DDX5 promotes oncogene C3 and FABP1 expressions and drives intestinal inflammation and tumorigenesis.

Tumorigenesis in different segments of the intestinal tract involves tissue-specific oncogenic drivers. In the colon, complement component 3 (C3) activation is a major contributor to inflammation and malignancies. By contrast, tumorigenesis in the small intestine involves fatty acid-binding protein 1 (FABP1). However, little is known of the upstream mechanisms driving their expressions in different segments of the intestinal tract. Here, we report that the RNA-binding protein DDX5 binds to the mRNA transcripts of C3 and Fabp1 to augment their expressions posttranscriptionally. Knocking out DDX5 in epithelial cells protected mice from intestinal tumorigenesis and dextran sodium sulfate (DSS)-induced colitis. Identification of DDX5 as a common upstream regulator of tissue-specific oncogenic molecules provides an excellent therapeutic target for intestinal diseases.

Augmentation strategies for clozapine refractory schizophrenia: A systematic review and meta-analysis.

BACKGROUND: Although clozapine is the most effective medication for treatment refractory schizophrenia, only 40% of people will meet response criteria. We therefore undertook a systematic review and meta-analysis of global literature on clozapine augmentation strategies. METHODS: We systematically reviewed PubMed, PsycInfo, Embase, Cochrane Database, Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database for randomised control trials of augmentation strategies for clozapine resistant schizophrenia. We undertook pairwise meta-analyses of within-class interventions and, where possible, frequentist mixed treatment comparisons to differentiate treatment effectiveness Results: We identified 46 studies of 25 interventions. On pairwise meta-analyses, the most effective augmentation agents for total psychosis symptoms were aripiprazole (standardised mean difference: 0.48; 95% confidence interval: -0.89 to -0.07) fluoxetine (standardised mean difference: 0.73; 95% confidence interval: -0.97 to -0.50) and, sodium valproate (standardised mean difference: 2.36 95% confidence interval: -3.96 to -0.75). Memantine was effective for negative symptoms (standardised mean difference: -0.56 95% confidence interval: -0.93 to -0.20). However, many of these results included poor-quality studies. Single studies of certain antipsychotics (penfluridol), antidepressants (paroxetine, duloxetine), lithium and Ginkgo biloba showed potential, while electroconvulsive therapy was highly promising. Mixed treatment comparisons were only possible for antipsychotics, and these gave similar results to the pairwise meta-analyses. CONCLUSIONS: On the basis of the limited data available, the best evidence is for the use of aripiprazole, fluoxetine and sodium valproate as augmentation agents for total psychosis symptoms and memantine for negative symptoms. However, these conclusions are tempered by generally short follow-up periods and poor study quality.

Effectiveness of Pharmacological Treatment for Attention-Deficit/Hyperactivity Disorder on Physical Injuries: A Systematic Review and Meta-Analysis of Observational Studies.

BACKGROUND: Patients with attention-deficit/hyperactivity disorder (ADHD) are more prone to physical injuries, including motor vehicle accidents, fractures and brain injuries. Several observational studies have been published investigating the association between the use of pharmacological treatment for ADHD and the incidence of physical injuries among patients with ADHD; however, the findings are not concordant. OBJECTIVE: This study is a systematic review and meta-analysis of the existing literature and estimates the overall association between the use of ADHD medications and physical injury. Injury is defined as medically attended physical injuries in the form of hospitalisations, emergency department visits or general practitioners visits. METHODS: The PubMed, EMBASE, PsycINFO, CINAHL and Cochrane Review databases were searched for relevant studies published up to May 2017 relating to ADHD medication and risk of injuries. Observational studies with any study design, all age groups (children and adults) and all ADHD medications (stimulant and non-stimulants) were included. Studies relevant to the association between ADHD medication exposure and risk of injuries in ADHD patients were extracted and compiled for meta-analysis. Both within-individual and between-individual analyses were conducted. RESULTS: Overall, 2001 citations were identified and 10 observational studies were included. Three self-controlled case series and two self-controlled cohorts were eligible for meta-analysis of within-individual studies. Five cohort studies were included in the meta-analysis of between-individual studies. The adjusted rate ratio of the within-individual methods was 0.76 (95% confidence interval [CI] 0.61-0.93) and 0.88 (95% CI 0.85-0.92) for between-individual studies. CONCLUSION: The findings of this meta-analysis support a reduced risk of injuries among ADHD patients who were treated with ADHD medications.

Comparison of the Fagerström Test for Cigarette Dependence and the Heaviness of Smoking Index in the Second and Third Trimester of Pregnancy.

INTRODUCTION: Smoking cessation at any stage of pregnancy can benefit the mother and fetus. Cigarette dependence is a significant factor in women who continue to smoke during pregnancy and accurate assessment of cigarette dependence can be helpful in planning smoking cessation programs. The objective of our study was to investigate the validity of the Fagerstrom Test for Cigarette Dependence (FTCD) and Heaviness of Smoking Index (HSI) as measures of cigarette dependence in the second and third trimesters of pregnancy by comparing them to serum cotinine levels. METHODS: Prospective cohort study of 167 women in their second and third trimester of pregnancy who self-reported cigarette smoking. They were administered the FTCD questionnaire and blood was drawn for cotinine measurements using a direct enzyme linked immunoassay. Linear regression was used to adjust for maternal age, body mass index, gestation, and parity to investigate the association between cotinine levels and the two scores. RESULTS: Both the FTCD and HSI correlated significantly with serum cotinine levels (Spearman coefficient 0.42 and 0.37, respectively, p < .001). The correlation coefficients of both scores were higher in primigravidas (n = 51) compared to multigravidas, but the difference was statistically nonsignificant. Using multiple linear regression, both scores were significantly related to serum cotinine levels. For each unit increase in the FTCD and HSI, the serum cotinine level increased by 21.4 ng/mL (95% confidence interval 10.1-32.7, p <0.001) and 37 ng/mL (95% confidence interval 18.6-55.4, p < 0.001), respectively. CONCLUSIONS: Both the FTCD and HSI can be used to assess cigarette dependence in the second and third trimester of pregnancy. IMPLICATIONS: There is lack of data on the validity of the FTCD and the HSI as markers of cigarette dependence during the second and third trimester of pregnancy. Our study suggests that both the FTCD and HSI perform well in assessing cigarette dependence in the second and third trimester of pregnancy and can be used to plan smoking cessation programs.

Metabotropic NMDA receptor signaling couples Src family kinases to pannexin-1 during excitotoxicity.

Overactivation of neuronal N-methyl-D-aspartate receptors (NMDARs) causes excitotoxicity and is necessary for neuronal death. In the classical view, these ligand-gated Ca(2+)-permeable ionotropic receptors require co-agonists and membrane depolarization for activation. We report that NMDARs signal during ligand binding without activation of their ion conduction pore. Pharmacological pore block with MK-801, physiological pore block with Mg(2+) or a Ca(2+)-impermeable NMDAR variant prevented NMDAR currents, but did not block excitotoxic dendritic blebbing and secondary currents induced by exogenous NMDA. NMDARs, Src kinase and Panx1 form a signaling complex, and activation of Panx1 required phosphorylation at Y308. Disruption of this NMDAR-Src-Panx1 signaling complex in vitro or in vivo by administration of an interfering peptide either before or 2 h after ischemia or stroke was neuroprotective. Our observations provide insights into a new signaling modality of NMDARs that has broad-reaching implications for brain physiology and pathology.