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This study explored the potential effects of mild hyperhomocysteinemia (HHcy) on the blood–brain barrier (BBB) and neuroinflammation. Seven-week-old male wild-type C57BL/6 mice were fed normal mouse chow (the control group) or a methionine-enriched diet (the HHcy group) for 14 weeks. Mice in the HHcy group exhibited a slight increase in serum Hcy levels (13.56 ± 0.61 μmol/L). Activation of the ERK signaling pathway, up-regulation of matrix metalloproteinase-9 (MMP-9), and degradation of tight junction proteins (occludin and claudin-5) were observed in both the cerebral cortex and hippocampus of mice with mild HHcy. However, microglia were not activated and the levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were not changed in either the cerebral cortex or hippocampus of mice with mild HHcy. Moreover, the signaling activity of STAT3 also did not differ significantly between the two groups. These findings demonstrate that the BBB is highly vulnerable to homocysteine insult. Even a slight increase in serum homocysteine levels up-regulates MMP-9 expression and disrupts the BBB integrity. Meanwhile, microglia activation or the STAT3 pathway might not contribute to the effects of mild HHcy on the brain.

Background and Purpose: Whether imaging parameters would independently predict stroke recurrence in low-risk minor ischemic stroke (MIS) or transient ischemic attack (TIA) according to traditional score system (such as ABCD 2 score, which was termed on the basis of the initials of the five factors: age, blood pressure, clinical features, duration, diabetes) remains unclear. We sought to evaluate the association between imaging parameters and 1-year stroke recurrence in patients with TIA or MIS in different risk stratum stratified by ABCD 2 score. Methods: We included patients with TIA and MIS (National Institutes of Health Stroke Scale score ≤3) with complete baseline vessel and brain imaging data from the Third China National Stroke Registry III. Patients were categorized into different risk groups based on ABCD 2 score (low risk, 0–3; moderate risk, 4–5; and high risk, 6–7). The primary outcome was stroke recurrence within 1 year. Multivariable Cox proportional-hazards regression models were used to assess whether imaging parameters (large artery stenosis, infarction number) were independently associated with stroke recurrence. Results: Of the 7140 patients included, 584 patients experienced stroke recurrence within 1 year. According to the ABCD 2 score, large artery stenosis was associated with higher stroke recurrence in both low-risk (adjusted hazard ratio, 1.746 [95% CI, 1.200–2.540]) and moderate-risk group (adjusted hazard ratio, 1.326 [95% CI, 1.042–1.687]) but not in the high-risk group ( P >0.05). Patients with multiple acute infarctions or single acute infarction had a higher risk of recurrent stroke than those with no infarction in both low- and moderate-risk groups, but not in the high-risk group. Conclusions: Large artery stenosis and infarction number were independent predictors of 1-year stroke recurrence in low-moderate risk but not in high-risk patients with TIA or MIS stratified by ABCD 2 score. This finding emphasizes the importance of early brain and vascular imaging evaluation for risk stratification in patients with TIA or MIS.

The study aimed to investigate the role of serum homocysteine in hemorrhagic transformation (HT) and symptomatic intracranial hemorrhage (sICH) within 24 h of intravenous (IV) recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke (AIS) patients. 236 consecutive AIS patients (169 men, median 65 years old) who underwent to IV rt-PA within 4.5 h of symptom onset were retrospectively recruited and analyzed. The serum homocysteine levels ranged from 4.45 to 67.71 (median 12.05) μmol/L. HT was observed in 28 (11.9%) patients, including 7 (3.0%) sICH patients within 24 h of IV rt-PA. Multiple parameters were compared between HT and non-HT patients as well as sICH and non-sICH patients. The serum homocysteine levels were higher in patients with HT than in those without HT (13.00 vs. 11.70 μmol/L, P = 0.025) and an independent association between serum homocysteine level and HT within 24 h of IV rt-PA was identified via multivariable logistic regression analysis (odds ratio [OR] = 1.103, 95% confidence interval [CI] = 1.021–1.191, P = 0.013). Moreover, serum homocysteine levels were also significantly higher in patients with sICH than in those without sICH (15.19 vs. 11.73 μmol/L, P = 0.005).Our study suggests that serum homocysteine level is an independent predictor for HT within 24 h of IV rt-PA in AIS patients.

