Associations of vitamin D-related single nucleotide polymorphisms with post-stroke depression among ischemic stroke population

ObjectiveTo investigate the relationship between single nucleotide polymorphisms (SNPs) related to vitamin D (VitD) metabolism and post-stroke depression (PSD) in patients with ischemic stroke.MethodsA total of 210 patients with ischemic stroke were enrolled at the Department of Neurology in Xiangya Hospital, Central South University, from July 2019 to August 2021. SNPs in the VitD metabolic pathway (VDR, CYP2R1, CYP24A1, and CYP27B1) were genotyped using the SNPscan™ multiplex SNP typing kit. Demographic and clinical data were collected using a standardized questionnaire. Multiple genetic models including dominant, recessive, and over-dominant models were utilized to analyze the associations between SNPs and PSD.ResultsIn the dominant, recessive, and over-dominant models, no significant association was observed between the selected SNPs in the CYP24A1 and CYP2R1 genes and PSD. However, univariate and multivariate logistic regression analysis revealed that the CYP27B1 rs10877012 G/G genotype was associated with a decreased risk of PSD (OR: 0.41, 95% CI: 0.18–0.92, p = 0.030 and OR: 0.42, 95% CI: 0.18–0.98, p = 0.040, respectively). Furthermore, haplotype association analysis indicated that rs11568820-rs1544410-rs2228570-rs7975232-rs731236 CCGAA haplotype in the VDR gene was associated with a reduced risk of PSD (OR: 0.14, 95% CI: 0.03–0.65, p = 0.010), whereas no significant association was observed between haplotypes in the CYP2R1 and CYP24A1 genes and PSD.ConclusionOur findings suggest that the polymorphisms of VitD metabolic pathway genes VDR and CYP27B1 may be associated with PSD in patients with ischemic stroke

The clinic-based predictive modeling for prognosis of patients with cryptococcal meningitis

Abstract Background Cryptococcal meningitis (CM) is the most common fungal infection of the central nervous system that can cause significant morbidity and mortality. Although several prognostic factors have been identified, their clinical efficacy and use in combination to predict outcomes in immunocompetent patients with CM are not clear. Therefore, we aimed to determine the utility of those prognostic factors alone or in combination in predicting outcomes of immunocompetent patients with CM. Methods The demographic and clinical data of patients with CM were collected and analyzed. The clinical outcome was graded by the Glasgow outcome scale (GOS) at discharge, and patients were divided into good (score of 5) and unfavorable (score of 1–4) outcome groups. Prognostic model was created and receiver-operating characteristic curve analyses were conducted. Results A total of 156 patients were included in our study. Patients with higher age at onset (p = 0.021), ventriculoperitoneal shunt placement (p = 0.010), Glasgow Coma Scale (GCS) score of less than 15(p< 0.001), lower CSF glucose concentration (p = 0.037) and immunocompromised condition (p = 0.002) tended to have worse outcomes. Logistic regression analysis was used to create a combined score which had a higher AUC (0.815) than those factors used alone for predicting outcome. Conclusions Our study shows that a prediction model based on clinical characteristics had satisfactory accuracy in prognostic prediction. Early recognition of CM patients at risk of poor prognosis using this model would be helpful in providing timely management and therapy to improve outcomes and to identify individuals who warrant early follow-up and intervention

NDR2 overexpression in hippocampus suppressesed the effect of CNO administration on epileptogenesis in PTZ kindling rat model infected with hM4Di vector in DG.

Mortality(A), kindling rate(B), latency of kindling(C), severe seizure latency(D), tendency of kindling(E) and seizure stage(F) between DREADD+CNO group and DREADD+CNO+NDR2 group. CNO, clozapine N-oxide; DG, dentate gyrus. *indicates P P P < 0.001.</p

The effect of multiple CNO doses on epileptogenesis in PTZ kindling rat model infected with hM4Di DREADD in DG.

Mortality(A), kindling rate(B), latency of kindling(C), severe seizure latency(D), tendency of kindling(E) and seizure stage(F) of DREADD rats with CNO at 1 mg/kg, 5mg/kg and 10 mg/kg. CNO, clozapine N-oxide; DG, dentate gyrus. Δindicates P P < 0.05, 5mg/kg CNO vs 1mg/kg CNO.</p

CNO administration alleviates epileptogenesis in PTZ kindling rat model infected with hM4Di vector in DG.

