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Aim: Atrial cardiomyopathy (ACM) is characterized by atrial dysfunction. This study aims to assess the prognostic significance of ACM in patients with noncardioembolic stroke (NCS)., Methods: Patients with NCS within seven days of onset were prospectively enrolled between January 2019 and December 2020. ACM was defined as either an N-terminal pro-brain natriuretic peptide (NT-pro BNP) ＞250 pg/ml or a P-terminal force in precordial lead V1 (PTFV1) ≥ 5000µV·ms. A poor functional outcome was determined as a score of 3-6 on the modified Rankin Scale (mRS) within a 2-year follow-up period. Logistic regression and Cox regression analyses were employed to examine the relationship between ACM and the long-term prognosis of patients with NCS., Results: A total of 1,346 patients were enrolled, of whom 299 (22.2%) patients were diagnosed with ACM. A total of 207(15.4%) patients experienced a poor functional outcome, and 58 (4.3%) patients died. A multivariate logistic regression analysis indicated that ACM was significantly associated with a poor functional outcome in NCS patients [adjusted odds ratio (aOR): 2.01; 95% confidence interval (CI): 1.42-2.87; p＜0.001]. Additionally, a multivariate Cox regression analysis showed that an NT-pro BNP ＞250 pg/ml was significantly associated with an increased risk of all-cause mortality [adjusted hazard ratio (aHR), 2.51; 95% CI: 1.42-4.43; p=0.001]., Conclusions: ACM may serve as a novel predictor of a poor long-term functional outcome in patients with NCS. Elevated NT-pro BNP levels (＞250 pg/ml) were found to be associated with a higher risk of all-cause mortality. These findings warrant further validation in multicenter studies.

The present study was driven by the scarcity of suitable materials for mending partial breast defects and the imperative considerations of safety and durability. The current study presents findings from two female patients, aged 59 and 40, who underwent breast cancer treatment. Patient 1 underwent a mastectomy with a sentinel lymph node biopsy, while patient 2 underwent a partial mastectomy with axillary lymph node dissection. Core needle biopsy confirmed invasive ductal carcinoma in both cases. Breast ultrasound revealed hypoechoic lesions with smooth edges. The reconstruction of the breast defect employed an acellular dermal matrix, and the safety and cosmetic outcomes for each patient were analyzed. At 3 months post-radiotherapy, neither patient experienced significant complications. The preservation of breast contour and volume was satisfactory, with no postoperative tumor recurrences detected. In summary, utilizing an acellular dermal matrix with a three-dimensional grid design for partial breast defect reconstruction offers a viable alternative that aligns with oncological safety standards and provides good cosmetic results., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Wang et al.)

