Analyzing the causal relationship between lipid-lowering drug target genes and epilepsy: a Mendelian randomization study.

Background: Previous research has yielded conflicting results on the link between epilepsy risk and lipid-lowering medications. The aim of this study is to determine whether the risk of epilepsy outcomes is causally related to lipid-lowering medications predicted by genetics. Methods: We used genetic instruments as proxies to the exposure of lipid-lowering drugs, employing variants within or near genes targeted by these drugs and associated with low-density lipoprotein cholesterol (LDL cholesterol) from a genome-wide association study. These variants served as controlling factors. Through drug target Mendelian randomization, we systematically assessed the impact of lipid-lowering medications, including HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and Niemann-Pick C1-like 1 (NPC1L1) inhibitors, on epilepsy. Results: The analysis demonstrated that a higher expression of HMGCR was associated with an elevated risk of various types of epilepsy, including all types (OR = 1.17, 95% CI:1.03 to 1.32, p = 0.01), focal epilepsy (OR = 1.24, 95% CI:1.08 to 1.43, p = 0.003), and focal epilepsy documented with lesions other than hippocampal sclerosis (OR = 1.05, 95% CI: 1.01 to 1.10, p = 0.02). The risk of juvenile absence epilepsy (JAE) was also associated with higher expression of PCSK9 (OR = 1.06, 95% CI: 1.02 to 1.09, p = 0.002). For other relationships, there was no reliable supporting data available. Conclusion: The drug target MR investigation suggests a possible link between reduced epilepsy vulnerability and HMGCR and PCSK9 inhibition.

Sex differences in the association between serum α-Klotho and depression in middle-aged and elderly individuals: A cross-sectional study from NHANES 2007-2016.

BACKGROUND: Klotho is a well-known anti-aging protein that exerts pleiotropic effects; however, little is known regarding serum α-Klotho in the context of depression. Here, we evaluated the association between serum α-Klotho levels and depression in middle-aged and older individuals. METHODS: In this cross-sectional study, data were collected from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016 with a total of 5272 participants who were ≥40 years of age. Depression was evaluated using the 9-item Patient Health Questionnaire (PHQ-9). The association between serum α-Klotho levels and depression was determined on the basis of multivariable logistic regression models. RESULTS: The mean age of the enrolled adults was 58.94 ± 10.54 years, of which 49.5 % were female. When serum α-Klotho was log10-transformed, it was significantly inversely associated with depression in females in the final adjusted model (odds ratio [OR], 0.32; 95 % confidence interval [CI], 0.12-0.85). In the contrast, serum α-Klotho (log10) was significantly positively associated with depression in males in one of the adjusted models (OR, 3.71; 95 % CI, 1.17-11.8), and this disappeared after adjusting other covariates (all P > 0.05). Based on further stratified respective analyses of females and males, the results were stable. LIMITATIONS: The cross-sectional study could not yield any conclusions regarding causality. CONCLUSIONS: In the present study, serum α-Klotho levels were negatively related to the prevalence of depression in middle-aged and elderly women. This study provides new evidence of sex differences in the association between serum α-Klotho levels and depression.

Association of concomitant headache with hypoperfusion in ischemic stroke: A multimodal CT-based study.

Previous investigations indicate that vessel wall elasticity may contribute to the occurrence of an ischemic stroke-associated headache. In this prospective study, the association between radiologic parameters of intracranial hemodynamic changes and concomitant headaches during the early phase of ischemic stroke was examined. Consecutive patients with acute ischemic stroke (AIS) from the First Affiliated Hospital of Soochow University were recruited and divided into two groups according to their questionnaire results and the International Classification of Headache Disorder 3 criteria. Baseline data, including stroke sub-types and neurological function, at admission and discharge were collected. Non-contrast computed tomography (CT), CT angiography, and CT perfusion were performed to assess intracranial hemodynamic changes. Multiple adjusted logistic models were used and possible confounding factors were included in sequential models. A total of 190 patients with AIS (93 headaches and 97 non-headache) were recruited. There were significant differences between the two groups in gender, hypertension, Alberta stroke program early CT score, relative cerebral blood flow (rCBF), and relative cerebral blood volume (rCBV). Furthermore, rCBV (adjusted odds ratio [OR] 0.160; 95% confidence interval [CI], 0.055-0.461; p < 0.001) and rCBF (adjusted OR, 0.309; 95% CI, 0.113-0.844; p < 0.05) were significantly associated with concomitant headache during the early phase of AIS in fully adjusted models. After adjusting for sociodemographic characteristics and other confounding factors, p values for the ORs were robust and intensified. Patients with lower rCBV and rCBF tended to experience the concomitant headache during the early phase of AIS. Regional hypoperfusion and microcirculation might play an important role in this separate clinical entity.

High serum complement component C4 as a unique predictor of unfavorable outcomes in diabetic stroke.

Previous studies demonstrated that diabetic stroke patients had a poor prognosis and excess complement system activation in the peripheral blood. In this study, the association of serum complement levels with the prognosis of diabetic stroke was examined. Patients with acute ischemic stroke were recruited and were divided into two groups according to their history of diabetes. Baseline data on the admission, including C3 and C4 were collected. Neurologic function at discharge was the primary outcome and was quantified by the National Institutes of Health Stroke Scale (NIHSS). A total of 426 patients with acute ischemic stroke (116 diabetic strokes and 310 non-diabetic strokes) were recruited in this study. There were significant differences between the two groups in hypertension, coronary disease, triglyceride, high-density lipoprotein cholesterol, fasting blood sugar, C4, and mortality rates. Furthermore, the values of complement protein levels were divided into tertiles. In the diabetic stroke group, serum C4 level at the acute phase in the upper third was independently associated with NIHSS score at discharge and concurrent infection. These associations were not significant in non-diabetic stroke. High serum C4 level at admission, as a unique significant predictor, was associated with unfavorable clinical outcomes in the diabetic stroke, independently of traditional risk factors.

