Synergistic association of STX1A and VAMP2 with cryptogenic epilepsy in North Indian population

Introduction “Common epilepsies”, merely explored for genetics are the most frequent, nonfamilial, sporadic cases in hospitals. Because of their much debated molecular pathology, there is a need to focus on other neuronal pathways including the existing ion channels. Methods For this study, a total of 214 epilepsy cases of North Indian ethnicity comprising 59.81% generalized, 40.19% focal seizures, and based on epilepsy types, 17.29% idiopathic, 37.38% cryptogenic, and 45.33% symptomatic were enrolled. Additionally, 170 unrelated healthy individuals were also enrolled. Here, we hypothesize the involvement of epilepsy pathophysiology genes, that is, synaptic vesicle cycle, SVC genes (presynapse), ion channels and their functionally related genes (postsynapse). An interactive analysis was initially performed in SVC genes using multifactor dimensionality reduction (MDR). Further, in order to understand the influence of ion channels and their functionally related genes, their interaction analysis with SVC genes was also performed. Results A significant interactive two-locus model of STX1A_rs4363087|VAMP2_rs2278637 (presynaptic genes) was observed among SVC variants in all epilepsy cases (P1000-value = 0.054; CVC = 9/10; OR = 2.86, 95%CI = 1.88–4.35). Further, subgroup analysis revealed stronger interaction for the same model in cryptogenic epilepsy patients only (P1000-value = 0.012; CVC = 10/10; OR = 4.59, 95%CI = 2.57–8.22). However, interactive analysis of presynaptic and postsynaptic genes did not show any significant association. Conclusions Significant synergistic interaction of SVC genes revealed the possible functional relatedness of presynapse with pathophysiology of cryptogenic epilepsy. Further, to establish the clinical utility of the results, replication in a large and similar phenotypic group of patients is warranted

Markedly disturbed sleep in medically refractory compared to controlled epilepsy – A clinical and polysomnography study

AbstractPurposeTo evaluate sleep disturbances or sleep related events and their characteristics among patients with medically refractory epilepsy, compared to those with controlled epilepsy.MethodsIn a prospective case-controlled study, patients of medically refractory and controlled epilepsy were recruited and history pertaining to epilepsy and sleep related events and Epworth sleepiness scores were recorded and all patients underwent over night polysomnography.ResultsAmong 40 patients, 20 with medically refractory (Group 1) and 20 with controlled epilepsy (Group 2) (median age 18, range 10–35 years), the self reported sleep parameters in Group 1 patients were found to be significantly different as compared to Group 2, in terms of the duration of night time sleep, day time sleep, day time nap frequency, total sleep hours per day, excessive daytime sleepiness (EDS)(45% vs. 15%) and average sleep hours over the week prior to polysomnography. On PSG, Group 1 patients showed significantly less total sleep time [340.4min (147–673) vs. 450.3min (330–570)] with delayed sleep latency and REM latency, poor sleep efficiency [80.45 (40.5–98.0) vs. 95.45 (88.4–99.7)] and frequent arousals and wake after sleep onset (WASO) compared to Group 2 patients. Four patients (20%) in Group 1 compared to none in Group 2 were found to have mild obstructive sleep apnea.ConclusionsOur results indicate that medically refractory epilepsy patients believe that they spend more time sleeping, in contrast to the documented shorter sleep duration on polysomnography. This difference between perceived and actual sleep seems, by their data, to arise mainly from sleep fragmentation, disturbed architecture and the interesting finding of associated sleep apnea among the medically refractory epilepsy patients

Downregulation of peripheral PTGS2/COX-2 in response to valproate treatment in patients with epilepsy

Antiepileptic drug therapy has significant inter-patient variability in response towards it. The current study aims to understand this variability at the molecular level using microarray-based analysis of peripheral blood gene expression profiles of patients receiving valproate (VA) monotherapy. Only 10 unique genes were found to be differentially expressed in VA responders (n = 15) and 6 genes in the non-responders (n = 8) (fold-change >2, p < 0.05). PTGS2 which encodes cyclooxygenase-2, COX-2, showed downregulation in the responders compared to the non-responders. PTGS2/COX-2 mRNA profiles in the two groups corresponded to their plasma profiles of the COX-2 product, prostaglandin E(2) (PGE(2)). Since COX-2 is believed to regulate P-glycoprotein (P-gp), a multidrug efflux transporter over-expressed at the blood-brain barrier (BBB) in drug-resistant epilepsy, the pathway connecting COX-2 and P-gp was further explored in vitro. Investigation of the effect of VA upon the brain endothelial cells (hCMEC/D3) in hyperexcitatory conditions confirmed suppression of COX-2-dependent P-gp upregulation by VA. Our findings suggest that COX-2 downregulation by VA may suppress seizure-mediated P-gp upregulation at the BBB leading to enhanced drug delivery to the brain in the responders. Our work provides insight into the association of peripheral PTGS2/COX-2 expression with VA efficacy and the role of COX-2 as a potential therapeutic target for developing efficacious antiepileptic treatment