BGT-002, a new type of ATP-citrate lyase inhibitor, is a promising therapeutic for treatment of hypercholesterolemia. After an oral administration of BGT-002 to subjects, it underwent extensive metabolism and an acyl monoglucuronide (ZM326E-M2) on 1- carboxylic acid group was the major circulating metabolite. In this study, an LC-MS/MS method was developed and validated for the simultaneous determination of BGT-002 and ZM326E-M2 in plasma and the evaluation of their pharmacokinetic characteristics in humans. After extraction from the plasma by acetonitrile-induced protein precipitation, the analytes were separated on a Waters ACQUITY UPLC® BEH C 18 column using acetonitrile and 2 mM ammonium acetate containing 0.1% formic acid as the mobile phase for gradient elution. Negative electrospray ionization was performed using multiple reaction monitoring (MRM) of m/z 501.3→325.4 for ZM326E-M2 and m/z 507.3→331.2 for D 6 -ZM326E-M2, and pseudo-MRM of m/z 325.3→325.3 for BGT-002 and m/z 331.3→331.3 for D 6 -ZM326E, respectively. The method was validated with respect to accuracy, precision, linearity, stability, selectivity, matrix effect, and recovery. The analytical range in human plasma was linear over a concentration range of 0.0500-50.0 μg/mL for BGT-002 and 0.0100-10.0 μg/mL for ZM326E-M2. The pharmacokinetic results showed that after a single oral administration of 100 mg BGT-002, the parent drug was rapidly absorbed with a mean time to peak concentration (t max ) of 1.13 h, compared with BGT-002, the t max (4.00 h) of ZM326E-M2 was significantly delayed. The peak concentration and plasma exposure of ZM326E-M2 were about 14.1% and 19.5% of the parent drug, suggesting that attention should be paid to the safety and efficacy of ZM326E-M2 in clinical research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The p.Thr61Ile (p.T61I) mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) was deemed a causative factor in Parkinson's disease (PD). However, the pathomechanism of the CHCHD2 p.T61I mutation in PD remains unclear. Few existing mouse models of CHCHD2-related PD completely reproduce the features of PD, and no transgenic or knock-in (KI) mouse models of CHCHD2 mutations have been reported. In the present study, we generated a novel CHCHD2 p.T61I KI mouse model, which exhibited accelerated mortality, progressive motor deficits, and dopaminergic (DA) neurons loss with age, accompanied by the accumulation and aggregation of α-synuclein and p-α-synuclein in the brains of the mutant mice. The mitochondria of mouse brains and induced pluripotent stem cells (iPSCs)-derived DA neurons carrying the CHCHD2 p.T61I mutation exhibited aberrant morphology and impaired function. Mechanistically, proteomic and RNA sequencing analysis revealed that p.T61I mutation induced mitochondrial dysfunction in aged mice likely through repressed insulin-degrading enzyme (IDE) expression, resulting in the degeneration of the nervous system. Overall, this CHCHD2 p.T61I KI mouse model recapitulated the crucial clinical and neuropathological aspects of patients with PD and provided a novel tool for understanding the pathogenic mechanism and therapeutic interventions of CHCHD2-related PD., (© 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Objective: The study aimed to investigate the differences in clinical features between pediatric and adult patients with first-episode MOG-IgG associated disorders (MOGAD) and evaluate the relationship between the fibrinogen-to-albumin ratio (FAR) and the severity of neurological deficits at disease onset., Methods: We retrospectively collected and analyzed biochemical test results, imaging characteristics, clinical manifestations, expanded disability status scale (EDSS) score, and FAR. The Spearman correlation analysis and logistic regression models were used to examine the association between FAR and severity. Receiver operating characteristic (ROC) curve analysis was to analyze the predictive ability of FAR for the severity of neurological deficits., Results: Fever (50.0%), headache (36.1%), and blurred vision (27.8%) were the most common clinical manifestations in the pediatric group (<18 years old). However, in the adult group (≥18 years old), the most common symptoms were blurred vision (45.7%), paralysis (37.0%), and paresthesia (32.6%). Fever was more common in the pediatric group, while paresthesia was more common in the adult patients, with all differences statistically significant ( P < 0.05). The most frequent clinical phenotype in the pediatric group was acute disseminated encephalomyelitis (ADEM; 41.7%), whereas optic neuritis (ON; 32.6%) and transverse myelitis (TM; 26.1%) were more common in the adult group. The differences in clinical phenotype between the two groups were statistically significant ( P < 0.05). In both pediatric and adult patients, cortical/subcortical and brainstem lesions were the most common lesions on cranial magnetic resonance imaging (MRI), whereas, for spinal MRI, cervical and thoracic spinal cord lesions were the most commonly observed. According to binary logistic regression analysis, FAR was an independent risk factor for the severity of neurological deficits (odds ratio = 1.717; 95% confidence interval = 1.191-2.477; P = 0.004). FAR ( r = 0.359, P = 0.001) was positively correlated with the initial EDSS score. The area under the ROC curve was 0.749., Conclusion: The current study found age-dependent phenotypes in MOGAD patients as ADEM was more commonly observed in patients < 18 years old, while ON and TM were more frequently found in patients ≥18 years old. A high FAR level was an independent indicator for more severe neurological deficits at disease onset in patients with a first episode of MOGAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Wang, Liu, Ma, Liu and Yuan.)

Autoimmune demyelinating diseases can be induced by an immune response against myelin peptides; however, the exact mechanism underlying the development of such diseases remains unclear. In experimental autoimmune encephalomyelitis, we found that the clearance of exogenous myelin antigen at the peak of the primary immune response is key to the pathogenesis of the disease. The generation of effector T cells requires continuous antigen stimulation, whereas redundant antigen traps and exhausts effector T cells in the periphery, which induces resistance to the disease. Moreover, insufficient antigenic stimulation fails to induce disease efficiently owing to insufficient numbers of effector T cells. When myelin antigen is entirely cleared, the number of effector T cells reaches a peak, which facilitates infiltration of more effector T cells into the central nervous system. The peripheral antigen clearance initiates the first wave of effector T cell entry into the central nervous system and induces chronic inflammation. The inflamed central nervous system recruits the second wave of effector T cells that worsen inflammation, resulting in loss of self-tolerance. These findings provide new insights into the mechanism underlying the development of autoimmune demyelinating diseases, which may potentially impact future treatments., (© 2023 Wiley-VCH GmbH.)

