and function. Our data suggest that although human NSCs are less effective than human MSCs in suppressing monocyte differentiation into DCs, these stem cells can still affect the function of DCs, ultimately regulating specific immune responses.

A worldwide epidemic of stroke is exacting a huge level of patient suffering and social cost. The ischemia damage to neural cells and the associated permanent neural function loss are central to the pathophysiology of stroke. In the current study, we were endeavored to identify NR4A1, an orphan nuclear receptor as a novel protector for neural cells in an in vitro neural ischemia model. Our results showed that oxygen and glucose deprivation (OGD) dramatically induced primary culture neural cell apoptosis and NR4A1 expression at both protein and mRNA level. Furthermore, hyperexpression or knock-down of NR4A1 significantly ameliorated or exacerbated OGD induced neural damage as manifested by decreased or increased apoptotic rates and key apoptotic protein expression respectively. As part of effort to identify the underlying mechanism, we also found that survivin is highly inducible following OGD and is required for NR4A1 action in this scenario. Our data seemed to be logical extensions of previous observations showing that NR4As are highly inducible following focal cerebral ischemia. Of note, our results also demonstrated that NR4A1 induction in this scenario may be functionally important as well and targeting NR4A1 protein can be intriguing as part of the effort to develop novel therapeutic strategies for neural protection after stroke.