Pharmacokinetics and pharmacodynamics of intravenous delafloxacin in healthy subjects: model-based dose optimization.

Delafloxacin, a fluoroquinolone antibiotic to treat skin infections, exhibits a broad-spectrum antimicrobial activity. The first randomized, open-label phase I clinical trial was conducted to assess the safety and pharmacokinetics (PK) of intravenous delafloxacin in the Chinese population. A population pharmacokinetic (PopPK) model based on the clinical trial was conducted by NONMEM software. Monte Carlo simulation was performed to evaluate the antibacterial effects of delafloxacin at different doses in different Chinese populations. The PK characteristics of delafloxacin were best described by a three-compartment model with mixed linear and nonlinear clearance. Body weight was included as a covariate in the model. We simulated the AUC0-24h in a steady state at five doses in patient groups of various weights. The results indicated that for patients weighing 70 kg and treated with methicillin-resistant Staphylococcus aureus (MRSA) infections, a minimum dose of 300 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, suggesting an ideal bactericidal effect. For patients weighing less than 60 kg, a dose of 200 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, also suggesting an ideal bactericidal effect. Additionally, this trial demonstrated the high safety of delafloxacin in single-dose and multiple-dose groups of Chinese. Delafloxacin (300 mg, q12h, iv) was recommended for achieving optimal efficacy in Chinese bacterial skin infections patients. To ensure optimal efficacy, an individualized dose of 200 mg (q12h, iv) could be advised for patients weighing less than 60 kg, and 300 mg (q12h, iv) for those weighing more than 60 kg.

A novel nonsense mutation in PPP2R5D is associated with neurodevelopmental disorders and shows incomplete penetrance in a Chinese pedigree.

BACKGROUND AND PURPOSE: PPP2R5D mutations are known to cause neurodevelopmental disorders in an autosomal-dominant manner. To date, the vast majority of the reported cases in the literature have been sporadic with de novo mutations. There are no data regarding PPP2R5D mutation penetrance. We aimed to unravel the underlying genetic defects in 3 generations of a family affected by intellectual disability, neurodevelopmental delay, and facial dysmorphology. METHODS: We performed detailed clinical examinations and whole-exome sequencing in the family. RESULTS: We identified a novel mutation, c.1321 C>T (p.Arg441*), in PPP2R5D. The mutation cosegregated with affected family members I-2 and II-7 but not II-3, who bears the mutation but is phenotypically healthy. Our whole-exome sequencing also excluded the involvement of pathogenic mutations in other genes known to be related to neurodevelopmental disorders. The mutation was predicted to introduce a premature stop codon at position 441, thereby truncating the 162 amino acids at the C-terminus of the encoded protein. CONCLUSIONS: We report a familial transmitted PPP2R5D-related neurodevelopmental disorder as well as a novel nonsense pathogenic mutation and its incomplete penetrance. Our study expands the mutational and phenotypic spectra of PPP2R5D-related neurodevelopmental disorders, broadens our understanding of these disorders, and will thus be valuable for mutation-based pre- and postnatal screening and genetic diagnosis of neurodevelopmental disorders.

Vanillin Attenuates Proinflammatory Factors in a tMCAO Mouse Model via Inhibition of TLR4/NF-kB Signaling Pathway.

Vanillin has been reported to reduce hippocampal neuronal death in rat models of global cerebral ischemia. However, the immunoregulatory mechanism of vanillin in ischemic stroke is still unclear. To investigate the role of vanillin in a mouse model of ischemic stroke, we administered vanillin to mice after transient middle cerebral artery occlusion (tMCAO) by tail vein injection. Vanillin reduced infarct volume and improved motor function in mice after ischemia and reperfusion. IL-1ß and TNF-α were decreased in ischemic brain tissue of tMCAO mice after vanillin treatment compared with saline treatment. Similar effects were observed using the in vitro LPS-stimulated microglia cell model. Moreover, the reduced expression of proinflammatory cytokines in the vanillin group was related to TLR4/NF-κB signaling. Taken together, the findings suggest that vanillin decreased microglial activation by inhibiting the TLR4 /NF-κB signaling pathway, which reduced expression of proinflammatory cytokines IL-1ß and TNF-α, and finally reduced the infarct volume and improved motor function in tMCAO mice.

Association of LINC00673 rs11655237 polymorphism with pediatric glioma susceptibility in a Chinese population.