Hemorrhagic transformation (HT) is a frequent and severe complication of ischemic stroke. This study aimed to evaluate the factors associated with the occurrence of HT in patients with acute cerebellar infarction.A total of 190 patients, 141 male (74.2%) and 49 female (25.8%) with mean age 61.84 ± 12.16 years, who were admitted within 72 h of acute cerebellar infarction onset from January 2017 to March 2021 were retrospectively recruited. The multivariate logistic regression analysis was used to evaluate the independent influent factors for HT and receiver-operating characteristic (ROC) curve was applied to calculate the predictive value of those factors for HT in patients with acute cerebellar infarction.37 out of 190 recruited patients (19.47%) had HT within 14 days after acute cerebellar infarction onset. The incidence rates of HT occurring within 3 days, 3-7 days and 7-14 days were 13.5%, 40.5% and 45.9%, respectively. Results of the multivariable logistic regression analysis indicated that atrial fibrillation (AF) (OR 6.196, 95% CI 1.357-28.302, P = 0.019), infarct diameter (OR 5.813, 95% CI 2.932-11.526, P 0.001), white matter hyperintensity (WMH) (OR 2.44, 95% CI 1.134-5.252, P = 0.023) were independent risk factors for HT in acute cerebellar infarction, while lymphocyte count (OR 0.319, 95% CI 0.142-0.716, P = 0.006) showed an independently protective effect.Infarct diameter, AF and WMH are independent risk factors for HT in patients with acute cerebellar infarction, while the lymphocyte count is a protective factor.

BACKGROUND Multiple studies have evaluated the associations between 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and migraine risk with conflicting results. Therefore, we conducted a meta-analysis on this theme. METHODS We searched the electronic databases of PubMed, EmBase, ScienceDirect, and Cochrane Library for all relevant studies published until April 6, 2018. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) in allelic, dominant, recessive, homozygous, and heterozygous models were calculated using random effects model to assess the strength of associations. We also performed subgroup analyses stratified by ethnicity and migraine subtypes, respectively. RESULTS Twenty-six studies (20 in Caucasians, 3 in Asians, 2 in Indians, and 1 in Pakistanis) with 10,228 migraineurs and 28,608 controls were included in this meta-analysis. In the overall population, the allele 677T and TT genotype were associated with an increased risk for total migraine and migraine with aura (MA) (total migraine: T vs C: OR = 1.19, 95%CI = 1.06-1.33, P = .004; TT vs CC: OR = 1.32, 95%CI = 1.07-1.64, P = .011; MA: T vs C: OR = 1.28, 95%CI = 1.09-1.51, P = .003; TT vs CC: OR = 1.51, 95%CI = 1.09-2.08, P = .012), but not for migraine without aura (MO). Subgroup analysis stratified by ethnicity revealed similar findings in Caucasians. In Asians, the association was detected only in recessive model in total migraine (TT vs CT + CC: OR = 1.80, 95%CI = 1.14-2.85, P = .012). Results in Indians did not suggest any association in either total migraine or its subtypes. Pooled results of 5 studies (4 in Caucasians and 1 in Indians) on A1298C polymorphism indicated a significant association between the CC genotype and migraine risk (CC vs AA: OR = 1.78, 95%CI = 1.03-3.07, P = .038), which only appeared for MO (CC vs AA: OR = 2.83, 95%CI = 1.30-6.16, P = .009). CONCLUSIONS Our meta-analysis suggested that allele 677T in MTHFR C677T polymorphism might be a genetic risk factor for MA in Caucasians, and genotype 1298CC might contribute to MO susceptibility.