A Chinese CADASIL Family with a Novel Mutation on Exon 10 of Notch3 Gene.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is caused by the Notch3 gene mutation, has its unique clinical and imaging characteristics. Here we present a Chinese family with a novel mutation on exon 10 of Notch3 gene. METHODS: Clinical and MRI data of the three patients in the family during the 7-year follow-up were collected. The CADASIL Scale Score was calculated to evaluate the disease risk of the three patients at their first admission or clinic visit. Five family members underwent genetic test. RESULTS: Genetic test confirmed the diagnosis of CADASIL in this family. A novel mutation of p.C533S on exon 10 of Notch3 gene was detected. The CADASIL score of the proband and her sister was both 17 and that of her brother was 14. CONCLUSIONS: Our report not only expands the mutation spectrum of Notch3 gene in CADASIL, but also shows the distinct heterogeneity of CADASIL patients in the same family with the same mutation.

P2X4R Contributes to Central Disinhibition Via TNF-α/TNFR1/GABAaR Pathway in Post-stroke Pain Rats.

Central post-stroke pain (CPSP) is a disabling condition in stroke patients. It is a type of neuropathic pain for which the mechanism and relevant drug pathways remain unknown. Inflammatory response and central disinhibition have been suggested recently. Our previous research has shown targeting P2X4 receptors (P2X4R) may be effective in the treatment of CPSP, but the downstream pathway of the P2X4R has not been studied. In this study, we found the increase in tumor necrosis factor alpha (TNF-α) level and endocytosis of surface gamma-aminobutyric acid a receptors (GABAaR) in CPSP, and these effects were inhibited by blocking P2X4R. Furthermore, antagonizing TNF-α can increase surface GABAaR expression and mechanical pain threshold. Meanwhile, knocking down TNFR1 but not TNFR2 reversed the endocytosis of surface GABAaR and alleviated mechanical allodynia. Thus, the neuropathic pain was mediated, in part, through P2X4R/TNF-α/TNFR1/GABAaR signaling, which was induced after stroke. PERSPECTIVE: P2X4R regulates the pathophysiological mechanism of CPSP through central disinhibition mediated by TNF-α/TNFR1. Our results suggest that modulation of P2X4R-TNF-α/TNFR1-GABAaR signaling could provide a new therapeutic strategy to treat CPSP.

Association Between Autoimmune Diseases and Spontaneous Cervicocranial Arterial Dissection.

A series of biopsies and reports showed autoimmune diseases might be involved in the process of local inflammation related to spontaneous cervicocranial arterial dissection (SCCAD) occurrence. This retrospective case-control study examined the association between SCCADs and autoimmune diseases in patients and control subjects from 2014 to 2020. SCCAD patients and age/sex-matched control subjects were recruited, and clinical data were collected. SCCAD was confirmed by digital subtraction angiography or high-resolution magnetic resonance imaging. The study included 215 SCCAD patients and 430 control subjects. Totally, 135 (62.8%) of the 215 cases were found SCCAD in the anterior circulation, 26 (12.0%) patients involved multiple vessels. Autoimmune disease occurred in 27 (12.6%) cases with SCCAD and 4 (0.9%) control subjects (p<0.001). A conditional multivariable logistic regression model was used to calculate the odds ratio for SCCAD among patients with a history of autoimmune disease, adjusting for hypertension, diabetes, hyperlipidemia, and smoking. After adjustment, autoimmune diseases were associated with SCCAD (p<0.001). After sub-analysis by a similar modeling strategy, significant associations were still observed in different subgroups, such as female group and male group as well as intramural hematoma (IMH) group and Non-IHM group. The association of SCCAD with autoimmune disease suggested that autoimmune mechanisms may be involved in some etiologies of SCCAD.

Neutrophil to Lymphocyte Ratio Predicts Outcome of Stroke by Cervicocranial Arterial Dissection.

Background and Purpose: Neutrophil to lymphocyte ratio (NLR) is positively associated with poor prognosis in patients with cerebral infarction. The goal of this prospective study is to explore the predictive value of NLR in patients with acute ischemic stroke (AIS) caused by cervicocranial arterial dissection (CCAD). Methods: Ninety-nine patients with AIS caused by CCAD met criteria for inclusion and exclusion were selected for this study. We collected baseline data on the admission including NLR. The primary poor outcome was major disability (modified Rankin Scale score ≥ 3) or death at 3 months after AIS. Results: A total of 20 (20.2%) patients had a poor outcome at 3 months after AIS. According to the 3-month outcome, the patients were divided into two groups and univariate and multivariable analyses were conducted. Among the risk factors, elevated NLR levels were independently associated with 3-month poor outcomes. Further, we made the ROC curve to evaluate the predictive value of NLR level on prognosis. The area under the curve was 0.79 and a cut-off value of NLR was 2.97 for differentiating the poor outcome. We divided patients into groups according to the cut-off value. Patients with high NLR have a higher risk of poor outcome than those with low NLR (P < 0.05). Conclusion: As an inflammatory marker, elevated NLR levels were associated with 3-month poor outcome in AIS caused by CCAD.