BACKGROUND: Previous researches have suggested that LINC00673 rs11655237 C>T polymorphism might be correlated to cancer susceptibility. However, its correlation with pediatric glioma is unknown. Therefore, this study aimed to determine whether LINC00673 rs11655237 C>T polymorphism is correlated with pediatric glioma. METHODS: In total, we included 399 subjects from South China. The Student's t-test was performed to evaluate age differences between glioma cases and controls. Differences in the categorical variables between the two groups were assessed using the χ2 test. A logistic regression was conducted to calculate the odds ratio (OR) and the 95% confidence interval (CI). RESULTS: We conducted this case-control study to investigate the association between LINC00673 polymorphism and pediatric glioma susceptibility. Our results revealed that LINC00673 rs11655237 C>T polymorphism was not correlated to pediatric glioma susceptibility in a Chinese population (CC/CT compared with TT: adjusted OR =2.49, 95% CI: 0.87-7.15, P=0.091). Furthermore, a stratified analysis also indicated LINC00673 rs11655237 C>T polymorphism did not increase the risk of glioma in different subgroups. CONCLUSIONS: Our study revealed that LINC00673 rs11655237 C>T polymorphism was not correlated to pediatric glioma susceptibility in a Chinese population. In the future, further exploration of this genetic factor in relation to glioma susceptibility will require a larger sample size to verify the current findings.

The correlation between polymorphisms in the XPC gene and glioma susceptibility in a Chinese pediatric population.

BACKGROUND: A previous study revealed that single nucleotide polymorphisms (SNPs) in coding genes play a key role in tumorigenesis, genetic disorders, and drug resistance. Xeroderma pigmentosum group C (XPC) protein is a key DNA damage recognition factor that is required for maintaining the genomic stability. However, the correlation between XPC polymorphisms and glioma susceptibility is still unclear. Hence, this study aimed to investigate the correlation between XPC polymorphisms and pediatric glioma susceptibility. METHODS: A total of 399 participants (171 glioma patients and 228 controls) were enrolled to evaluate the correlation between XPC polymorphism and pediatric glioma susceptibility. The count data of two groups was analyzed by chi-squared (χ2) test. Moreover, logistic regression was used to assess the strength of XPC polymorphisms associated with glioma susceptibility. RESULTS: We identified that XPC rs1870134 G>C reduced pediatric glioma susceptibility. Compared to participants with rs1870134 GG/GC genotypes, those with rs1870134 CC genotype had a significantly lower risk for glioma [adjusted odds ratio (AOR) =0.10, 95% confidence interval (CI): 0.01 to 0.78, P=0.028]. Patients with 4-5 genotypes have higher risk of glioma than those with 0-3 genotypes (AOR =1.59, 95% CI: 1.04 to 2.43, P=0.031). The stratified analysis showed that the risky effects of rs2228000 CT/TT genotypes and rs2229090 GC/CC genotypes were more predominant among children aged ≥60 months, astrocytic tumors, and clinical stage I. CONCLUSIONS: We found for the first time that XPC polymorphisms had a statistically significant correlation with pediatric glioma susceptibility in a Chinese population. The XPC rs2228000 CT/TT and rs2229090 GC/CC genotypes could both increase the risk of pediatric glioma in subgroups with females, astrocytic tumors, and clinical stage I. The XPC polymorphism has potential to be a useful adjunct method to screen pediatric glioma.

Yohimbine Ameliorates Temporomandibular Joint Chondrocyte Inflammation with Suppression of NF-κB Pathway.

Local joint inflammation plays an important role in the pathogenesis of temporomandibular joint (TMJ) osteoarthrosis (TMJOA). Yohimbine, an alpha-2 adrenergic receptor antagonist, possesses anti-inflammatory properties; however, the ability of Yohimbine to protect against TMJOA-associated chondrocyte inflammation remains unclear. We conducted in vitro and in vivo analyses to investigate whether Yohimbine could ameliorate TMJOA-induced chondrocyte inflammation and to elucidate the mechanisms involved. Chondrocytes of TMJOA mice were stimulated with interleukin (IL)-1ß or noradrenaline (NE), and the resulting production of inflammation-related factors was evaluated in the presence or absence of Yohimbine. Furthermore, two TMJOA mouse models were treated with Yohimbine and the therapeutic effect was quantified. NE (10-6 M) triggered inflammatory cytokine secretion by TMJ chondrocytes, and Yohimbine suppressed IL-1ß- or NE-induced IL-6 upregulation in TMJ chondrocytes with the nuclear factor (NF)-κB pathway inhibition. Yohimbine also ameliorated cartilage destruction in the TMJOA models. Interestingly, αmpT, a tyrosine hydroxylase inhibitor, reversed the effects of Yohimbine by activating the NF-κB pathway. Collectively, these findings show that Yohimbine ameliorated TMJ chondrocyte inflammation and the suppression of NF-κB pathway contributes to this effect.

Connectivity map identifies luteolin as a treatment option of ischemic stroke by inhibiting MMP9 and activation of the PI3K/Akt signaling pathway.

