Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson's Disease Patients from India.

Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease-relevant monogenic genes, rare variants of significance, and polygenic risk-associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies pathogenic/likely pathogenic variants in eight of the 90 individuals (8.8%). It includes large homozygous coding exon deletions in PRKN and SNV/InDels in VPS13C, PLA2G6, PINK1, SYNJ1, and GCH1. Eleven rare heterozygous GBA coding variants are also identified in 13 (14.4%) individuals. In 34 (56.6%) individuals, one or more variants of uncertain significance (VUS) in PD/PD-relevant genes are observed. Though YOPD patients with a prioritized pathogenic variant show a low polygenic risk score (PRS), patients with prioritized VUS or no significant rare variants show an increased PRS odds ratio for PD. This study suggests that both significant rare variants and polygenic risk from common variants together may contribute to the genesis of PD. Further validation using a larger cohort of patients will confirm the interplay between monogenic and polygenic variants and their use in routine genetic PD diagnosis and risk assessment.

Association of APOE Gene Polymorphism with Stroke Patients from Rural Eastern India.

CONTEXT: Studies from the different ethnic regions of the world have reported variable results on association of APOE gene polymorphism in stroke. AIM: The aim of this study is to find out the possible association of APOE polymorphism in stroke patients in ethnic Bengali population. SETTINGS AND DESIGN: A prospective case-control study was undertaken in the Department of Neurology, Burdwan Medical College, Burdwan, West Bengal, India, over a period of 3 years. METHODS: We collected 10 ml venous blood samples from 148 clinically and radiologically diagnosed acute stroke patients (80 of ischemic stroke and 68 of intracerebral hemorrhage) and consecutive 108 ethnic age- and sex-matched controls, in ethylenediaminetetraacetic acid vials after informed written consent. Genomic DNA was prepared at S.N. Pradhan Centre of Neurosciences, University of Calcutta, Kolkata, India. Exotic single-nucleotide polymorphisms (rs429358, rs 7412) were analyzed by polymerase chain reaction-restriction fragment length polymorphism for genotype of APOE. RESULTS: The frequencies of different APOE allele among 80 ischemic stroke patients were 5.6% (n = 9) for E2, 75.68% (n = 121) for E3, and 18.7% (n = 30) for E4. The E3 allele is significantly over-represented (P = 0.004) in controls compared to the patients (88% in controls vs 75.6% ischemic stroke patients and 80% hemorrhagic patients). A significantly high frequency of APOE4 allele was observed in ischemic (18.7%) and hemorrhagic patients (11%) compared to controls (8%). The E4 allele plays a major risk for developing ischemic stroke [odds ratio (OR) = 2.744; 95% confidence interval (CI): 1.43-5.10] and E3 plays a protective role for hemorrhagic stroke (OR = 0.53; 95% CI: 0.29-0.96), while E4 allele plays a nonsignificant (P = 0.31) increase in trend in hemorrhage stroke (OR = 1.4). CONCLUSIONS: There is significant association of APOE gene polymorphism in stroke patients of ethnic Bengali population. The E4 allele increases significant risk for development of ischemic strokes, and it also plays nonsignificant increase in trend in hemorrhagic strokes.

Pharmacokinetics of ceftriaxone in carbontetrachloride-induced hepatopathic and uranyl nitrate-induced nephropathic goats following single dose intravenous administration.

The pharmacokinetic profile of ceftriaxone was studied in female healthy goats, induced hepatopathic and nephropathic goats after a single intravenous dose at 50 mg kg(-1). Ceftriaxone persisted for 2 h in plasma of hepatopathic goats compared to 1 h of healthy goats, but the kinetic behaviour followed 'one-compartment open model' in both healthy and hepatopathic goats. Mean value of t((1/2))beta (0.32 +/- 0.008 h) was significantly higher in hepatopathic goats compared to healthy goats (0.19 +/- 0.002 h). Ceftriaxone was recovered at 24 h in urine of hepatopathic goats but it could not be detected in urine of healthy goats. However, its metabolite ceftizoxime was present in urine of healthy goats but not in urine of hepatopathic goats. On the other hand ceftriaxone persisted for 2 h in plasma of kidney damaged goats with significant higher concentration compared to healthy goats but kinetic behaviour followed 'one Compartment open model'. Ceftizoxime was identified with an adequate plasma concentration from 8 h to 12 h post dosing in nephropathic goats. Elimination halflife (t(1/2)beta) of Elimination ceftriaxone (0.38 +/- 0.01 h) in nephropathic goats increased significantly compared to healthy goats (0.19 +/- 0.002 h). Ceftriaxone, not the metabolite ceftizoxime was recovered at 24 h and 48 h post dosing in urine of nephropathic goats, while only ceftizoxime not ceftriaxone was detected in urine of healthy goats.