Background: Whether maternal anti-HBs acquired transplacentally plays a negative role in newborn infants’ immune response to hepatitis B vaccine (HepB Vac), it remains controversial and has not been paid enough attention.Methods: 267 BALB/c mice were bred. All mice were divided into two groups according to different doses of HepB Vac (2μg, 5μg) injected to mice. Each group was sub-divided into three subgroups according to different doses of hepatitis B immunoglobulin (HBIG) (50 IU, 25 IU, 0 IU) injected combined with the first dose of HepB Vac. Three doses of HepB Vac were administrated at 0 week, 4week and 8 week respectively. Antibodies against hepatitis B surface antigen (anti-HBs) were tested four weeks after the third dose of HepB Vac.Results: Among 267 mice, 40 were of low- and non-response to HepB Vac (anti-HBs

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene has been reported to be a candidate gene for susceptibility to Parkinson's disease (PD), but results of different studies are conflicting. Here, we conducted a meta-analysis of published case-control studies to evaluate the association between MTHFR C677T and A1298C gene polymorphisms with the risk of PD. Electronic search through PubMed, EmBase, ScienceDirect and Cochrane Library was conducted to identify all relevant studies. A total of 19 studies with 2746 cases and 8967 controls were included. No significant association between MTHFR C677T polymorphism and PD risk was found in the overall population in all five genetic models. In the subgroup analysis stratified by ethnicity, a significant association between MTHFR C677T and PD risk was observed in the dominant model in Caucasians (OR=1.175, 95%CI: 1.008-1.369, P=0.040), but not in Asians. Significant association was found between MTHFR A1298C polymorphism and PD risk in the overall population in the dominant (OR=1.168, 95%CI: 1.008-1.353, P=0.039) and heterozygous model (OR=1.172, 95%CI: 1.004-1.367, P=0.044). But in the subgroup analysis, no association was found between MTHFR A1298C and PD neither in Caucasians nor in Asians. Our meta-analysis suggests that MTHFR C677T polymorphism may be associated with increased PD risk in Caucasians and MTHFR A1298C polymorphism may also increase susceptibility to PD.

The relationships between vitamin D receptor (VDR) gene polymorphisms, particularly ApaI, BsmI, FokI, and TaqI, and Parkinson's disease (PD) has received increasing attention in the research community. However, as the results yielded by this increased research have hitherto conflicted, we performed an updated meta-analysis of reports on the relationships between VDR polymorphisms and PD published before October 2019 that we collected from the PUBMED, EMBASE, EBSCO, China National Knowledge Infrastructure (CNKI), and Wanfang databases. The ten articles that met our screening criteria included 2782 patients and 3194 healthy controls. All the data that we received were analyzed with Stata 12.0 statistical software. The odds ratio (OR) and 95 % confidence intervals (CIs) were used to determine the relationship between VDR gene diversity and PD. While we did not find a significant correlation between the ApaI, BsmI, and TaqI polymorphisms and the risk of PD in any of the considered genetic models, we found a clear association between the FokI polymorphism and susceptibility to PD (C vs. T: OR = 1.246, 95 % CI: 1.101–1.411, P = 0; CC vs. TT: OR = 1.630, 95 % CI: 1.243–2.139, P = 0; CT vs. TT: OR = 1.382, 95 % CI: 1.059–1.804, P = 0.017; CC + CT vs. TT: OR = 1.491, 95 % CI: 1.159–1.919,P = 0.002; CC vs. CT + TT: OR = 1.261, 95 % CI: 1.062–1.496, P = 0.008). Our subgroup analysis performed according to ethnicity revealed that FokI increased the risk of PD in Asian populations (C vs. T: OR = 1.261, 95 % CI: 1.080–1.472, P = 0.003; CC vs. TT: OR = 1.664, 95 % CI: 1.189–2.330, P = 0.003; CT vs.TT: OR = 1.387, 95 % CI: 1.000–1.925, P = 0.05; CC + CT vs. TT: OR = 1.497, 95 % CI: 1.098–2.042, P = 0.011; CC vs. CT + TT: OR = 1.285, 95 % CI: 1.036–1.593, P = 0.022). Overall, the gene polymorphism of FokI only increases the risk of PD among Asian populations. Given the limited sample size of this study, the findings should be carefully explained.