This study aimed to explore potential new drugs in the treatment of ischemic stroke by Connectivity Map (CMap) and to determine the role of luteolin on ischemic stroke according to its effects on matrix metalloproteinase-9 (MMP9) and PI3K/Akt signaling pathway. Based on published gene expression data, differentially expressed genes were obtained by microarray analysis. Potential compounds for ischemic stroke therapy were obtained by CMap analysis. Cytoscape and gene set enrichment analysis (GSEA) were used to discover signaling pathways connected to ischemic stroke. Cell apoptosis and viability were, respectively, evaluated by flow cytometry and an MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were used to test the expression of MMP9 and the PI3K/Akt signaling pathway-related proteins in human brain microvascular endothelial cells (HBMECs) and tissues. Additionally, the infarct volume after middle cerebral artery occlusion (MCAO) was determined by a TTC (2,3,5-triphenyltetrazolium chloride) assay. The microarray and CMap analyses identified luteolin as a promising compound for future therapies for ischemic stroke. Cytoscape and GSEA showed that the PI3K/Akt signaling pathway was crucial in ischemic stroke. Cell experiments revealed that luteolin enhanced cell viability and downregulated apoptosis via inhibiting MMP9 and activating the PI3K/Akt signaling pathway. Experiments performed in vivo also demonstrated that luteolin reduced the infarct volume. These results suggest that luteolin has potential in the treatment of ischemic stroke through inhibiting MMP9 and activating PI3K/Akt signaling pathway.

ePIANNO: ePIgenomics ANNOtation tool.

Recently, with the development of next generation sequencing (NGS), the combination of chromatin immunoprecipitation (ChIP) and NGS, namely ChIP-seq, has become a powerful technique to capture potential genomic binding sites of regulatory factors, histone modifications and chromatin accessible regions. For most researchers, additional information including genomic variations on the TF binding site, allele frequency of variation between different populations, variation associated disease, and other neighbour TF binding sites are essential to generate a proper hypothesis or a meaningful conclusion. Many ChIP-seq datasets had been deposited on the public domain to help researchers make new discoveries. However, researches are often intimidated by the complexity of data structure and largeness of data volume. Such information would be more useful if they could be combined or downloaded with ChIP-seq data. To meet such demands, we built a webtool: ePIgenomic ANNOtation tool (ePIANNO, http://epianno.stat.sinica.edu.tw/index.html). ePIANNO is a web server that combines SNP information of populations (1000 Genomes Project) and gene-disease association information of GWAS (NHGRI) with ChIP-seq (hmChIP, ENCODE, and ROADMAP epigenomics) data. ePIANNO has a user-friendly website interface allowing researchers to explore, navigate, and extract data quickly. We use two examples to demonstrate how users could use functions of ePIANNO webserver to explore useful information about TF related genomic variants. Users could use our query functions to search target regions, transcription factors, or annotations. ePIANNO may help users to generate hypothesis or explore potential biological functions for their studies.

Effect of Angiotensin-Converting Enzyme Inhibitors on Physical Function in Elderly Subjects: A Systematic Review and Meta-Analysis.

BACKGROUND: Sarcopenia has been accepted as a new geriatric syndrome, which will become a common and important public health challenge. And angiotensin-converting enzyme inhibitors (ACEIs) have been shown to improve exercise capacity in elderly without heart failure. OBJECTIVES: To evaluate the effect of angiotensin-converting enzyme inhibitors (ACEIs) on physical function in elderly. DATA SOURCES: The Cochrane Library, PubMed, EMBASE and Web of Science were searched. ELIGIBILITY CRITERIA: All researches included were randomized controlled trials (RCTs) which compared any kind of ACEIs with placebo or other anti-hypertensives in elderly, and provided empirical data of grip strength and 6-min walk distance change from baseline. STUDY APPRAISAL AND SYNTHESIS METHODS: Risk of bias was systematically assessed by using the Cochrane risk of bias tool. Data of grip strength and 6-min walk distance change from baseline were collected and mean differences (MDs) were calculated along with 95% CI (confidence interval) by using a random effects model. RESULTS: In 3 RCTs including 337 elderly participants, ACEIs (n = 178) did not significantly improved 6-min walk distance (13.45, 95% CI: -16.71 to 43.61; P = 0.38) versus placebo or other antihypertensives (n = 159). In 3 RCTs including 499 elderly participants, grip strength was not significantly different (-0.67, 95% CI: -1.53 to 0.19; P = 0.12) between ACEIs (n = 260) and placebo or other antihypertensives (n = 239). LIMITATIONS: There exists only 4 RCTs and the number of participants is limited. Pooling of data were from different trials including different participant characteristics. And intervention is not strictly consistent. CONCLUSION: This study shows that ACEIs can not significantly improve walk distance or the age-related decline of muscle strength for older participants in clinical trials.