Development and Validation of a Risk Scoring Tool for Bronchopulmonary Dysplasia in Preterm Infants Based on a Systematic Review and Meta-Analysis.

Background: Bronchopulmonary dysplasia (BPD) is the most common serious pulmonary morbidity in preterm infants with high disability and mortality rates. Early identification and treatment of BPD is critical. Objective: This study aimed to develop and validate a risk scoring tool for early identification of preterm infants that are at high-risk for developing BPD. Methods: The derivation cohort was derived from a systematic review and meta-analysis of risk factors for BPD. The statistically significant risk factors with their corresponding odds ratios were utilized to construct a logistic regression risk prediction model. By scoring the weights of each risk factor, a risk scoring tool was established and the risk stratification was divided. External verification was carried out by a validation cohort from China. Results: Approximately 83,034 preterm infants with gestational age < 32 weeks and/or birth weight < 1500 g were screened in this meta-analysis, and the cumulative incidence of BPD was about 30.37%. The nine predictors of this model were Chorioamnionitis, Gestational age, Birth weight, Sex, Small for gestational age, 5 min Apgar score, Delivery room intubation, and Surfactant and Respiratory distress syndrome. Based on the weight of each risk factor, we translated it into a simple clinical scoring tool with a total score ranging from 0 to 64. External validation showed that the tool had good discrimination, the area under the curve was 0.907, and that the Hosmer-Lemeshow test showed a good fit (p = 0.3572). In addition, the results of the calibration curve and decision curve analysis suggested that the tool showed significant conformity and net benefit. When the optimal cut-off value was 25.5, the sensitivity and specificity were 0.897 and 0.873, respectively. The resulting risk scoring tool classified the population of preterm infants into low-risk, low-intermediate, high-intermediate, and high-risk groups. This BPD risk scoring tool is suitable for preterm infants with gestational age < 32 weeks and/or birth weight < 1500 g. Conclusions: An effective risk prediction scoring tool based on a systematic review and meta-analysis was developed and validated. This simple tool may play an important role in establishing a screening strategy for BPD in preterm infants and potentially guide early intervention.

Identification and characterization of Jingmen tick virus in rodents from Xinjiang, China.

Jingmen tick virus (JMTV) is a recently identified virus which provides an unexpected connection between segmented and unsegmented RNA viruses. Recent investigations reveal that JMTV including JMTV-like virus (Alongshan virus) could be associated with human disease, suggesting the significance of JMTV in public health. To better understand the genetic diversity and host range of JMTV, a total of 164 rodents representing 8 species were collected in Qapqal Xibe county of Xinjiang Uygur Autonomous Region, China, and were screened for JMTVs using RT- PCR. Consequently, JMTV was identified in 42 rodents including 23 Microtus arvalis voles (24.5%), 9 Apodemus uralensis mice (29.0%), 5 Mus musculus mice, 1 Rhombomys opimus gerbil, 1 Meriones tamariscinus gerbil, 1 Meriones libycus gerbil, 1 Cricetulus migratorius hamster and 1 Microtus gregalis vole. Interestingly, nearly complete genome sequences were successfully recovered from 7 JMTV positive samples. Although the newly identified rodent JMTVs were closely related to those previously identified in ticks from China, based on the phylogenetic analysis of the S1, S2 and S3 segments, the newly identified rodent viruses clustered into two genetic groups. One group comprised of viruses only found in M. arvalis, while another group included viruses from A. uralensis, C. migratorius and M. gregalis. However, all rodent viruses clustered together in the S4 tree. Considering rodents live in close proximity to humans, more efforts are needed to investigate the role of rodents in the evolution and transmission of JMTV in nature.

Diversity and circulation of Jingmen tick virus in ticks and mammals.

Since its initial identification in ticks in 2010, Jingmen tick virus (JMTV) has been described in cattle, rodents, and primates. To better understand the diversity, evolution, and transmission of JMTV, we sampled 215 ticks, 104 cattle bloods, 216 bats, and 119 rodents in Wenzhou city, Zhejiang Province, China as well as 240 bats from Guizhou and Henan Provinces. JMTV was identified in 107 ticks (from two species), 54 bats (eleven species), 8 rodents (three species), and 10 cattle, with prevalence levels of 49.8, 11.8, 6.7, and 9.6 per cent, respectively, suggesting that bats may be a natural reservoir of JMTV. Phylogenetic analyses revealed that all the newly identified JMTVs were closely related to each other and to previously described viruses. Additionally, all tick and mammalian JMTV sampled in Wenzhou shared a consistent genomic structure, suggesting that the virus can cocirculate between ticks and mammals without observable variation in genome organization. All JMTVs sampled globally could be divided into two phylogenetic groups, Mantel tests suggested that geographic isolation, rather than host species, may be the main driver of JMTV diversity. However, the exact geographical origin of JMTV was difficult to determine, suggesting that this virus has a complex evolutionary history.

Miltefosine treatment reduces visceral hypersensitivity in a rat model for irritable bowel syndrome via multiple mechanisms.