Acute ischemic stroke (AIS) induces high level of neutrophils, which correlates inversely with patient survival. Pyroptosis induced by gasdermin D (GSDMD) has been shown to have an important role in the pathophysiology of several inflammatory disorders. The role of GSDMD in the high level of neutrophils after AIS is unknown. Using a middle cerebral artery occlusion (MCAO) mouse model, we identified activation of pyroptosis signal, including expression of caspase-1/11, GSDMD, and interleukin-1β/18 (IL-1β/18), in the brain and spleen at early ischemic injury. Knockout of GSDMD in mice reduced infarct size, improved neurological function, and increased survival after MCAO. GSDMD deficiency decreased the overall degree of inflammation and the proportion of neutrophils in the brain after MCAO. Quantitative studies of neutrophils at several time intervals and organs demonstrated that early inflammatory leucocyte production and supplement (1 day after MCAO) was GSDMD-dependent. A series of bone marrow transplantation experiments, neutrophil depletion experiments, and RNA sequencing results demonstrated that neutrophil specific GSDMD is essential for the production and supply of neutrophil in bone marrow to blood. Moreover, pharmacological suppression of GSDMD decreased pathological abnormalities, infarct volume, and ameliorated neurological function. These results provided a new viewpoint on the immunological modulation of neutrophils after MCAO and suggest that suppression of GSDMD may relieve the neuroinflammatory load, thereby providing a potential treatment strategy for stroke. The absence of GSDMD reduces the high level of neutrophils in the brain, the production of neutrophils in bone marrow, and the supply of blood and spleen, while simultaneously the neutrophil-specific GSDMD signal deficiency restrains leukocytosis to improve the pathological outcome of AIS., (© 2023. The Author(s).)

Edaravone dexborneol (EDB) is a traditional prescription that consists of two components, edaravone and (+)-borneol, which have synergistic antioxidant and anti-inflammatory activities in animal models of ischemic stroke. Pyroptosis is a form of cell death that has only recently been discovered. In this study, we investigated the therapeutic effects and potential mechanisms of EDB in acute ischemic stroke. We used an in vivo mouse transient middle cerebral artery occlusion (tMCAO) model along with an in vitro BV2 cell oxygen-glucose deprivation (OGD) model to perform specific experiments. The executive protein of pyroptosis, gasdermin D (GSDMD), was increased after tMCAO. The administration of EDB dramatically reduced sensorimotor deficits and infarct sizes in mice with tMCAO. In addition, EDB inhibited the production of the NLRP3-inflammasome and the activation of the NF-κB signaling pathway. This effect inhibited both the in vitro and in vivo expression of inflammatory factors, including IL-1β and IL-18. Collectively, our data indicate that EDB exerted positive effects after ischemic stroke. EDB inhibited the activation of NLRP3 inflammasome-induced microglial pyroptosis in experimental ischemic stroke. The findings of this research indicate that the NF-κB/NLRP3/GSDMD signaling pathway may serve as a therapeutic target for EDB to promote functional recovery after stroke., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The incidence and prevalence of hypothyroidism in pregnancy have increased over the past two decades, leading to the occurrence of neuropsychiatric disorders. However, the underlying mechanisms of thyroid hormone (TH)-regulated gene expression and neuropsychiatric development during the postnatal period remain unknown. Recent achievements have shown that reelin, a large extracellular glycoprotein, plays a crucial role in neuronal migration and localization during the development of neocortex and cerebellar cortex, thereby participating in the development of neuropsychiatric diseases. Reelin-induced neuronal migration requires triiodothyronine (T3) from the deiodination of thyroxine (T4) by fetal brain deiodinases. Previous studies have reported decreased reelin levels and abnormal gene expression, which are the same as the pathological alternations in reelin-induced neuropsychiatric disorders including schizophrenia and autism. Low T3 in the fetal brain due to hypothyroxinemia during pregnancy may be detrimental to neuronal migration, leading to neuropsychiatric disorders. In this review, we focus on the reelin expression between hypothyroidism and neuropsychiatric disorders.

Existing techniques have many limitations in the diagnosis and classification of ischemic stroke (IS). Considering this, we used metabolomics to screen for potential biomarkers of IS and its subtypes and to explore the underlying related pathophysiological mechanisms. Serum samples from 99 patients with acute ischemic stroke (AIS) [the AIS subtypes included 49 patients with large artery atherosclerosis (LAA) and 50 patients with small artery occlusion (SAO)] and 50 matched healthy controls (HCs) were analyzed by non-targeted metabolomics based on liquid chromatography-mass spectrometry. A multivariate statistical analysis was performed to identify potential biomarkers. There were 18 significantly different metabolites, such as oleic acid, linoleic acid, arachidonic acid, L-glutamine, L-arginine, and L-proline, between patients with AIS and HCs. These different metabolites are closely related to many metabolic pathways, such as fatty acid metabolism and amino acid metabolism. There were also differences in metabolic profiling between the LAA and SAO groups. There were eight different metabolites, including L-pipecolic acid, 1-Methylhistidine, PE, LysoPE, and LysoPC, which affected glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, histidine metabolism, and lysine degradation. Our study effectively identified the metabolic profiles of IS and its subtypes. The different metabolites between LAA and SAO may be potential biomarkers in the context of clinical diagnosis. These results highlight the potential of metabolomics to reveal new pathways for IS subtypes and provide a new avenue to explore the pathophysiological mechanisms underlying IS and its subtypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Zhang, Sun, Pei, Tian, Liang, Liu, Zhang, Fang, Wu, Sun, Xu, Kang and Song.)

