Risk factors for ischemic stroke in patients with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms.

BACKGROUND: Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-negative MPNs) are linked with various complications, notably ischemic stroke. The study aims to identify risk factors for ischemic stroke in Ph-negative MPNs patients. METHODS: Patients were categorized into two groups based on whether they had experienced ischemic stroke. Subsequently, an analysis of demographics, biochemical makers, and genetic mutations (JAK2V617F and CALR mutations), was conducted to identify potential associations with an elevated risk of ischemic stroke in individuals with Ph-negative MPNs. RESULTS: A total of 185 patients diagnosed with Ph-negative MPNs participated in the study, including 82 with essential thrombocythemia (ET), 78 with polycythemia vera (PV), and 25 with primary myelofibrosis (PMF). Among these, 57 patients (30.8 %) had a history of ischemic stroke. Independent risk factors associated with ischemic stroke in Ph-negative MPNs patients included hypertension (OR = 5.076) and smoking (OR = 5.426). Among ET patients, smoking (OR = 4.114) and an elevated percentage of neutrophils (OR = 1.080) were both positively correlated with ischemic stroke incidence. For PV patients, hypertension (OR = 4.647), smoking (OR = 6.065), and an increased percentage of lymphocytes (OR = 1.039) were independently associated with ischemic stroke. Regardless of the presence of the JAK2V617F mutation, hypertension was the sole positively and independently associated risk factor for ischemic stroke. The odds ratios for patients with the JAK2V617F mutation was 3.103, while for those without the mutation, it was 11.25. CONCLUSIONS: Hypertension was a more substantial factor associated with an increased incidence of ischemic stroke in Ph-negative MPNs patients.

Pre-administration of BAX-inhibiting peptides decrease the loss of the nigral dopaminergic neurons in rats.

AIMS: In this study, we investigated the effects of Bax-inhibiting peptide (Bip)-V5, an anti-apoptosis membrane-permeable peptide, on the 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) model rats. MATERIALS AND METHODS: Rats were randomly divided into five groups: Control, 6-OHDA only, Vehicle+6-OHDA, zVAD+6-OHDA, and V5+6-OHDA, that rats were preadministrated with different reagents before 6-OHDA administration. KEY FINDINGS: The result showed that intrastriatal preadministration of Bip-V5 significantly decreased the amphetamine-induced rotation of the 6-OHDA model rats and the loss of the nigral dopaminergic (DA) neurons. Moreover, Bip-V5 intrastriatal preadministration not only significantly decreased the expression of activated caspase 9 and activated caspase 3 but also decreased the enhanced expression of AIF and its nuclear translocation in the SNpc. The results in our study provide the first experimental evidence that both caspase-dependent and AIF-dependent apoptosis pathways are involved in the loss of the nigral DA neurons caused by intrastriatal administration of 6-OHDA, and intrastriatal preadministration of Bip-V5 can inhibit the above two apoptosis pathways to protect the nigral DA neurons. SIGNIFICANCE: Our results provide a new idea that Bax-inhibiting peptide may be a promising preventive or therapeutic method for PD.

Bone marrow mesenchymal stem cells ameliorate neurological deficits and blood-brain barrier dysfunction after intracerebral hemorrhage in spontaneously hypertensive rats.

Spontaneous intracerebral hemorrhage (ICH) is a common and fatal subtype of stroke, with hypertension the most common cause of this disorder. Bone marrow derived mesenchymal stem cells (BM-MSCs) have been shown to elicit protective properties in stroke models. In the present study, male spontaneously hypertensive rats (SHR) were subjected to ICH by intracerebral injection with autologous blood, Wistar-Kyoto (WKY) rats were employed as control. The neurological function outcomes and blood-brain barrier (BBB) were assessed after BM-MSCs transplantation. Our results showed that BM-MSCs grafts via the tail vein significantly decreased the modified neurological severity score (mNSS) and the modified limb placing test (MLPT) score at 14 days after ICH, and the scores were gradually lowered till the end of test. Furthermore, BM-MSCs transplantation effectively attenuated the BBB permeability compared with the vehicle only group, as evidenced by the low level of Evans blue leakage in the BM-MSC group. In addition, we found that BM-MSCs grafts elevated the levels of tight junction associated protein occludin, and type IV collagen. Taken together, our results suggest that intravenously transplanted BM-MSCs exert therapeutic effects on ICH in spontaneously hypertensive rats. The underlying mechanisms are associated with the enhanced neurological function recovery and increased integrity of BBB. Our results provide the increased understanding of the underlying mechanisms and perspective of BMSCs in treatment for stroke.

Bone marrow stromal cells combined with oxiracetam influences the expression of B-cell lymphoma 2 in rats with ischemic stroke.