CD1 and immunoglobulin G Fc receptor (FcγR) genes have been proposed to be involved in the pathogenesis of Guillain–Barre syndrome (GBS). However, results of different studies are conflicting. This meta-analysis aimed to systematically examine the association between CD1 and FcγR gene polymorphisms and GBS. A comprehensive literature search through PubMed, EmBase, ScienceDirect, and Cochrane Library was performed to identify all eligible studies. The strength of association was assessed by pooled odds ratios (ORs) and corresponding 95% confidence intervals (95% CI) in allelic, dominant, recessive, homozygous and heterozygous genetic models. Four case–control studies about polymorphisms of exon 2 in CD1A and CD1E genes and GBS risk and five studies (six cohorts) about FcγR gene polymorphisms and GBS risk were included in this meta-analysis. The association between exon 2 of CD1E gene polymorphism and GBS was marginally significant in Caucasians in allelic model (OR = 1.193, 95% CI = 1.001–1.423, P = 0.049). FcγRIIA gene polymorphism was significantly associated with GBS risk in Caucasians under allelic model (OR = 1.553, 95% CI = 1.018–2.368, P = 0.041) and dominant model (OR = 1.320, 95% CI = 1.027–1.697, P = 0.030). However, no significant association was found between polymorphisms in exon 2 of CD1A, FcγRIIIA and FcγRIIIB genes and GBS susceptibility. This meta-analysis suggested that FcγRIIA gene polymorphism may contribute to GBS risk in Caucasians and revealed a certain trend toward significance in the association of exon 2 of CD1E gene with GBS in Caucasians. Further studies with larger sample size are required to validate these results.

Background: A new phenomenon has appeared that more and more child-bearing age women are positive for anti-HBs as a result of the effective hepatitis B vaccination. Whether maternal anti-HBs acquired transplacentally plays a negative role in newborn infants' immune response to hepatitis B vaccine (HepB Vac), it remains controversial and has not been paid enough attention. We first design the study to access if maternal anti-HBs inhibit the immune response of HepB Vac in mice Methods: From 2016 to 2018, 361 BALB/c mice were bred. All the mice were divided into two groups (group A and group B) according to the different doses of HepB Vac (2μg, 5μg) injected to mice. Each group was sub-divided into four subgroups according to the different doses of hepatitis B immunoglobulin (HBIG) (50 IU, 25 IU, 0 IU) injected combined with the first dose of HepB Vac and different intervals between HepB Vac doses (0- 4-8 week, 0-1-2 week). Antibody against hepatitis B surface antigen (anti-HBs) was tested four weeks after the third dose of HepB Vac. Findings: Among 361 mice, 10 were anti-HBs＜10 mIU/mL, 31 were anti-HBs＜ 100 mIU/mL and 199 were anti-HBs >1000 mIU/mL. Multivariate logistic regression analysis showed that among groups of HBIG=0 IU(1), HBIG=25IU(2) and HBIG=50 IU(3), anti-HBs＜100 mIU/mL accounted for 1*1%, 23*1%, 20*7% respectively, p= 0*002, (1) vs (3), RR= 0*032, 95% CI [0*004, 0*255], p= 0*001, (2) vs (3), RR= 1*359, 95% CI [0*588, 3*144], p= 0*473; HepB Vac 5 μg vs 2 μg, the rate of anti-HBs＜100 mIU/mL was 4*5% vs 25*6%, RR=0*093, 95% CI [0*035, 0*250], p=0*000; intramuscular injection vs hypodermic injection, the rate of anti-HBs＜100 mIU/mL was 6.1% vs 23*7%, RR=0*139, 95% CI [0*056, 0*346], p= 0*000. Among groups of HBIG= 0 IU, HBIG= 25 IU and HBIG= 50 IU, the mean titer of anti-HBs (log10mIU/m) in subgroup of HepB Vac 5 μg was 5*09±0*36, 4*29±1*07, 3*97±1*02 respectively, p= 0*000; the mean titer of anti-HBs (log10mIU/m) in subgroup of HepB Vac 2 μg was 4*89±0*59, 3*32±1*21, 2*56±0*85 respectively, p= 0*000. Group of 0-4-8 week vs 0-1-2 week, the mean titer of anti-HBs (log10mIU/m) in subgroup of HepB Vac 5 μg was 4*54±0*83 vs 5*09±0*36, p= 0*003; the mean titer of anti-HBs (log10mIU/m) in subgroup of HepB Vac 2 μg was3*97±0*85 vs 4*89±0*59, p= 0*000. Another multivariate logistic regression analysis showed that HBIG= 0 IU, HepB Vac 5μg and intramuscular injection are the independent promotion factors for anti-HBs >1000 mIU/mL. Interpretation: HBIG has a negative impact on both the rate of effective immune response and the response level of anti-HBs. Schemes of higher dose of HepB Vac, longer intervals between doses of HepB Vac and intramuscular injection can be considered as factors contributed to obtaining an optimal immune effect. Funding Statement: This study was funded by National Nature Science Foundation (youth scientific fund). grant number 81502900 Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: The study was approved by the Ethics Committee of Qingdao Municipal Hospital affiliated with Qingdao University.

