A Detailed Epidemiological and Clinical Description of 6 Human Cases of Avian-Origin Influenza A (H7N9) Virus Infection in Shanghai

Background

The world’s first reported patient infected with avian influenza H7N9 was treated at the Fifth People’s Hospital of Shanghai. Shortly thereafter, several other cases emerged in the local area. Here, we describe the detailed epidemiological and clinical data of 6 cases of avian influenza H7N9.

Methods and Findings

We analyzed the epidemiologic and clinical data from clustered patients infected with H7N9 in the Minhang District of Shanghai during a 2-week period. Of the 6 patients, 2 were from a single family. In addition, 3 patients had a history of contact with poultry; however, all 6 patients lived in the proximity of 2 food markets where the H7N9 virus was detected in chickens and pigeons. The main symptoms were fever, cough, and hemoptysis. At onset, a decreased lymphocyte count and elevated creatine kinase, lactate dehydrogenase, procalcitonin, and C-reactive protein levels were observed. As the disease progressed, most patients developed dyspnea and hypoxemia. Imaging studies revealed lung consolidation and multiple ground-glass opacities in the early stage, rapidly extending bilaterally. All patients were treated with oseltamivir tablets beginning on days 3–8 after onset. The main complications were as follows: acute respiratory distress syndrome (ARDS; 83.3%), secondary bacterial infection (66.7%), pleural effusion (50%), left ventricular failure (33.3%), neuropsychiatric symptoms (33.3%), and rhabdomyolysis (16.7%). Of the 6 patients, 4 died of ARDS, with 2 patients recovering from the infection.

Conclusions

An outbreak of H7N9 infection occurred in the Minhang District of Shanghai that easily progressed to acute respiratory distress syndrome. Two cases showed family aggregation, which led us to identify the H7N9 virus and indicated that human transmission may be involved in the spread of this infection.     

Bradykinin Preconditioning Improves Therapeutic Potential of Human Endothelial Progenitor Cells in Infarcted Myocardium

Objectives

Stem cell preconditioning (PC) is a powerful approach in reducing cell death after transplantation. We hypothesized that PC human endothelial progenitor cells (hEPCs) with bradykinin (BK) enhance cell survival, inhibit apoptosis and repair the infarcted myocardium.

Methods

The hEPCs were preconditioned with or without BK. The hEPCs apoptosis induced by hypoxia along with serum deprivation was determined by annexin V-fluorescein isothiocyanate/ propidium iodide staining. Cleaved caspase-3, Akt and eNOS expressions were determined by Western blots. Caspase-3 activity and vascular endothelial growth factor (VEGF) levels were assessed in hEPCs. For in vivo studies, the survival and cardiomyocytes apoptosis of transplanted hEPCs were assessed using 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodi- carbocyanine,4-chlorobenzenesul-fonate salt labeled hEPCs and TUNEL staining. Infarct size and cardiac function were measured at 10 days after transplantation, and the survival of transplanted hEPCs were visualized using near-infrared optical imaging.

Results

In vitro data showed a marked suppression in cell apoptosis following BK PC. The PC reduced caspase-3 activation, increased the Akt, eNOS phosphorylation and VEGF levels. In vivo data in preconditioned group showed a robust cell anti-apoptosis, reduction in infarct size, and significant improvement in cardiac function. The effects of BK PC were abrogated by the B2 receptor antagonist HOE140, the Akt and eNOS antagonists LY294002 and L-NAME, respectively.

Conclusions

The activation of B2 receptor-dependent PI3K/Akt/eNOS pathway by BK PC promotes VEGF secretion, hEPC survival and inhibits apoptosis, thereby improving cardiac function in vivo. The BK PC hEPC transplantation for stem cell-based therapies is a novel approach that has potential for clinical used.     

Involvement of MAPK/NF-κB Signaling in the Activation of the Cholinergic Anti-Inflammatory Pathway in Experimental Colitis by Chronic Vagus Nerve Stimulation

Background

Autonomic nervous system dysfunction is implicated in the etiopathogenesis of inflammatory bowel diseases (IBD). Therapies that increase cardiovagal activity, such as Mind-Body interventions, are currently confirmed to be effective in clinical trials in IBD. However, a poor understanding of pathophysiological mechanisms limits the popularization of therapies in clinical practice. The aim of the present study was to explore the mechanisms of these therapies against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats using a chronic vagus nerve stimulation model in vivo, as well as the lipopolysaccharide (LPS)-induced inflammatory response in human epithelial colorectal adenocarcinoma cells (Caco-2) by acetylcholine in vitro.

