Reductions in tonic GABAergic current in substantia gelatinosa neurons and GABAA receptor δ subunit expression after chronic constriction injury of the sciatic nerve in mice.

BACKGROUND: Decreased Gamma-aminobutyric acid (GABA)-ergic phasic inhibitory transmission in the spinal cord is thought to be responsible for the development of neuropathic pain. However, the role of GABAergic tonic current in substantia gelatinosa (SG) neurons in neuropathic pain remains to be fully elucidated. In this study, we assessed GABAergic tonic currents of SG neurons in a sciatic nerve chronic constriction injury (CCI) mouse. METHOD: Whole-cell patch clamp recordings form lumbar spinal cord slices was performed to evaluate GABAergic currents. We also investigated the expression changes of GABAA receptor subunits which are considered to mediate tonic currents. RESULTS: The percentage of SG neurons receiving GABAergic tonic currents decreased in CCI mice compared with Naïve mice. No significant change was observed in the mean amplitude of GABAergic tonic currents. RT-PCR and Western blot revealed that the expression of GABAA receptor δ subunits decreased following CCI. CONCLUSION: A reduction in the expression the δ subunit of the GABAA receptor and diminished GABAergic tonic current in SG neurons were observed after CCI in mice. GABAergic tonic current plays a key role in neuropathic pain. The GABAA receptor δ subunit may be a therapeutic target in neuropathic pain. WHAT DOES THIS STUDY ADD?: In spinal SG neurons, GABAergic inhibitory transmission operates through both phasic and tonic currents, but physiological role is largely unknown. In this study, we report dysregulation of GABAA receptor δ subunit-mediated tonic current in SG neurons may result in spinal disinhibition resulting in neuropathic pain in CCI mice.

MSX2 is an oncogenic downstream target of activated WNT signaling in ovarian endometrioid adenocarcinoma.

Ovarian endometrioid adenocarcinomas (OEAs) frequently exhibit constitutive activation of canonical WNT signaling, usually as a result of oncogenic mutations that stabilize and dysregulate the ß-catenin protein. In previous work, we used microarray-based methods to compare gene expression in OEAs with and without dysregulated ß-catenin as a strategy for identifying novel ß-catenin/TCF target genes with important roles in ovarian cancer pathogenesis. Among the genes highlighted by the microarray studies was MSX2, which encodes a homeobox transcription factor. We found MSX2 expression was markedly increased in primary human and murine OEAs with dysregulated ß-catenin compared with OEAs with intact ß-catenin regulation. WNT pathway activation by WNT3a ligand or GSK3ß inhibitor treatment potently induced MSX2 and ectopic expression of a dominant negative form of TCF4 inhibited MSX2 expression in ovarian cancer cells. Chromatin immunoprecipitation studies demonstrated that ß-catenin/TCF directly regulates MSX2 expression via binding to TCF binding elements in multiple regions of the MSX2 gene. Notably, ectopic MSX2 expression was found to promote neoplastic transformation of the rodent RK3E model epithelial cell line and to enhance the invasiveness of immortalized human ovarian epithelial cells in vitro and ovarian carcinoma cells in vivo. Inhibition of endogenous MSX2 expression in ovarian endometrioid cancer cells carrying a ß-catenin mutation using shRNA approaches inhibited neoplastic properties of the cells in vitro and in vivo. Expression of MSX2 in selected ovarian carcinoma cells induced changes suggestive of epithelial-mesenchymal transition (EMT), but based on analysis of ovarian cell lines and primary tumor tissues, effects of MSX2 on EMT appear to be complex and context-dependent. Our findings indicate MSX2 is a direct downstream transcriptional target of ß-catenin/TCF and has a key contributing role in the cancer phenotype of OEAs carrying WNT/ß-catenin pathway defects.

Survival of testicular cancer patients in Osaka, Japan.

BACKGROUND: Testicular cancer is one of those cancers for which the prognosis has improved remarkably since the introduction of effective chemotherapy. METHODS: Study subjects were 709 testicular cancer patients who were registered to the population-based Osaka Cancer Registry (OCR) as diagnosed between 1975 and 1992. The testicular cancer patients diagnosed/treated in the Osaka Medical Center for Cancer and Cardiovascular Diseases (OMCC) were also analyzed for comparison. RESULTS: The 5-year relative survival was 75.2% for the total of 709 patients and 77.9% for those diagnosed during 1990-92. These figures were much lower than those for patients in the USA and in Europe. In contrast, the 5-year survival of the 113 patients diagnosed in the OMCC during 1975-93 was 91.5% and similar to those in the USA and in Europe. CONCLUSIONS: The present study suggests that there are problems in the speed and extent of diffusion of effective chemotherapy for testicular cancer in Osaka.

HCV and GBV-c/HGV infection in HIV positive patients in southern Italy.

Flaviviridae-hepatitis C virus (HCV) and GB virus C/hepatitis G virus (GBV-C/HGV)--and human immunodeficiency virus (HIV) frequently show similar modes of transmission. HCV and GBV-C/HGV infection was assessed in 134 consecutive patients with evidence of HIV infection, living in Campania, Italy. Data obtained from this cohort were compared with those obtained from 252 age- and sex-matched HCV infected patients without evidence of HIV infection (HCV control group). Following enzymatic immunoassays, samples were tested for the presence of HCV-RNA by RT-PCR. The HCV-RNA positive sera were genotyped by LiPA procedure. The prevalence of HCV infection in HIV patients was 19.40% and the largest group of HIV-HCV co-infected patients (84.62%) was represented by intravenous drug users (IVDU). The distribution of HCV genotypes in HIV-HCV patients was different, compared to that observed in HCV control group. HCV genotypes la (50%) and 3a (23.08%) were more frequently detected in HIV HCV patients, compared to HCV control group (5.16 and 5.56% for la and 3a, respectively). Conversely, HCV genotypes lb (55.70%) and 2a/2c (30.26%) were more represented in HCV control group, compared to HIV-HCV patients (15.38 and 0% for lb and 2a/2c, respectively). GBV-C/HGV seroprevalence was 41.04% in HIV patients and 6.54% in healthy control individuals. Differently from HCV, GBV-C/HGV infection did not correlate to a preferential risk behaviour in the HIV cohort. Comparative analysis of HCV and GBV-C/HGV infection indicates that the use of injecting drugs might play a key role in the epidemiology of HCV and, in particular, of la and 3a HCV genotypes, in HIV patients.

[Possible role of altered levels of plasma docosahexaenoic acid in the pathogenesis of retinitis pigmentosa. Preliminary results]. / Possibile ruolo di alterati livelli dell'acido docosoexaenoico plasmatico nella patogenesi della retinite pigmentosa. Risultati preliminari.

Plasma samples obtained from Retinitis Pigmentosa (R.P.) patients and controls were assayed for docosahexaenoic acid (DXA), the major fatty acid in photoreceptor cells, in order to evaluate the possibility that abnormalities in PUFA metabolism could be involved in R.P. pathogenesis. Our preliminary results show levels of plasma DXA in dominantly inherited R.P. lower than in the recessive forms and controls.

The decrease of free epsilon-amino groups in senile and diabetic cataracts.

Free epsilon-amino groups in soluble and insoluble proteins were measured in clear human lenses and in diabetic and nondiabetic senile cataractous lenses. The free epsilon-amino group content of soluble and insoluble proteins was significantly lower in diabetic cataracts than in clear lenses and nondiabetic senile cataracts. Our results seem to demonstrate that nonenzymatic glycosylation of lens proteins could play a role in the pathogenesis of diabetic cataract.