Previous studies have acknowledged that inflammatory reaction has implicated in Parkinson's disease (PD) pathogenesis nowadays. Toll-like receptors (TLRs), as key players in the inflammatory reaction, play a pivotal role in the PD pathogenesis and accumulating evidences have shown that TLRs are increased in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of PD. Therefore, the present study aimed to identify the role of the polymorphisms of rs187084 and rs352140 in TLR9 gene with PD. The genotypes were detected by polymerase chain reaction and restriction fragment length polymorphism analysis in 380 PD patients and 380 healthy matched individuals in Chinese Han population. For rs352140, our data revealed a significant difference in allele distribution in female PD group and its healthy matched control (P = 0.040). Moreover, rs352140 T allele carriers of female group were associated with a reduced risk of PD (TT + TC vs. CC, P = 0.018). However, no significant differences in genotype and allele distribution were found between the age and gender subgroups for rs187084. Therefore, our studies indicate that the rs352140 gene polymorphism may be associated with the susceptibility of female PD in Chinese Han population.

Previous studies have corroborated receptor for advanced glycation end-products (RAGE) ablation had a protective effect on nigral dopaminergic neurons in the MPTP model of Parkinson's disease (PD). Genetic variation of RAGE gene may be associated with the development of onset of sporadic PD. The present study aimed to explore the possible association of RAGE gene polymorphisms namely -374T/A,-429T/C, and G82S with PD. A total of 285 PD patients and 285 healthy-matched individuals in Chinese Han population were enrolled. Genotype analyses were performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Only the -429T/C polymorphism denoted a significant difference between PD patients and controls (P=0.015) of the three examined single nucleotide polymorphisms (SNPs). Our data also revealed that -429C allele carriers seem to have a decreased risk of PD (OR=0.617, P=0.007). Moreover, there were significant differences in genotype distribution in female PD group and its healthy-matched control subgroup (P=0.014), as well as between late-onset PD (LOPD) and the controls subgroup (P=0.016). However, for -374T/A and 82GS polymorphisms, there was no significant difference in the genotype and allele frequencies between PD patients and the controls, as well as gender- and age-related differences. Our present findings indicate that the RAGE -429T/C polymorphism may be associated with the susceptibility of PD and the CC genotype of -429T/C may be a protective factor for PD in Chinese Han population.

Ginseng has been used for mood adjustment in traditional Chinese medicine for thousands of years. Our previous study has shown that, total ginsenosides, the major pharmacologically functional ingredients of ginseng, possess antidepressant activity. In the present study, we hypothesized that an intestinal metabolite of ginseng, 20(S)-protopanaxadiol (code name S111), as a post metabolism compound (PMC) of ingested ginsenosides, may be responsible for the antidepressant activity of ginseng. To test this hypothesis, antidepressant-like activity of orally given S111 was measured in animal tests including tail suspension test, forced swimming test and rat olfactory bulbectomy depression model. In all those tests, S111 demonstrated antidepressant-like activity as potent as fluoxetine. S111 treated bulbectomy animals had higher levels of monoamine neurotransmitters in the brain and in vitro reuptake assay showed that S111 had a mild inhibitory effect. Furthermore, S111 but not fluoxetine significantly reduced brain oxidative stress and down-regulated serum corticosterone concentration in bulbectomy animals. No disturbance to central nervous system (CNS) normal functions were found in S111 treated animals. These results suggest that the ginseng active metabolite S111 is a potential antidepressant. Since the monoamine reuptake activity of this compound is rather weak, it remains to be investigated whether its antidepressant-like effect is by mechanisms that are different from current antidepressants. Furthermore, this study has demonstrated that post metabolism compounds (PMCs) of herb medicines such as S111 may be a novel source for drug discovery from medicinal herbs.