Background: Ischemic Stroke (IS) is a serious cerebrovascular disease, which leads to irreversible damage or death of brain cells. Effective control of stroke risk factors can effectively reduce the incidence of IS. However, there was an "obesity paradox" about the relationship between obesity and the prognosis of IS, in which obesity would not bring worse outcomes than non-obese IS patients., Objective: Herein, we aimed to investigate the transcriptional response to IS in obese and nonobese mice brain via RNA-Seq technology. The datasets of obese and non-obese mice with/without IS were obtained from the Gene Expression Omnibus (GEO) database., Methods: Differentially expressed genes (DEGs) between Control and Obesity (DEGsObesity) and between Obesity and Obese-Stroke (DEGsObese-Stroke) were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Protein-Protein Interaction (PPI) network analysis were performed to predict the function of DEGs. 28 and 109 DEGs were screened in DEGsObesity and DEGsObese-Stroke, respectively., Results: Significantly, in the top 10 key-genes of DEGsObese-Stroke (Tnf, Lgals3, Serpinb2, Ly6c2, Chil3, Clec4e, Mmp3, Mefv, Spn, Tlr8), Tnf and Mefv were involved in the NOD-like receptor signaling pathway, which was consistent with KEGG pathway enrichment results. And Chil3, as a mononuclear cell marker, was significantly elevated in Obese-Stroke compared with Stroke, suggesting mononuclear cell, rather than other peripheral immune cells, infiltrated into the brain of Obese-stroke., Conclusion: Hence, we concluded that obesity could affect the brain microenvironment at the transcriptome level and Stroke after obesity could lead to more changes in NOD-like receptor signaling pathway and monocyte infiltration, compared with non-obese Stroke., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Interleukin-33 (IL-33) is known to activate the regulatory T lymphocytes (Tregs), which are negatively correlated with brain damage after ischemic stroke. In this study, we aimed to investigate the role of Tregs in IL-33-mediated neuroprotection and elucidate the underlying mechanisms. In vivo, male C57BL/6 N mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO), followed by daily administration of vehicle or IL-33 immediately after injury. Tregs were depleted by intraperitoneal administration of anti-CD25 antibody (anti-CD25Ab). Behavioral changes, brain edema, neuronal injury, Treg percentages, and cytokine expression levels were investigated in each group. In vitro experiments, primary mouse neuronal cells were subjected to oxygen-glucose deprivation (OGD) for 3 h. Vehicle- or drug-conditioned Tregs were applied to the neurons at the time of induction of hypoxia. Neuronal apoptosis and cytokine expression were measured in each group. The results indicate that intraperitoneal administration of anti-CD25Ab reduced CD4 + CD25 + Foxp3+ Tregs, increased infarct volume, enhanced stroke-induced cell death, and decreased sensorimotor functions. Notably, IL-33 increased CD4 + CD25 + Foxp3+ Tregs in the spleen and brain. However, blockading ST2 attenuated these effects of IL-33. The supernatant of the IL-33-treated Treg culture reduced neuronal apoptosis and elevated the production of the Treg cytokines IL-10, IL-35, and transforming growth factor-β (TGF-β). Anti-CD25Ab abrogated the neuroprotective effect of IL-33. Mechanistically, the neuroprotective effects of IL-33 were associated with reduction in apoptosis-related proteins and production of Tregs related cytokines. Overall, these findings showed that IL-33 afforded neuroprotection against ischemic brain injury by enhancing ST2-dependent regulatory T-cell expansion and activation via a mechanism involving anti-apoptosis proteins and cytokines, representing a promising immune modulatory target for the treatment of stroke., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Inc.)