Mortality(A), kindling rate(B), latency of kindling(C), severe seizure latency(D), tendency of kindling(E) and seizure stage(F) of two control groups and DREADD+CNO group. *indicates P P P P P < 0.05, DREADD+CNO group vs Non-DREADD+CNO group; CNO, clozapine N-oxide.</p

The NDR2 levels in the control, DREADD+CNO and DREADD+CNO+NDR2 groups were measured by immunofluorescence.

A and D, Representative fluorescence pictures of the CA3 and DG are displayed; B, the level of NDR2 in the DG and CA3 of the hippocampus were down-regulated in DREADD+CNO group(n = 5) compared with that of control group(n = 5, Mann-Whitney test); C, Comparing NDR2 levels in CA3 and DG in DREADD rats treated with 1 mg/kg CNO(n = 4), decreased NDR2 in CA3 was observed in DREADD rats treated with 5 and 10 mg/kg CNO(n = 4 and 5 respectively), and decreased NDR2 in DG was observed in DREADD rats treated with 10 mg/kg CNO(Kruskal-Wallis test);E, The level of NDR2 in the DG and CA3 of the hippocampus were up-regulated in DREADD+CNO+NDR2 group(n = 7) compared with that of DREADD+CNO group(Mann-Whitney test). CNO, clozapine N-oxide; DG, dentate gyrus. All data represent the median with range. *indicates P P P < 0.001. White arrows show the positive cells.</p

Raw data of statistical analysis.

Epileptogenesis is a potential process. Mossy fiber sprouting (MFS) contributes to epileptogenesis. Silencing of the dentate gyrus (DG) suppressed spontaneous seizures model of epilepsy and hyperactivity of granule cells resulted in MFS in vitro. However, the role of DG’s excitability in epileptogenesis have not yet been well explored, and underlying mechanisms has not been elucidated. Using chemical genetics, we studied whether MFS and epileptogenesis could be modulated by silencing of DG in the PTZ kindling rat model of epilepsy. MFS and protein expression was measured by Timm staining, Western blotting, and Immunofluorescence. Previous studies demonstrated that MFS and epileptogenesis could be modulated by a regulator of axonal growth (e.g. RGMa, PTEN). NDR2 kinase regulate neuronal polarity and prevents the formation of supernumerary axons in the hippocampus. We experimentally confirmed chemogenetic inhibition in DG resulted in decreased MFS and NDR2 expression, and alleviated epileptogenesis. Furthermore, our results showed that injection of AVV vector expressing NDR2 into DG induced upregulation of NDR2 in the hippocampus, and over expression of NDR2 in the hippocampus promote MFS and block protective effect of chemogenetic silencing of DG on epileptogenesis. Overall, we concluded that silencing of DG inhibits MFS and prevents epileptogenesis through NDR2 in the hippocampus in the PTZ kindling rat model of TLE, thereby providing a possible strategy to prevent epileptogenesis.</div

NDR2 expression in control, DREADD+CNO and DREADD+CNO+NDR2 groups by Western blot analysis.

A, The level of NDR2 in DREADD+CNO group (n = 4) was decreased compared with that in control group (n = 4, Mann-Whitney test): B, The level of NDR2 in DREADD+CNO+NDR2 group (n = 4) was increased compared with that in DREADD+CNO group. CNO, clozapine N-oxide. All data represent the mean ± SD. *indicates P P < 0.01.</p

MFS in control, DREADD+CNO and DREADD+CNO+NDR2 groups.

A, Representative pictures of MFS in the CA3 and DG regions; B, MFS of CA3 region in DREADD+CNO group(n = 6) was distinctly decreased in comparison with that in control group (n = 4, Mann-Whitney test); C, MFS of CA3 and DG were similar in DREADD rats treated with 1,5 and10 mg/kg CNO(n = 4,6 and 6 respectively, Kruskal-Wallis test); D, MFS of CA3 region in DREADD+CNO+NDR2 group(n = 5) was distinctly increased in comparison with that in DREADD+CNO group (Mann-Whitney test). CNO, clozapine N-oxide; DG, dentate gyrus; m, molecular layer; g, granule cell layer; h, hilus; c: CA3 region; All data represent the mean ± SD. *indicates P P P < 0.001.</p