This study aimed to investigate the combination effects of bone marrow stromal cells (BMSCs) and oxiracetam for ischemic stroke. Forty Sprague Dawley female rats (220 ± 20 g) were subjected to a 2-hour ischemic middle cerebral artery occlusion (MCAO)-24 hours reperfusion model. The rats were randomly divided into 4 groups. Rats from BMSCs group, oxiracetam group, and BMSCs + oxiracetam group accepted injection of BMSCs (3 × 10(6) cells), oxiracetam (800 mg/kg), and BMSCs + oxiracetam, respectively. Rats from control group did not receive any interventions after ischemia reperfusion. The neurologic function was examined by modified neurological severity scores (mNSS). B-cell lymphoma 2 (Bcl-2) expression and apoptosis were detected by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The mNSS was decreased in all treatment groups and that in BMSCs + oxiracetam group was lower than BMSCs group and oxiracetam group (P < .05). The expression of Bcl-2 was unregulated in all treatment groups (P < .05), and similarly, the expression of Bcl-2 in BMSCs + oxiracetam group was higher than BMSCs group and oxiracetam group (P < .05). Control group displayed more TUNEL-positive cells than the treatment groups, and BMSCs + oxiracetam group displayed less apoptotic cells than BMSCs group or oxiracetam group (P < .05). Transplantation of BMSCs can promote the recovery of neurologic function in MCAO rats, and the effect of BMSCs combined with oxiracetam was better than the either one. Upregulation of Bcl-2 resulting in a decrease of apoptosis may be one of the mechanisms of BMSCs treatment for cerebral ischemic stroke.

Stratification of gene coexpression patterns and GO function mining for a RNA-Seq data series.

RNA-Seq is emerging as an increasingly important tool in biological research, and it provides the most direct evidence of the relationship between the physiological state and molecular changes in cells. A large amount of RNA-Seq data across diverse experimental conditions have been generated and deposited in public databases. However, most developed approaches for coexpression analyses focus on the coexpression pattern mining of the transcriptome, thereby ignoring the magnitude of gene differences in one pattern. Furthermore, the functional relationships of genes in one pattern, and notably among patterns, were not always recognized. In this study, we developed an integrated strategy to identify differential coexpression patterns of genes and probed the functional mechanisms of the modules. Two real datasets were used to validate the method and allow comparisons with other methods. One of the datasets was selected to illustrate the flow of a typical analysis. In summary, we present an approach to robustly detect coexpression patterns in transcriptomes and to stratify patterns according to their relative differences. Furthermore, a global relationship between patterns and biological functions was constructed. In addition, a freely accessible web toolkit "coexpression pattern mining and GO functional analysis" (COGO) was developed.

T cell CD40LG gene expression and the production of IgG by autologous B cells in systemic lupus erythematosus.

CD40 ligand (CD40LG), encoded on the X chromosome, has been reported to be overexpressed on lupus T cells. Herein, we investigated the effect of DNA demethylation on T cell CD40LG expression and the production of IgG by autologous B cells in lupus. We found normal human T cells transfected with CD40LG induced autologous B cell activation and plasma cell differentiation. Both female lupus CD4+ T cells and demethylating agents treated CD4+ T cells overexpressed CD40LG mRNA. Further, lupus T cells from both genders or demethylated CD4+ T cells from healthy women overstimulated autologous B cells, and this could be reversed with anti-CD40LG Ab in only females. We demonstrated that female lupus CD4+ T cells and demethylated CD4+ T cells express high level of CD40LG and overstimulate B cells to produce IgG. This is due to DNA demethylation and thereby reactivation of the inactive X chromosome in female.

Identification of novel genetic susceptibility loci for Behçet's disease using a genome-wide association study.

INTRODUCTION: Behçet's disease is a chronic systemic inflammatory disease that remains incompletely understood. Herein, we perform the first genome-wide association study in Behçet's disease. METHODS: Using DNA pooling technology and the Affymetrix 500K arrays, we identified possible candidate gene associations with Behçet's disease in a cohort of 152 Behçet's disease patients and 172 healthy ethnically matched controls. Genetic loci that were identified in the pooling study were genotyped in patients and controls using TaqMan genotyping technology. RESULTS: We identified genetic associations between Behçet's disease and single-nucleotide polymorphisms (SNPs) in KIAA1529, CPVL, LOC100129342, UBASH3B, and UBAC2 (odds ratio = 2.04, 2.26, 1.84, 1.71, and 1.61, respectively; P value = 4.2 x 10-5, 1.0 x 10-4, 3.0 x 10-4, 1.5 x 10-3, and 5.8 x 10-3, respectively). Among the associated SNPs, the Behçet's disease-risk allele in rs2061634 leads to substitution of serine to cysteine at amino acid position 995 (S995C) in the KIAA1529 protein. CONCLUSIONS: Using an unbiased whole-genome genetic association approach, we identified novel candidate genetic loci that are associated with increased susceptibility for Behçet's disease. These findings will help to better understand the pathogenesis of Behçet's disease and identify novel targets for therapeutic intervention.