Background: Noncontrast computed tomography hypodensities (HD) and ultraearly hematoma growth (uHG) are reliable markers for outcome prediction in patients with spontaneous intracerebral hemorrhage (sICH). The present study aimed to assess whether the combination of these 2 markers could improve the prognostic value for sICH., Methods: We recruited 242 patients with sICH who had been admitted within 6 hours from the onset of symptoms. HD was assessed by 2 independent blinded readers, and uHG was calculated as baseline ICH volume/onset-to-imaging time. We divided the study population into 4 groups: uHG(L) HD(-) (uHG <6.16 mL/hour and HD negative), uHG(L) HD(+) (uHG<6.16 mL/hour and HD positive), uHG(H) HD(-) (uHG ≥6.16 mL/hour and HD negative), and uHG(H) HD(+) (uHG ≥6.16 mL/h and HD positive). The outcome at 90 days was evaluated by the modified Rankin Scale (mRS) score and was dichotomized as good (mRS score 0-3) and poor (mRS score 4-6). The association between the combined indicators and unfavorable outcome was investigated using multivariable logistic regression models., Results: Patients with poor outcomes were more likely to have HD and higher uHG in univariate analysis. In multivariate logistic regression analysis, uHG(H) HD(+) had a higher risk of unfavorable outcomes compared with uHG(L) HD(-) (odds ratio [OR], 5.710; P < 0.001). In addition, the risk of unfavorable outcomes was increased in uHG(H) HD(-) (OR, 2.957, P = 0.044) and uHG(L) HD(+) (OR, 1.924; P = 0.232). The proportions of unfavorable prognoses were 32.6% in uHG(L) HD(-), 48.3% in uHG(L) HD(+), 72.2% in uHG(H) HD(-), and 87.5% in uHG(H) HD(+) (P < 0.001)., Conclusions: The combination of uHG and HD improves the stratification of unfavorable prognoses in patients with sICH., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the association of dynamic neutrophil-to-lymphocyte ratio (NLR) with 3-month functional outcomes in patients with sICH. We retrospectively identified 213 consecutive patients with sICH hospitalized in The First Affiliated Hospital of Zhengzhou University from January 2017 to May 2018. Patients were divided into functional independence (FI) or unfavorable prognosis (UP) groups based on 3-month outcomes. Admission leukocyte counts within 24 hours of symptom onset were obtained, and the recorded fraction, of which the numerator is neutrophil and the denominator is lymphocyte, as NLR0. Determined NLR1, NLR3, NLR7, and NLR14 were recorded on day 1 (n = 77), day 3 (n = 126), day 7 (n = 123), and day 14 (n = 105), respectively. The relationships between dynamic NLR or leukocyte counts and clinical features were evaluated using Spearman's or Kendall's correlation analysis. Logistic regression analyses were used to identify the risk factors for unfavorable 3-month prognosis. The patients' dynamic NLR was positively associated with the National Institutes of Health Stroke Scale, ICH score, and hematoma volume at admission, while inversely correlated to the onset GCS score and FI at 3-month follow-up. Furthermore, higher NLR or lower absolute lymphocyte count obtained at admission was independently risk factor for UP at 3 months (adjusted odds ratio [OR]: 1.06, 95% confidence interval [CI]: 1.003, 1.12; OR: 0.41, 95% CI: 0.18, 0.94, respectively). In conclusion, higher NLR and lower lymphocyte counts at early stages were predictive of 3-month unfavorable outcomes in sICH patients., Competing Interests: The author have declared that no competing interests exist.

To determine whether positive or negative DWI TIA patients could get benefits from HST we conducted a cohort study which data from the prospective, hospital-based, TIA database of the First Affiliated Hospital of Zhengzhou University. The end-point was 7-day and 90-day incidence of stroke. Cox proportional hazard regression models were used to analyze the association between end-points and high-intensity statin treatment in TIA patients with positive and negative DWI. A total of 987 eligible TIA patients were analyzed. The stroke risk of patients with positive DWI was about a four-fold increase compared to that with negative DWI (7 d, 10.9 versus 1.8, p < 0.001 and 90 d, 18.3 versus 4.2, p < 0.001). After adjusting confounding factors, HST significantly improved both 7-day (HR 0.331, 95% CI 0.165-0.663; p = 0.002) and 90-day (HR 0.480, 95% CI 0.288-0.799; p = 0.005) outcomes in positive DWI patients. As a conclusion, high-intensity statin use reduces the 90 days' recurrent stroke risk in DWI-positive TIA patients but not in DWI-negative patients.