Mobilization of Stem Cells Using G-CSF for Acute Ischemic Stroke: A Randomized Controlled, Pilot Study

Background. There is emerging evidence to support the use of granulocyte colony-stimulating factor (G-CSF) therapy in patients with acute ischemic stroke. Aims. To explore feasibility, safety, and preliminary efficacy of G-CSF therapy in patients with acute ischemic stroke. Patients and Method. In randomized study, 10 patients with acute ischemic stroke were recruited in 1 : 1 ratio to receive 10 μg/kg G-CSF treatment subcutaneously daily for five days with conventional care or conventional treatment alone. Efficacy outcome measures were assessed at baseline, one month, and after six months of treatment included Barthel Index (BI), National Institute of Health Stroke Scale, and modified Rankin Scale. Results. One patient in G-CSF therapy arm died due to raised intracranial pressure. No severe adverse effects were seen in rest of patients receiving G-CSF therapy arm or control arm. No statistically significant difference between intervention and control was observed in any of the scores though a trend of higher improvement of BI score is seen in the intervention group. Conclusion. Although this study did not have power to examine efficacy, it provides preliminary evidence of potential safety, feasibility, and tolerability of G-CSF therapy. Further studies need to be done on a large sample to confirm the results

Challenges in setting up a large population-based prospective cohort study in India – learnings from the LoCARPoN cohort

Population-based prospective cohort studies can yield vital new evidence. However, they are difficult to setup especially in non-western contexts such as India. We describe our experience in establishing the Longitudinal Cognition and Aging Research on Population of the National Capital Region (LoCARPoN) cohort, which was the first-of-its-kind public-funded study with target sample size of 15,000, 3 sites, and funds of approx. US$ five million for eight years (2014–2022). LoCARPoN aimed to study incident stroke and dementia in adults aged ≥50 years in urban and rural populations of north India. Among the numerous challenges encountered, important were inadequate funding, lack of adequate space for medical and field sites, difficulty in hiring manpower, lack of IT infrastructure, non-availability of storage facility for biological samples, and absence of dedicated MRI machines. Meticulous planning, adequate funding, trained personnel, institutional and community support are critical for establishing such cohorts in the non-western contexts. Funding: The LoCARPoN cohort study was funded by the Department of Biotechnology (Grant No. BT/IN/Netherlands/03/KP/2012 dated 14/02/2014); and Department of Health Research (Grant No. R.11012/15/2018-HR, dated 09/08/2018), Government of India. The Erasmus component was funded through the Erasmus Medical Centre, Rotterdam, The Netherlands, and the Erasmus University, Rotterdam ( Alzheimer Nederland WE.15-2014-09).</p

Genetic landscape of common epilepsies: advancing towards precision in treatment

Epilepsy, a neurological disease characterized by recurrent seizures, is highly heterogeneous in nature. Based on the prevalence, epilepsy is classified into two types: common and rare epilepsies. Common epilepsies affecting nearly 95% people with epilepsy, comprise generalized epilepsy which encompass idiopathic generalized epilepsy like childhood absence epilepsy, juvenile myoclonic epilepsy, juvenile absence epilepsy and epilepsy with generalized tonic-clonic seizure on awakening and focal epilepsy like temporal lobe epilepsy and cryptogenic focal epilepsy. In 70% of the epilepsy cases, genetic factors are responsible either as single genetic variant in rare epilepsies or multiple genetic variants acting along with different environmental factors as in common epilepsies. Genetic testing and precision treatment have been developed for a few rare epilepsies and is lacking for common epilepsies due to their complex nature of inheritance. Precision medicine for common epilepsies require a panoramic approach that incorporates polygenic background and other non-genetic factors like microbiome, diet, age at disease onset, optimal time for treatment and other lifestyle factors which influence seizure threshold. This review aims to comprehensively present a state-of-art review of all the genes and their genetic variants that are associated with all common epilepsy subtypes. It also encompasses the basis of these genes in the epileptogenesis. Here, we discussed the current status of the common epilepsy genetics and address the clinical application so far on evidence-based markers in prognosis, diagnosis, and treatment management. In addition, we assessed the diagnostic predictability of a few genetic markers used for disease risk prediction in individuals. A combination of deeper endo-phenotyping including pharmaco-response data, electro-clinical imaging, and other clinical measurements along with genetics may be used to diagnose common epilepsies and this marks a step ahead in precision medicine in common epilepsies management

