Influence of glutamate and GABA transport on brain excitatory/inhibitory balance

An optimally functional brain requires both excitatory and inhibitory inputs that are regulated and balanced. A perturbation in the excitatory/inhibitory balance—as is the case in some neurological disorders/diseases (e.g. traumatic brain injury Alzheimer’s disease, stroke, epilepsy and substance abuse) and disorders of development (e.g. schizophrenia, Rhett syndrome and autism spectrum disorder)—leads to dysfunctional signaling, which can result in impaired cognitive and motor function, if not frank neuronal injury. At the cellular level, transmission of glutamate and GABA, the principle excitatory and inhibitory neurotransmitters in the central nervous system control excitatory/inhibitory balance. Herein, we review the synthesis, release, and signaling of GABA and glutamate followed by a focused discussion on the importance of their transport systems to the maintenance of excitatory/inhibitory balance.     

Effects of Multidisciplinary Rehabilitation on Chronic Fatigue in Multiple Sclerosis: A Randomized Controlled Trial

Background

Several rehabilitation programmes aim at reducing the impact of fatigue in MS patients. Acute and chronic fatigue should require different management.

Objectives

To assess the effects of individually tailored, multidisciplinary outpatient rehabilitation (MDR) on chronic fatigue.

Methods

Forty-eight ambulatory MS patients with chronic fatigue were randomized to MDR or to MS–nurse consultation. Fatigue was assessed by the Checklist Individual Strength (CIS-20R). Secondary outcomes included the Modified Fatigue Impact Scale, Fatigue Severity Scale, Functional Independence Measure, Disability and Impact Profile (DIP), Multiple Sclerosis Impact Scale and the Impact on Participation and Autonomy (IPA).

Results

The primary outcome measure CIS-20R overall score showed no significant differences between groups at 12 weeks (P = 0.39) and 24 weeks follow-up (P = 0.14), nor for subscales (t = 12 and t = 24, 0.19≤P≤0.88). No significant within-group effects were found for both groups with respect to the primary (0.57≤p≤0.97) and secondary (0.11≤p≤0.92) outcome measures from baseline to 12 or 24 weeks.

Conclusion

Multidisciplinary rehabilitation was not more effective in terms of reducing self-reported fatigue in MS patients compared to MS-nurse consultation. Our results suggest that chronic fatigue in patients with MS may be highly invariant over time, irrespective of interventions.

Trial Registration

controlled-trials.com ISRCTN05017507     

Strong association of 677 C>T substitution in the MTHFR gene with male infertility--a study on an indian population and a meta-analysis

Background

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies.

Methodology/Principal Findings

We undertook genotyping on a total of 837 individuals including well characterized infertile (N = 522) and confirmed fertile (N = 315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included ‘Pubmed’, ‘Ovid’ and ‘Google Scholar’. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p = 0.0025) and genotypes (CT+TT) (p = 0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p = 0.000), 1.310 (p = 0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility.

Conclusions/Significance

677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.     

High fat diet prevents over-crowding induced decrease of sex ratio in mice

Adaptive theory predicts that mothers would be advantaged by adjusting the sex ratio of their offspring in relation to their offspring's future reproductive success. In the present study, we tested the effect of housing mice under crowded condition on the sex ratio and whether the fat content of the diet has any influence on the outcome of pregnancies. Three-week-old mice were placed on the control diet (NFD) for 3 weeks. Thereafter the mice were allotted randomly to two groups of 7 cages each with 4, 6, 8, 10, 12, 14, and 16 mice in every cage to create increasing crowding gradient and fed either NFD or high fat diet (HFD). After 4 weeks, dams were bred and outcomes of pregnancy were analyzed. The average dam body weight (DBW) at conception, litter size (LS) and SR were significantly higher in HFD fed dams. Further, male biased litters declined with increasing crowding in NFD group but not in HFD. The LS and SR in NFD declined significantly with increasing crowding, whereas only LS was reduced in HFD group. We conclude that female mice housed under overcrowding conditions shift offspring SR in favor of daughters in consistent with the TW hypothesis and high fat diet reduces this influence of overcrowding.     

A microRNA network regulates proliferative timing and extracellular matrix synthesis during cellular quiescence in fibroblasts

Background

Although quiescence (reversible cell cycle arrest) is a key part in the life history and fate of many mammalian cell types, the mechanisms of gene regulation in quiescent cells are poorly understood. We sought to clarify the role of microRNAs as regulators of the cellular functions of quiescent human fibroblasts.

Results

Using microarrays, we discovered that the expression of the majority of profiled microRNAs differed between proliferating and quiescent fibroblasts. Fibroblasts induced into quiescence by contact inhibition or serum starvation had similar microRNA profiles, indicating common changes induced by distinct quiescence signals. By analyzing the gene expression patterns of microRNA target genes with quiescence, we discovered a strong regulatory function for miR-29, which is downregulated with quiescence. Using microarrays and immunoblotting, we confirmed that miR-29 targets genes encoding collagen and other extracellular matrix proteins and that those target genes are induced in quiescence. In addition, overexpression of miR-29 resulted in more rapid cell cycle re-entry from quiescence. We also found that let-7 and miR-125 were upregulated in quiescent cells. Overexpression of either one alone resulted in slower cell cycle re-entry from quiescence, while the combination of both together slowed cell cycle re-entry even further.

Conclusions

microRNAs regulate key aspects of fibroblast quiescence including the proliferative state of the cells as well as their gene expression profiles, in particular, the induction of extracellular matrix proteins in quiescent fibroblasts.     