Background: Recent studies have reported that the levels of serum interleukin-33 (IL- 33) and its receptor, suppression of tumorigenicity 2 (ST2), are potential biomarkers for susceptibility of cardiovascular diseases. However, the genetic association of the IL-33/ST2 axis with cardiovascular diseases remains controversial., Objective: We aimed to investigate the association between common variants in the IL-33/ST2 axis and ischemic stroke in the Han Chinese population., Methods: We consecutively enrolled 1166 patients with ischemic stroke and 1079 age- and gender- matched controls. Eight single nucleotide polymorphisms (SNPs) within IL-33/ST2 axis were genotyped using the improved Multiple Ligase Detection Reaction platform. We analyzed the association between the tested SNPs and ischemic stroke at both the genotype and haplotype levels., Results: Binary logistic regression analysis indicated that rs10435816 (additive model: odds ratio [OR]=0.72, 95% confidence interval [CI], 0.54-0.95; recessive model: OR=0.72, 95%CI, 0.56- 0.94) was associated with a decreased risk of ischemic stroke after adjustment of confounding factors. Subgroup analysis indicated that rs10435816 (additive model: OR=0.61, 95%CI, 0.41-0.89; recessive model: OR=0.56, 95%CI, 0.40-0.80), rs7025417 (additive model: OR=0.57, 95%CI, 0.39-0.83), rs11792633 (additive model: OR=0.66, 95%CI, 0.46-0.95; recessive model: OR=0.67, 95%CI, 0.49-0.93), and rs7044343 (additive model: OR=0.69, 95%CI, 0.48-0.97; recessive model: OR=0.67, 95%CI, 0.49-0.91) were associated with a decreased risk of large-artery atherosclerosis stroke after adjustment of confounding factors., Conclusion: Our findings suggested an association between common variants in the IL-33/ST2 axis and a decreased risk of ischemic stroke in the Han Chinese population., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Lymphocyte to monocyte ratio (LMR) is associated with functional outcome in patients with stroke. But the relationship between the LMR value and the prognosis of cerebral venous sinus thrombosis (CVST) has not been investigated., Methods: CVST patients, admitted to the First Affiliated Hospital of Zhengzhou University, were retrospectively identified from November 2010 to January 2017. Functional outcomes of patients were evaluated with the modified Rankin Scale (mRS). Patients were divided into good (mRS 0-2) and poor (mRS 3-6) outcomes groups. Univariate and multivariate Cox regression analyses were used to assess the relationship between LMR and the poor survival outcome., Results: A total of 228 patients were included of which 41 had poor outcomes (18.0%). The duration of follow-up was 22 months (6-66 months). LMR (2.3±1.2 vs 3.2±1.8, p<0.01) was significantly lower in the poor outcome group. Multivariate Cox regression analysis showed that LMR (HR 0.726, 95% CI 0.546 to 0.964, p=0.027) was a independent predictor of poor prognosis., Conclusions: LMR may be a predictor of poor prognosis in CVST patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

CD4 + Foxp3 + regulatory T cells (Tregs) are critical in maintaining the peripheral tolerance and homeostasis of the immune system, yet their development and role in transplantation are poorly understood. Here we show that the levels of Tregs in neonatal transplant tolerant mice are similar to the levels in naive mice when they are kept in a state of homeostasis devoid of an immune response. An increased frequency of Tregs was observed only in recipients with allograft rejection, in naive mice that received alloantigens, or in tolerant mice adoptively transferred with alloreactive T cells. Even though an antigen-specific immune response is a prerequisite for the development of Tregs, both antigen-specific and nonspecific Tregs are generated in this process. We conclude that Tregs are induced and function in an inflammatory environment and in a negative feedback loop., Competing Interests: None., (IJCEP Copyright © 2018.)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease caused by mutations in NOTCH3. Prevailing models suggest that demyelination occurs secondary to vascular pathology. However, in zebrafish, NOTCH3 is also expressed in mature oligodendrocytes. Thus, we hypothesized that in addition to vascular defects, mutant NOTCH3 may alter glial function in individuals with CADASIL. The aim of this study was to characterize the direct effects of a mutant NOTCH3 protein in HS683 oligodendrocytes. HS683 oligodendrocytes transfected with wild-type NOTCH3, mutant NOTCH3(R90C), and empty control vector were used to study the impact of the NOTCH3(R90C) mutant on its protein hydrolytic processing, cell viability, apoptosis, autophagy, oxidative stress, and the related upstream events using immunoblotting, immunofluorescence, RT-PCR, and flow cytometry. We determined that HS683 oligodendrocytes transfected with mutant NOTCH3(R90C), which is the hotspot mutation site-associated with CADASIL, exhibited aberrant NOTCH3 proteolytic processing. Compared to cells overexpressing wild-type NOTCH3, cells overexpressing NOTCH3(R90C) were less viable and had a higher rate of apoptosis. Immunoblotting revealed that cells transfected with NOTCH3(R90C) had higher levels of intrinsic mitochondrial apoptosis, extrinsic death receptor path-related apoptosis, and autophagy compared with cells transfected with wild-type NOTCH3. This study suggests that in patients with CADASIL, early defects in glia influenced by NOTCH3(R90C) may directly contribute to white matter pathology in addition to secondary vascular defects. This study provides a potential therapeutic target for the future treatment of CADASIL.