Methods and Results

Colitis was induced in rats with rectal instillation of TNBS, and the effect of chronic VNS (0.25 mA, 20 Hz, 500 ms) on colonic inflammation was evaluated. Inflammatory responses were assessed by disease activity index (DAI), histological scores, myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS), TNF-α and IL-6 production. The expression of Mitogen-activated protein kinases (MAPK) family members, IκB-α, and nuclear NF-κB p65 were studied by immunoblotting. Heart rate variability (HRV) analysis was also applied to assess the sympathetic-vagal balance. DAI, histological scores, MPO activity, iNOS, TNF-α and IL-6 levels were significantly decreased by chronic VNS. Moreover, both VNS and acetylcholine reduced the phosphorylation of MAPKs and prevented the nuclear translocation of NF-κB p65. Methyllycaconitine (MLA) only reversed the inhibitory effect on p-ERK and intranuclear NF-κB p65 expression by ACh in vitro, no significant change was observed in the expression of p-p38 MAPK or p-JNK by MLA.

Conclusion

Vagal activity modification contributes to the beneficial effects of the cholinergic anti-inflammatory pathway in IBD-related inflamed colonic mucosa based on the activation of MAPKs and nuclear translocation of NF-κB. Our work may provide key pathophysiological mechanistic evidence for novel therapeutic strategies that increase the cardiovagal activity in IBD patients.     

Chemical Constituents from a Soil‐Derived Actinomycete,Actinomadura miaoliensis BCRC 16873, and Their Inhibitory Activities on Lipopolysaccharide‐Induced Tumor Necrosis Factor Production

An investigation on the secondary metabolites from the BuOH extract of the fermentation broth of the thermotolerant polyester‐degrading actinomycete Actinomadura miaoliensis BCRC 16873 was carried out. One previously undescribed α‐pyrone (=pyran‐2‐one) derivative, designated as miaolienone ( 1 ), and a new butanolide, miaolinolide ( 2 ), together with 13 known compounds, 3 – 15 , were obtained. Their structures were established on the basis of extensive 1D‐ and 2D‐NMR analyses in combination with HR‐MS experiments. In addition, the isolated compounds 1 – 15 were evaluated for the inhibitory effects of the isolates on the production of tumor necrosis factor (TNF‐α) induced by lipopolysaccharide (LPS). Among the isolates, 1 and 2 significantly inhibited TNF‐α production in U937 cells in vitro, and the IC₅₀ values were 0.59 and 0.76 μM , respectively. Compounds 3 – 5 displayed moderate inhibitory activities on LPS‐induced TNF‐α production.     

Triterpenoids from the Stem Bark of Melia toosendan and Determination of Their Absolute Configurations at C(24)

Six new triterpenoids, meliasenins S–X ( 1 – 6 , resp.), were isolated from the stem bark of Melia toosendan. Their structures were elucidated by mass spectrometry, NMR experiments, and comparison with the known compounds. Particularly, the absolute configuration at C(24) in new compounds was determined through their CD spectra of the [Pr(FOD)₃] complex (fod=1,1,1,2,2,3,3,7,7,7‐decafluoroheptane‐4,6‐dione) in CCl₄, as well as by using Mosher's method.     

Jatropha curcas L. (Euphorbiaceae) exhibits a mixed mating system, high correlated mating and apomixis

The hierarchical mating system among and within fruits of Jatropha curcas was investigated in a base population using five microsatellite loci, employing mixed mating and correlated mating models. Open-pollinated fruits were collected from 15 randomly selected seed trees, sampling seven fruits per tree for a total of 21 seeds from each tree. We detected multilocus genotypes identical to the mother tree in 13 % of offspring, implying the occurrence of apomixis in J. curcas. The presumed apomictic individuals were excluded from the analysis of the remaining results. Evidence of substantial selfing was provided by the average multilocus outcrossing rate (t _m?=?0.683), showing that the species exhibits a mixed mating system. The outcrossing rate showed a large variation among seed trees, ranging from 0.21 to 1.0, indicating that the species is not self-incompatible. Significant differences were detected between the multilocus and the single locus outcrossing rates (t _m???t _s?=?0.347) that suggested mating among related individuals, possibly because of the presence of individuals from the same progeny (sibs) in the base population. The multilocus paternity correlation was extremely high for the population (r _p(m)?=?0.999), indicating that the progenies were manly composed of full-sibs. As a consequence of selfing and a high paternity correlation, the co-ancestry coefficient within the progeny was higher (Θ?=?0.369) than expected for panmictic populations. Our results indicated that J. curcas produces seeds asexually by apomixis and sexually by a mixed mating system, combining selfing and outcrossing.