Epidural analgesia and cesarean delivery in multiple sclerosis post-partum relapses: the Italian cohort study

Background

Few studies have systematically addressed the role of epidural analgesia and caesarean delivery in predicting the post-partum disease activity in women with Multiple Sclerosis (MS).The objective of this study was to assess the impact of epidural analgesia (EA) and caesarean delivery (CD) on the risk of post-partum relapses and disability in women with MS.

Methods

In the context of an Italian prospective study on the safety of immunomodulators in pregnancy, we included pregnancies occurred between 2002 and 2008 in women with MS regularly followed-up in 21 Italian MS centers. Data were gathered through a standardized, semi-structured interview, dealing with pregnancy outcomes, breastfeeding, type of delivery (vaginal or caesarean) and EA. The risk of post-partum relapses and disability progression (1 point on the Expanded Disability Status Sclae, EDSS, point, confirmed after six months) was assessed through a logistic multivariate regression analysis.

Results

We collected data on 423 pregnancies in 415 women. Among these, 349 pregnancies resulted in full term deliveries, with a post-partum follow-up of at least one year (mean follow-up period 5.5±3.1 years). One hundred and fifty-five patients (44.4%) underwent CD and 65 (18.5%) EA. In the multivariate analysis neither CD, nor EA were associated with a higher risk of post-partum relapses. Post-partum relapses were related to a higher EDSS score at conception (OR=1.42; 95% CI 1.11-1.82; p=0.005), a higher number of relapses in the year before pregnancy (OR=1.62; 95% CI 1.15-2.29; p=0.006) and during pregnancy (OR=3.07; 95% CI 1.40-6.72; p=0.005). Likewise, CD and EA were not associated with disability progression on the EDSS after delivery. The only significant predictor of disability progression was the occurrence of relapses in the year after delivery (disability progression in the year after delivery: OR= 4.00; 95% CI 2.0-8.2; p<0.001; disability progression over the whole follow-up period: OR= 2.0; 95% CI 1.2-3.3; p=0.005).

Conclusions

Our findings, show no correlation between EA, CD and postpartum relapses and disability. Therefore these procedures can safely be applied in MS patients. On the other hand, post-partum relapses are significantly associated with increased disability, which calls for the need of preventive therapies after delivery.

     

Direct cord implantation in brachial plexus avulsions: revised technique using a single stage combined anterior (first) posterior (second) approach and end-to-side side-to-side grafting neurorrhaphy

Background

The superiority of a single stage combined anterior (first) posterior (second) approach and end-to-side side-to-side grafting neurorrhaphy in direct cord implantation was investigated as to providing adequate exposure to both the cervical cord and the brachial plexus, as to causing less tissue damage and as to being more extensible than current surgical approaches.

Methods

The front and back of the neck, the front and back of the chest up to the midline and the whole affected upper limb were sterilized while the patient was in the lateral position; the patient was next turned into the supine position, the plexus explored anteriorly and the grafts were placed; the patient was then turned again into the lateral position, and a posterior cervical laminectomy was done. The grafts were retrieved posteriorly and side grafted to the anterior cord. Using this approach, 5 patients suffering from complete traumatic brachial plexus palsy, 4 adults and 1 obstetric case were operated upon and followed up for 2 years. 2 were C5,6 ruptures and C7,8T1 avulsions. 3 were C5,6,7,8T1 avulsions. C5,6 ruptures were grafted and all avulsions were cord implanted.

Results

Surgery in complete avulsions led to Grade 4 improvement in shoulder abduction/flexion and elbow flexion. Cocontractions occurred between the lateral deltoid and biceps on active shoulder abduction. No cocontractions occurred after surgery in C5,6 ruptures and C7,8T1 avulsions, muscle power improvement extended into the forearm and hand; pain disappeared.

Limitations include

spontaneous recovery despite MRI appearance of avulsions, fallacies in determining intraoperative avulsions (wrong diagnosis, wrong level); small sample size; no controls rule out superiority of this technique versus other direct cord reimplantation techniques or other neurotization procedures; intra- and interobserver variability in testing muscle power and cocontractions.

Conclusion

Through providing proper exposure to the brachial plexus and to the cervical cord, the single stage combined anterior (first) and posterior (second) approach might stimulate brachial plexus surgeons to go more for direct cord implantation. In this study, it allowed for placing side grafts along an extensive donor recipient area by end-to-side, side-to-side grafting neurorrhaphy and thus improved results.

Level of evidence

Level IV, prospective case series.     

The SAC1 domain in synaptojanin is required for autophagosome maturation at presynaptic terminals

Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinson's disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P₂, but this function appears normal in Synaptojanin^RQ knock‐in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P₂, two lipids found in autophagosomal membranes. Using advanced imaging, we show that Synaptojanin^RQ mutants accumulate the PI(3)P/PI(3,5)P₂‐binding protein Atg18a on nascent synaptic autophagosomes, blocking autophagosome maturation at fly synapses and in neurites of human patient induced pluripotent stem cell‐derived neurons. Additionally, we observe neurodegeneration, including dopaminergic neuron loss, in Synaptojanin^RQ flies. Thus, synaptojanin is essential for macroautophagy within presynaptic terminals, coupling protein turnover with synaptic vesicle cycling and linking presynaptic‐specific autophagy defects to Parkinson's disease.     

Incidence and Characteristics of Total Stroke in the United States

Background and Purpose  

Stroke, increasingly referred to as a "brain attack", is one of the leading causes of death and the leading cause of adult disability in the United States. It has recently been estimated that there were three quarters of a million strokes in the United States in 1995. The aim of this study was to replicate the 1995 estimate and examine if there was an increase from 1995 to 1996 by using a large administrative claims database representative of all 1996 US inpatient discharges.