VHL Type 2B Mutations Retain VBC Complex Form and Function

Background: von Hippel-Lindau disease is characterized by a spectrum of hypervascular tumors, including renal cell carcinoma, hemangioblastoma, and pheochromocytoma, which occur with VHL genotype-specific differences in penetrance. VHL loss causes a failure to regulate the hypoxia inducible factors (HIF-1a and HIF-2a), resulting in accumulation of both factors to high levels. Although HIF dysregulation is critical to VHL disease-associated renal tumorigenesis, increasing evidence points toward gradations of HIF dysregulation contributing to the degree of predisposition to renal cell carcinoma and other manifestations of the disease. Methodology/Principal Findings: This investigation examined the ability of disease-specific VHL missense mutations to support the assembly of the VBC complex and to promote the ubiquitylation of HIF. Our interaction analysis supported previous observations that VHL Type 2B mutations disrupt the interaction between pVHL and Elongin C but maintain partial regulation of HIF. We additionally demonstrated that Type 2B mutant pVHL forms a remnant VBC complex containing the active members ROC1 and Cullin-2 which retains the ability to ubiquitylate HIF-1a. Conclusions: Our results suggest that subtypes of VHL mutations support an intermediate level of HIF regulation via a remnant VBC complex. These findings provide a mechanism for the graded HIF dysregulation and genetic predisposition fo

Between personal wishes and medical "prescription": Mode of delivery and post-partum sterilisation among women with HIV in Brazil

HIV-positive women are confronted during pregnancy with a range of medical information and prescriptions that substantially affect the experience of pregnancy and birth. Based on antenatal and post-partum interviews with 60 HIV-positive pregnant women from Sao Paulo and Porto Alegre, Brazil, this article presents evidence of some of the factors that affect mode of delivery and access to post-partum sterilisation, and the implications of these. Whether women gave birth vaginally or by Caesarean section was medically prescribed, with women's own preferences taking second place. Some were advised that caesarean section was the only option with HIV in pregnancy; others were told it should be used only for medical indications, even if the woman wanted to be sterilised at the some time. The women in Porto Alegre were less likely to get a sterilisation than those in Sao Paulo, even with caesarean section, as sterilisation was not encouraged locally. Many of the women who accepted a Caesarean had been convinced before they gave birth that it was the best choice for them, either because it reduced the risk of perinatal HIV transmission or because it facilitated tubal ligation, or both. However, after they gave birth, the women judged their experience of delivery and the post-partum period mainly in comparison to previous deliveries, and many of them viewed the birth experience with HIV as more difficult than previous deliveries and worse than they had expected. (C) 2003 Reproductive Health Matters. All rights reserved.112211312

The impact of health care providers on female sterilization among HIV-positive women in Brazil

This paper explores the reproductive preferences and outcomes of HIV-positive women in two cities in Brazil. We used three types of data, all drawn from women who delivered in public sector hospitals: (1) clinical records of 427 HIVpositive women; (2) pre- and postpartum in-depth interviews with 60 HIV-positive women; and (3) a prospective survey carried out among 363 women drawn from the general population. The HIV-positive samples were collected on women who had prenatal care between July 1999 and June 2000, and the general population survey was conducted with women who started prenatal care between April 1998 and June 1999. Among the women in the clinic sample, we found dramatic differences in the proportion sterilized postpartum: 51% in Sao Paulo vs. 4% in Porto Alegre, compared to 3.4% and 1.1%, respectively, of women in the general population. Our qualitative data suggest that HIV-positive women in this study had strong preferences to have no more future children and that female sterilization was the preferred way to achieve this end. Therefore, we conclude that the large difference in rates is mainly due to HIV-positive women's differential access to sterilization in the two settings. In-depth interviews revealed that women in Sao Paulo were often encouraged by clinic staff to be sterilized postpartum. In contrast, HIV-positive women in Porto Alegre clinics were not offered sterilization as an option and those who requested it were repeatedly put off. The striking difference found in the frequency with which doctors provide postpartum sterilization to seropositive women in our study sites deserves attention and discussion in the respective medical communities. At the higher level of national policy on reproductive rights, there may be grounds for reopening discussion about the norms regarding postpartum procedures, and for devoting far more resources to expanding contraceptive options. (c) 2005 Elsevier Ltd. All rights reserved.61354155