The structural gene, hap, for the secreted hemagglutinin/protease (HA/protease), a putative virulence factor of Vibrio cholerae, has recently been cloned and sequenced (C. C. Hase and R. A. Finkelstein, J. Bacteriol. 173:3311-3317, 1991). The availability of the null mutant, HAP-1, and HAP-1 complemented with pCH2 (which expresses HA/protease), enabled an examination of the role of HA/protease in the virulence of V. cholerae in an animal model. However, the mutants exhibited reversible colonial variation similar but not identical to that which was previously associated with dramatic changes in virulence of parental strain 3083. Regardless of colonial morphology, the mutants were found to be fully virulent in infant rabbits. Thus, the HA/protease is not a primary virulence factor (for infant rabbits). Observations using cultured human intestinal cells indicated, instead, that the HA/protease is responsible for detachment of the vibrios from the cultured cells by digestion of several putative receptors for V. cholerae adhesins.

Background: Epidemics of enterovirus 71 infection have caused the death of many children throughout the world. Rhombencephalitis, brain stem encephalitis, and heart failure were present in all of the fatal cases. However, no evidence of myocarditis was noted in the heart specimens, and the mechanism of heart failure remains unknown. Aims: To characterise the presentation of cardiac complications in children with enterovirus rhombencephalitis and discuss its pathogenesis. Methods: Ninety one consecutive patients with enterovirus rhombencephalitis underwent echocardiography. Of these, 17 patients (nine male, eight female; median age 14 months, range 4-57 months) with left ventricular dysfunction were studied. Results: Tachycardia was noted in all patients and systemic hypertension in 12. Muscle-brain fraction of creatine kinase was .5% in 14 patients. Plasma norepinephrine and epinephrine levels were significantly raised in the three patients in whom these were analysed. Electrocardiographic abnormalities were noted in eight patients. Pulmonary oedema was complicated in 15 patients. The initial ejection fraction of the left ventricle was 22-58% (mean 37%, SD 11%). All patients deteriorated to hypotensive shock within 12 hours and 13 died. Heart specimens from seven patients showed no evidence of myocarditis, but significant coagulative myocytolysis, myofibrillar degeneration, and cardiomyocyte apoptosis were observed. Conclusions: Acute heart failure was noted in 19% of patients with enterovirus rhombencephalitis, which had a fatality rate of 77%. It was not caused by myocarditis but possibly by neurogenic cardiac damage.

Hair cell (HC) loss is the main cause of permanent hearing loss in mammals. Previous studies have reported that in neonatal mice cochleae, Wnt activation promotes supporting cell (SC) proliferation and Notch inhibition promotes the trans-differentiation of SCs into HCs. However, Wnt activation alone fails to regenerate significant amounts of new HCs, Notch inhibition alone regenerates the HCs at the cost of exhausting the SC population, which leads to the death of the newly regenerated HCs. Mitotic HC regeneration might preserve the SC number while regenerating the HCs, which could be a better approach for long-term HC regeneration. We present a two-step gene manipulation, Wnt activation followed by Notch inhibition, to accomplish mitotic regeneration of HCs while partially preserving the SC number. We show that Wnt activation followed by Notch inhibition strongly promotes the mitotic regeneration of new HCs in both normal and neomycin-damaged cochleae while partially preserving the SC number. Lineage tracing shows that the majority of the mitotically regenerated HCs are derived specifically from the Lgr5+ progenitors with or without HC damage. Our findings suggest that the co-regulation of Wnt and Notch signaling might provide a better approach to mitotically regenerate HCs from Lgr5+ progenitor cells.

Complete resection of early-stage non-small cell lung cancer (NSCLC) is potentially curative, yet approximately 50% of patients are at risk for developing metastatic recurrence. Met, the receptor for hepatocyte growth factor (HGF) is a receptor tyrosine kinase with demonstrated roles in regulating cellular proliferation, motility, morphogenesis, and apoptosis. Met receptor and its ligand, HGF, are commonly overexpressed in NSCLC, and their overexpression has been associated with poor prognosis, which could potentially involve a paracrine and/or autocrine activation loop. However, there is as yet no direct evidence that HGF-Met signaling directly promotes metastasis in NSCLC cells. Using retroviral transduction, we overexpressed the human c-met and hgf complementary DNA, alone or in combination in the NCI-H460 human large cell carcinoma cell line. The HGF/Met co-overexpressing (H460-HGF/Met) cells demonstrated enhanced tumorigenicity in xenograft SCID mice. When these cells are implanted orthotopically into the lungs of nude rats, only the H460-HGF/Met cells showed higher spontaneous metastases to distant organs including bone, brain, and kidney. These results provide evidence that autocrine overactivation of the Met- HGF loop enhances systemic metastases in NSCLC. Targeted interference of this loop may potentially be an effective adjuvant therapy to improve survival of early-stage NSCLC patients.