The UL29 and UL28 proteins encoded by herpes simplex virus type 1 (HSV-1) are critical for its replication and packaging, respectively. Research has demonstrated that synthesized siRNA molecules targeting the UL29 gene are able to suppress HSV-2 replication and the UL28-null HSV-1 gene cannot form infectious viruses in vitro. Silencing the UL28 and UL29 genes by RNAi might lead to the development of novel antiviral agents for the treatment of HSV-1 infections. Two kinds of short hairpin RNAs (shRNAs) targeting the UL29 and UL28 genes were chemically synthesized and then delivered into cells by a replication-defective human adenovirus type 5 (Adv5) vector. (-) shRNAs targeting none of the genome of HSV-1 were used as the control. Vero cells were inoculated with Ad-UL28shRNA or Ad-UL29shRNA at a multiplicity of infection (MOI) of 100 and challenged 24 h later with HSV-1 at an MOI of 0.01 to inhibit HSV-1 replication, as measured by the level of the corresponding RNA and proteins. In addition, the amount of progeny virus was assessed at daily intervals. The antiviral effects of Ad-shRNAs at ongoing HSV-1 infection were explored at 12 h after inoculation of the HSV-1. The results showed that the shRNAs delivered by Adv5 significantly suppressed HSV-1 replication in vitro, as determined by the levels of viral RNA transcription, viral protein synthesis, and viral production. The Ad-UL28shRNA and Ad-UL29shRNA suppressed the replication of HSV-1, respectively, compared with the control group (P < 0.001). When Ad-UL28shRNA and Ad-UL29shRNA were combined, a synergistic effect was observed. The antiviral effects could sustain for at least 4 days after the HSV-1 infection (P < 0.001). Furthermore, antiviral effects were achieved 12 h prior to inoculation of Adv5-shRNAs (P < 0.001). Our data demonstrated comparable antiviral activities against herpes simplex virus by shRNAs targeting either UL29 or UL28 sites in vitro and the effectiveness of using the Adv5 delivery of shRNAs. Therefore, the Adv5 delivery of shRNAs targeting the UL29 and UL28 sites probably may provide an alternative strategy for controlling HSV-1 infection.

Recent studies have convincingly documented that hypogonadism is a component of various hereditary disorders and is often recognized as an important clinical feature in combination with various neurological symptoms, yet, the causative genes in a few related families are still unknown. High-throughput sequencing has become an efficient method to identify causative genes in related complex hereditary disorders. In this study, we performed exome sequencing in a family presenting hypergonadotropic hypogonadism with neurological presentations of mental retardation, epilepsy, ataxia, and leukodystrophy. After bioinformatic analysis and Sanger sequencing validation, we identified compound heterozygous mutations: c.482G>A (p.R161Q) and c.609G>A (p.W203X) in MMACHC gene in this pedigree. MMACHC was previously confirmed to be responsible for methylmalonic aciduria (MMA) combined with homocystinuria, cblC type (cblC disease), a hereditary vitamin B12 metabolic disorder. Biochemical and gas chromatography-mass spectrometry (GC-MS) examinations in this pedigree further supported the cblC disease diagnosis. These results indicated that hypergonadotropic hypogonadism may be a novel clinical manifestation of cblC disease, but more reports on additional patients are needed to support this hypothesis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Multiple system atrophy (MSA) is a neurodegenerative disease, and its pathological hallmark is the accumulation of α-synuclein proteins. Homocysteine (Hcy) is an intermediate amino acid generated during the metabolism of methionine. Hcy may contribute to the pathogenesis of neurodegenerative disorders. Vitamin B12 and folate are cofactors necessary for the methylation of homocysteine., Methods: This study compared the levels of serum Hcy, vitamin B12 and folate in patients with MSA with those in healthy people to reveal the possible association between MSA and plasma levels of Hcy, vitamin B12 and folate. We enrolled 161 patients with MSA and 161 healthy people in this study. The association between MSA and the levels of Hcy, vitamin B12 and folate were analyzed using binary logistic regression., Results: The mean level of Hcy in patients with MSA was significantly higher than that in healthy controls (16.23 ± 8.09 umol/l vs 14.04 ± 4.25 umol/l, p < 0.05). After adjusting for age, sex and medical history, the odds ratio for Hcy was 1.07 (95% CI = 1.01-1.13, p < 0.05) for patients with MSA. Vitamin B12 and folate levels were not significantly different between patients with MSA and controls., Conclusion: Our data suggest that higher levels of Hcy may be associated with an increased risk for MSA.

Stem cell to be a new intervention for treating intracerebral hemorrhage (ICH) might benefit humans. Therefore, we collected animal studies to find the effect of this innovative treatment. In July 2014, we searched Medline (from 1950), Embase (from 1980), China Biology Medicine disk (from 1978) for studies on stem cells used for treating experimental ICH in animal models that reported neurobehavioral and structural outcome. We evaluated the quality of these studies and used a weighted mean difference random affects model for the meta-analysis. We have collected 30 studies from 650 publications identified through systematic review describing the effects of 5 different type of stem cells on 12 different neurobehavioral scales with 1101 rodents or monkeys. Although there is lack of uniformity of the evaluation methods, these researches showed consistent improvements both in neurobehavioral function and structural outcomes. Besides, the quality of these studies needs to be raised. In conclusion, stem cells hold extensive potential in treating ICH, which should be further evaluated with more evidence-based, high-quality animal studies.

