Gonadotropin-releasing hormone gene expression during the rat estrous cycle: effects of pentobarbital and ovarian steroids.

Although hypothalamic GnRH release is known to be modulated by neural and hormonal factors, the relationship between altered GnRH secretion and GnRH synthesis remains unclear. In an attempt to address this question, we examined GnRH gene expression in the rat hypothalamus using in situ hybridization histochemistry. An 25S-labeled antisense RNA probe was used to identify neurons expressing GnRH mRNA in an area that included the diagonal band of Broca, the organum vasculosum of the lamina terminalis, and the preoptic area. The number of GnRH mRNA-expressing cells was determined at various times during the rat estrous cycle. During proestrus, the number of GnRH mRNA-expressing cells decreased somewhat at 1400-1600 h, increased significantly at 1800 h (the time of the LH surge), then gradually returned to basal levels at 2200 h. Expression did not change substantially at other times during the estrous cycle. To understand this close temporal relationship between the LH surge and increased GnRH mRNA levels, we examined GnRH gene expression in proestrous animals in which the LH surge was blocked with pentobarbital. Pentobarbital treatment blocked the increase in the number of GnRH mRNA-expressing cells normally observed at 1800 h in saline-treated controls, suggesting that the increase in GnRH gene expression is closely coupled to secretion of GnRH from the hypothalamus. Finally, we addressed the question of whether ovarian steroids have direct effects on GnRH gene expression by examining GnRH mRNA levels in ovariectomized steroid-treated rats at a time before (1100 h) and a time after (1800 h) hypothalamic GnRH hypersecretion. At 1100 h, no significant changes were observed, but at 1800 h, estrogen-treated rats showed a significant increase in both the number of GnRH mRNA-expressing cells and serum LH levels. This suggests that estrogen influences GnRH gene expression indirectly, perhaps by altering hypothalamic GnRH release. Our results in each of these models suggest that GnRH mRNA levels increase in response to GnRH hypersecretion at the time of the LH surge.     

Study Protocol - Accurate assessment of kidney function in Indigenous Australians: aims and methods of the eGFR Study

Background

Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) in HIV-infected patients receiving a commonly used nevirapine-based antiretroviral therapy is a major concern for African clinicians owing to its high prevalence, the infrequent testing and treatment of viral hepatitis, and the impact of liver disease on the tolerability and effectiveness of anti-HIV treatment. We compared the hepatotoxicity and the immunological, virological and clinical effectiveness of a nevirapine-based antiretroviral therapy between patients infected with HIV only and patients coinfected with hepatitis B or C virus in Cameroon.

Methods

A retrospective cohort study was conducted among HIV-1-infected patients. Plasma HBV DNA and HCV RNA were tested in positive or indeterminate samples for HBsAg or HCV antibodies, respectively. All patients received nevirapine and lamivudine plus stavudine or zidovudine.

Results

Of 169 HIV-1-infected patients with a median baseline CD4 count of 135 cells/mm³ (interquartile range [IQR] 67-218), 21% were coinfected with HBV or HCV. In coinfected patients, the median viral load was 2.47 × 10⁷ IU/mL for HBV (IQR 3680-1.59 × 10⁸) and 928 000 IU/mL for HCV (IQR 178 400-2.06 × 10⁶). Multivariate analyses showed that the risk of hepatotoxicity was 2-fold higher in coinfected patients (p < 0.01). The response to antiretroviral therapy was however comparable between monoinfected and coinfected patients in terms of CD4 cell count increase (p = 0.8), HIV-1 viral load below 400 copies/mL (p = 0.9), death (p = 0.3) and death or new AIDS-defining event (p = 0.1). Nevirapine was replaced by a protease inhibitor in 4 patients owing to hepatotoxicity.

Conclusion

This study suggests that the nevirapine-based antiretroviral therapy could be used safely as first-line treatment in patients with low CD4 cell count in Africa despite frequent coinfections with HBV or HCV and infrequent testing of these infections. Although testing for HBV and HCV should be systematically performed before initiating antiretroviral therapy, transaminases elevations at baseline or during treatment should be a decisive argument for testing when hepatitis status is unknown.     

Higher human T-cell leukaemia virus type 1 (HTLV-1) proviral load is associated with end-stage kidney disease in Indigenous Australians: Results of a case-control study in central Australia

Case series suggest that human T-cell leukaemia virus type 1 (HTLV-1) is associated with kidney disease; however, little is known about the impact of proviral load (PVL). The present study was commenced to determine whether higher HTLV-1 PVL is associated with end stage kidney disease (ESKD) in Indigenous Australians. A case-control study was conducted in Alice Springs Hospital (ASH), 1 July 2007 to 30 November 2015. Cases included all 80 Indigenous adults (>17 years) with HTLV-1c and ESKD, matched 1:1 by sex to controls with HTLV-1 who had no renal disease or other recognised disease associations of HTLV-1, and were recruited during the same period. The association between PVL and ESKD was assessed using logistic regression. Median (IQR) HTLV-1c PVL for subjects with ESKD (6.86, IQR (3.35, 8.23) log copies per 10⁵ peripheral blood leukocytes (PBL) (ie, 0.95; IQR, 0.03; 3.70% PBL) was significantly higher than that of the asymptomatic group (3.47; IQR (−0.04, 6.61) log copies per 10 ⁵ PBL (ie, 0.01; IQR, 0.00; 0.52% PBL) (asymptomatic vs ESKD, P (ranksum) < .001). Major factors associated with ESKD were diabetes (adjusted odds ratio [aOR], 21.80; 95% CI, 4.84, 98.22; P < .001), hypertension (aOR, 4.16; 1.11, 15.64; P = .03), remote residence (aOR, 5.34; 95% CI, 1.17, 27.29; P = .03) and HTLV-1c PVL greater than or equal to 100 copies per 10 ⁵ PBL (aOR, 3.67; 95% CI, 1.36, 9.92; P = .01). Higher HTLV-1c PVL are strongly associated with inflammatory diseases. The high HTLV-1c PVL reported here may have clinical implications for people with HTLV-1 who require haemodialysis. Longitudinal studies are required to determine whether this association is causal.     

Topically applied imiquimod inhibits vascular tumor growth in vivo

Vascular tumors occur in approximately 10% of all infants and may be associated with significant morbidity. Available therapies for vascular tumors, such as systemic corticosteroids, vincristine, and interferon-alpha, may cause toxicity, limiting their use to complicated cases. Using a mouse hemangioendothelioma model, we investigated the efficacy and mechanism of action of imiquimod, a topically applied inducer of cytokines. Application of imiquimod cream, whether initiated at the time of cell inoculation or when tumors became visible, significantly decreased tumor growth and increased animal survival in comparison with control mice. Imiquimod-treated tumors showed decreased tumor cell proliferation, increased tumor apoptosis, and increased expression of tissue inhibitor of matrix metalloproteinase-1 with decreased activity of matrix metalloproteinase-9. The demonstration that local application of imiquimod inhibits vascular tumor enlargement in the mouse vascular tumor model suggests a novel, less toxic means of treating infantile hemangioendotheliomas and perhaps other cutaneous vascular tumors.     

Disseminated microsporidiosis with Encephalitozoon species in a renal transplant recipient

To our knowledge, 5 cases of disseminated microsporidiosis with Encephalitozoon species have been reported worldwide in transplant recipients. George et al. present the first such case in Australia, to be reported and treated with good clinical recovery.