Association of SUMOlation Pathway Genes With Stroke in a Genome-wide Association Study in India

OBJECTIVE: To undertake a genome-wide association study (GWAS) to identify genetic variants for stroke in an Indian population. METHODS: In a hospital-based case-control study, 8 teaching hospitals in India recruited 4,088 participants, including 1,609 stroke cases. Imputed genetic variants were tested for association with stroke subtypes using both single-marker and gene-based tests. Association with vascular risk factors was performed with logistic regression. Various databases were searched for replication, functional annotation, and association with related traits. Status of candidate genes previously reported in the Indian population was also checked. RESULTS: Associations of vascular risk factors with stroke were similar to previous reports and show modifiable risk factors such as hypertension, smoking, and alcohol consumption as having the highest effect. Single-marker–based association revealed 2 loci for cardioembolic stroke (1p21 and 16q24), 2 for small vessel disease stroke (3p26 and 16p13), and 4 for hemorrhagic stroke (3q24, 5q33, 6q13, and 19q13) at p < 5 × 10(−8). The index single nucleotide polymorphism of 1p21 is an expression quantitative trait locus (p(lowest) = 1.74 × 10(−58)) for RWDD3 involved in SUMOylation and is associated with platelet distribution width (1.15 × 10(−9)) and 18-carbon fatty acid metabolism (p = 7.36 × 10(−12)). In gene-based analysis, we identified 3 genes (SLC17A2, FAM73A, and OR52L1) at p < 2.7 × 10(−6). Eleven of 32 candidate gene loci studied in an Indian population replicated (p < 0.05), and 21 of 32 loci identified through previous GWAS replicated according to directionality of effect. CONCLUSIONS: This GWAS of stroke in an Indian population identified novel loci and replicated previously known loci. Genetic variants in the SUMOylation pathway, which has been implicated in brain ischemia, were identified for association with stroke

MtSNPscore: a combined evidence approach for assessing cumulative impact of mitochondrial variations in disease

Human mitochondrial DNA (mtDNA) variations have been implicated in a broad spectrum of diseases. With over 3000 mtDNA variations reported across databases, establishing pathogenicity of variations in mtDNA is a major challenge. We have designed and developed a comprehensive weighted scoring system (MtSNPscore) for identification of mtDNA variations that can impact pathogenicity and would likely be associated with disease. The criteria for pathogenicity include information available in the literature, predictions made by various in silico tools and frequency of variation in normal and patient datasets. The scoring scheme also assigns scores to patients and normal individuals to estimate the cumulative impact of variations. The method has been implemented in an automated pipeline and has been tested on Indian ataxia dataset (92 individuals), sequenced in this study, and other publicly available mtSNP dataset comprising of 576 mitochondrial genomes of Japanese individuals from six different groups, namely, patients with Parkinson's disease, patients with Alzheimer's disease, young obese males, young non-obese males, and type-2 diabetes patients with or without severe vascular involvement. MtSNPscore, for analysis can extract information from variation data or from mitochondrial DNA sequences. It has a web-interface http://bioinformatics.ccmb.res.in/cgi-bin/snpscore/Mtsnpscore.pl webcite that provides flexibility to update/modify the parameters for estimating pathogenicity

Value added utilization of by-product electric furnace ferronickel slag as construction materials: A review

This paper reviews the potential use of electric furnace ferronickel slag (FNS) as a fine aggregate and binder in Portland cement and geopolymer concretes. It has been reported that the use of FNS as a fine aggregate can improve the strength and durability properties of concrete. Use of some FNS aggregates containing reactive silica may potentially cause alkali-silica reaction (ASR) in Portland cement concrete. However, the inclusion of supplementary cementitious materials (SCM) such as fly ash and blast furnace slag as partial cement replacement can effectively mitigate the ASR expansion. When finely ground FNS is used with cement, it shows pozzolanic reaction, which is similar to that of other common SCMs such as fly ash. Furthermore, 20% FNS powder blended geopolymer showed greater strength and durability properties as compared to 100% fly ash based geopolymers. The utilization of raw FNS in pavement construction is reported as a useful alternative to natural aggregate. Therefore, the use of by-product FNS in the construction industry will be a valuable step to help conservation of natural resources and add sustainability to infrastructures development. This paper presents a comprehensive review of the available results on the effects of FNS in concrete as aggregate and binder, and provides some recommendations for future research in this field