Background: Little is known about the effects of induced pluripotent stem cell (iPSC) treatment on acute cerebral inflammation and injuries after intracerebral hemorrhage (ICH), though they have shown promising therapeutic potentials in ischemic stoke., Methods: An ICH model was established by stereotactic injection of collagenase VII into the left striatum of male Sprague-Dawley (SD) rats. Six hours later, ICH rats were randomly divided into two groups and received intracerebrally 10 μl of PBS with or without 1 × 10(6) of iPSCs. Subsequently, neural function of all ICH rats was assessed at days 1, 3, 7, 14, 28 and 42 after ICH. Inflammatory cells, cytokines and neural apoptosis in the rats' perihematomal regions, and brain water content were determined on day 2 or 3 post ICH. iPSC differentiation was determined on day 28 post ICH. Nissl(+) cells and glial fibrillary acidic protein (GFAP)(+) cells in the perihematoma and the survival rates of rats in two groups were determined on post-ICH day 42., Results: Compared with control animals, iPSCs treatment not only improved neurological function and survival rate, but also resulted in fewer intracephalic infiltrations of neutrophils and microglia, along with decreased interleukin (IL)-1β, IL-6 and tumour necrosis factor-alpha (TNF-α), and increased IL-10 in the perihematomal tissues of ICH rats. Furthermore, brain oedema formation, apoptosis, injured neurons and glial scar formation were decreased in iPSCs-transplanted rats., Conclusions: Our findings indicate that iPSCs transplantation attenuate cerebral inflammatory reactions and neural injuries after ICH, and suggests that multiple mechanisms including inflammation modulation, neuroprotection and functional recovery might be involved simultaneously in the therapeutic benefit of iPSC treatment against hemorrhagic stroke.

Background: Progressive pseudorheumatoid dysplasia (PPD) is an extremely rare autosomal recessive genetic disease caused by mutation of the Wnt1-inducible signaling pathway protein 3 (WISP3) gene. Here, we characterize the clinical manifestations and features of PPD and screen for WISP3 mutations., Materials and Methods: We performed genetic testing for PPD in a Chinese family, after investigating the clinical particulars and family history, in addition to 200 healthy individuals, who served as the controls for this study. All 5 exons and the exon-intron boundaries of the WISP3 gene were amplified by polymerase chain reaction (PCR) and sequenced directly., Results: We identified a missense mutation (c.667T>G, p.C223G) in the maternal allele and a nonsense mutation (c.756C>A, p.C252X) in the paternal allele in the two affected individuals. To our knowledge, the mutation c.756C>A has not been reported previously. In these patients, there was a specific period when their condition markedly improved after having been very serious. Moreover, severe compression of lumbar spinal cord led to conspicuous spinal disorders in the proband., Conclusions: Our study suggests that novel C223G and C252X mutations in exon 4 of the WISP3 gene are responsible for PPD in Chinese patients. Furthermore, we report certain unique phenotypic characteristics in our patients., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cerebral hemorrhage (ICH) is a serious stroke subtype, currently lacking effective treatment. Recent research has shown that CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) play a key role in the immune response of ischemic stroke. However, Tregs in human hemorrhagic stroke are poorly investigated. In this study, a total of 90 ICH patients and 60 healthy controls were recruited. The frequency of circulating Tregs, plasma levels of TGF-β and IL-10, and the severity of neural dysfunction in ICH patients were investigated at different time points post ICH. We found that the peripheral frequency of Tregs in ICH patients was significantly increased, accompanied by boosted activated T cells. Importantly, the elevation of circulating Tregs in patients with severe dysfunction was much higher than that in less-severe patients, suggesting that disease severity affects circulating Tregs to exert regulatory function. Furthermore, both TGF-β and IL-10 that are related to the function of Tregs, were also increased in the peripheral blood of ICH patients. Our results demonstrate that Tregs-mediated immune imbalance might affect the development and severity of ICH, and suggest that Tregs may be used as tools and targets of cellular immunotherapy to effectively treat acute hemorrhagic stroke., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Fatigue is a major debilitating symptom after stroke. The biological mechanisms underlying poststroke fatigue (PFS) are unknown. We hypothesized that PSF is associated with an alteration in the balance between Th17 and Treg cells. To test this hypothesis we assessed fatigue in 30 stroke survivors using the Fatigue Scale for Motor and Cognitive Functions (FSMC). Peripheral blood was collected for assessment of Th17 and Treg cell populations and measurement of interleukin-10 (IL-10). Participants were dichotomized into severe fatigue (n = 14) and low-moderate fatigue (n = 16) groups by K-mean cluster analysis of FSMC scores. There were no group differences in age, gender, stroke type, stroke severity, or time since stroke. Stroke survivors in the severe fatigue group reported greater anxiety (p = 0.004) and depression (p = 0.001) than in the low-moderate fatigue group. The ratio of Th17 to Treg cells was significantly increased in the severe fatigue group relative to the mild-moderate fatigue group (p = 0.035). Serum levels of IL-10 negatively correlated withTh17/Treg ratio (r = -0.408,  p = 0.025). Our preliminary findings suggest that an imbalance in the Th17/Treg ratio is associated with the severity of PSF.