Irritable bowel syndrome (IBS) is a heterogenic, functional gastrointestinal disorder of the gut-brain axis characterized by altered bowel habit and abdominal pain. Preclinical and clinical results suggested that, in part of these patients, pain may result from fungal induced release of mast cell derived histamine, subsequent activation of sensory afferent expressed histamine-1 receptors and related sensitization of the nociceptive transient reporter potential channel V1 (TRPV1)-ion channel. TRPV1 gating properties are regulated in lipid rafts. Miltefosine, an approved drug for the treatment of visceral Leishmaniasis, has fungicidal effects and is a known lipid raft modulator. We anticipated that miltefosine may act on different mechanistic levels of fungal-induced abdominal pain and may be repurposed to IBS. In the IBS-like rat model of maternal separation we assessed the visceromotor response to colonic distension as indirect readout for abdominal pain. Miltefosine reversed post-stress hypersensitivity to distension (i.e. visceral hypersensitivity) and this was associated with differences in the fungal microbiome (i.e. mycobiome). In vitro investigations confirmed fungicidal effects of miltefosine. In addition, miltefosine reduced the effect of TRPV1 activation in TRPV1-transfected cells and prevented TRPV1-dependent visceral hypersensitivity induced by intracolonic-capsaicin in rat. Miltefosine may be an attractive drug to treat abdominal pain in IBS.

Absence of diurnal variation in visceromotor response to colorectal distention in normal Long Evans rats.

BACKGROUND: Enhanced colorectal sensitivity (i.e. visceral hypersensitivity) is thought to be a pathophysiological mechanism in irritable bowel syndrome (IBS). In healthy men a circadian variation in rectal perception to colonic distention was described. Disturbed day and night rhythms, which occur in shift work and trans meridian flights, are associated with the prevalence of IBS. This raises the question whether disruptions of circadian control are responsible for the observed pathology in IBS. Prior to investigating altered rhythmicity in relation to visceral hypersensitivity in a rat model for IBS, it is relevant to establish whether normal rats display circadian variation similar to healthy men.  METHODOLOGY AND FINDINGS: In rodents colorectal distension leads to reproducible contractions of abdominal musculature. We used quantification of this so called visceromotor response (VMR) by electromyography (EMG) to assess visceral sensitivity in rats. We assessed the VMR in normal male Long Evans rats at different time points of the light/dark cycle. Although a control experiment with male maternal separated rats confirmed that intentionally inflicted (i.e. stress induced) changes in VMR can be detected, normal male Long Evans rats showed no variation in VMR along the light/dark cycle in response to colorectal distension. CONCLUSIONS: In the absence of a daily rhythm of colorectal sensitivity in normal control rats it is not possible to investigate possible aberrancies in our rat model for IBS.

Following OGD/R, annexin 1 nuclear translocation and subsequent induction of apoptosis in neurons are assisted by myosin IIA in a TRPM7 kinase-dependent manner.

Transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a bifunctional channel protein that contains an α-kinase domain at its C-terminal. Previous studies have indicated that oxygen-glucose deprivation/reoxygenation (OGD/R) induces neuronal apoptosis via TRPM7. Annexin 1 and myosin IIA have been identified as TRPM7 kinase substrates; however, the role of annexin 1 in OGD/R-induced neuron apoptosis remains unclear. Here, we report that OGD/R induces nuclear translocation of annexin 1 in primary cultured neurons. Interestingly, ablation of the TRPM7 kinase or a point mutation in Ser(5) interferes with TRPM7 kinase-annexin 1 binding, decreasing annexin 1 nuclear translocation, and thereby reducing neuronal apoptosis. Furthermore, mutation of Arg(205), which intercepts annexin 1-formyl peptide receptor binding, also decreased annexin 1 nuclear translocation. Coimmunoprecipitation indicated that annexin 1 is moved as cargo through the cytoplasm by myosin IIA. However, inhibiting myosin IIA can decrease annexin 1 nuclear translocation. Moreover, blocking myosin IIA function by antagonist injection into the lateral ventricle was found to improve learning and memory in rats after middle cerebral artery occlusion and could also improve cell viability after OGD/R. Last, we determined that the annexin 1-myosin IIA complex is recognized and translocated by the importin α/ß heterodimer. Therefore, TRPM7 kinase modulates OGD/R-induced neuronal apoptosis via annexin 1 carried by myosin IIA, while nuclear formyl peptide receptor (FPR)-annexin 1 binding and importin ß are involved in nuclear translocation.

Stress-induced visceral hypersensitivity in maternally separated rats can be reversed by peripherally restricted histamine-1-receptor antagonists.

BACKGROUND: The histamine-1 receptor (H1R) antagonist ketotifen increased the threshold of discomfort in hypersensitive IBS patients. The use of peripherally restricted and more selective H1R antagonists may further improve treatment possibilities. We examined the use of fexofenadine and ebastine to reverse post-stress visceral hypersensitivity in maternally separated rats. METHODS: The visceromotor response to colonic distension was assessed in adult maternally separated and nonhandled rats pre- and 24 hours post water avoidance. Subsequently rats were treated with vehicle alone or different dosages of fexofenadine (1.8 and 18 mg/kg) or ebastine (0.1 and 1.0 mg/kg) and re-evaluated. Colonic tissue was collected to assess relative RMCP-2 and occludin expression levels by Western blot and histamine-1 receptor by RT-qPCR. ß-hexosaminidase release by RBL-2H3 cells was used to establish possible mast cell stabilizing properties of the antagonists. KEY RESULTS: Water avoidance only induced enhanced response to distension in maternally separated rats. This response was reversed by 1.8 and 18 mg/kg fexofenadine. Reversal was also obtained by 1.0 but not 0.1 mg/kg ebastine. RMCP-2 expression levels were comparable in these two ebastine treatment groups but occludin was significantly higher in 1.0 mg/kg treated rats. There were no differences in histamine-1 receptor expression between nonhandled and maternally separated rats. Fexofenadine but not ebastine showed mast cell stabilizing quality. CONCLUSIONS: Our results indicate that the peripherally restricted 2(nd) generation H1-receptor antagonists fexofenadine and ebastine are capable of reversing post stress visceral hypersensitivity in rat. These data justify future IBS patient trials with these well tolerated compounds.