AIDS and South Africa--towards a comprehensive strategy. Part I. The world-wide experience

In this, the first of a three-part series of articles in which we propose steps towards a comprehensive strategy for the control of HIV infection, we consider briefly the world-wide experience with the HIV epidemic. Our objective is to highlight the problems and controversial issues which are pertinent to strategies for the control of HIV infection. We focus on problems of case-definition, differences between 'African' and 'Western' AIDS and the implications for South Africa, and problems with sensitivity and specificity of tests used at present, particularly in the context of false positivity in a community with a low prevalence of HIV infection. We consider some of the ethical issues, including the need for adequate counselling, the need for informed consent before testing, and the centrality of confidentiality, particularly in the context of possible victimisation and neglect of HIV-positive individuals. Differences between 'notification' and 'reporting' are emphasised. Recommendations are made regarding these problems.     

Scant activation of CD8 T cells by antigen loaded on heat shock protein

Heat shock proteins (HSP) not only function as chaperones for denatured proteins but also for antigenic peptides, thus inducing protective T cell responses. Here we show that vaccination with peptide-loaded HSP70 causes initial interferon-gamma production by murine CD8 T cells but no T cell expansion. These CD8 T cells lacked cytotoxic activity in vitro and in vivo, which was not due to apoptosis. Restimulation with peptide-pulsed dendritic cells both bypassed the proliferative block and suspended the non-protective state of CD8 T lymphocytes in an infection model with the bacterial pathogen, Listeria monocytogenes. Cotransfer of antigen-specific CD4 T cells circumvented the proliferative arrest of CD8 T cells. Our data suggest that HSP vaccines induce CD8 T cell unresponsiveness unless proficient help is provided. Assuming that this model reflects the antigenically experienced human condition where immunological space is restricted and any T cell response possibly leads to suppression of heterologous reactions, our findings bear implications for rational vaccination protocols including those for immunocompromised patients.     

The effects of ZD6474, an inhibitor of VEGF signaling, on cutaneous wound healing in mice

BACKGROUND: ZD6474 is an inhibitor of the VEGFR-2 receptor tyrosine kinase with additional activity against EGFR-1 receptor tyrosine kinases that has been shown to inhibit tumor growth and wound-induced neovascularization in pre-clinical studies and phase I clinical trials. The purpose of this study was to determine the effects of ZD6474 on breaking strength in a murine model of cutaneous wound healing. MATERIALS AND METHODS: Balb/C mice were given ZD6474 (50 or 100 mg/kg p.o.) or vehicle starting 7 days before wounding. Two full-thickness incisions were made in each mouse and closed using suture. On post-wounding day 7 or 28, laser Doppler blood flow measurements were made, and the breaking strength of the wounded skin was determined. Microvessel density measurements were performed using computer image analysis of CD31-stained sections. RESULTS: Compared with controls, mice treated with ZD6474 showed a significantly reduced dose-dependent decline in breaking strength, both at POD 7 (P < 0.001) and at POD 28 (P < 0.005). Histologically, the ZD6474-treated mice showed a qualitative reduction in the degree of fibrosis and epithelial proliferation at the wound site, but no significant difference was noted between the 50 mg/kg and 100 mg/kg ZD6474-treated groups. Also, microvessel density measurements demonstrated no significant difference between groups. CONCLUSION: In a murine model of wound healing, ZD6474 treatment did not prevent wound healing, but was associated with a reduced skin breaking strength compared with vehicle-treated controls at both 7 and 28 days post-wounding. These observations may have clinical relevance for the perioperative management of patients treated with inhibitors of angiogenesis.     

Changes in oxygen delivery during hemodialysis.

The effect of hemodialysis on oxygen delivery has been assessed in nine patients. During hemodialysis the arterial PO2 decreased from 76.89 mm Hg to 69.03 mm Hg. There was also an increase in pH from 7.39 to 7.49 which resulted in an increase in the affinity of the blood for oxygen. In the absence of compensatory changes this could result in a 17.9% decrease in oxygen delivery. This could be hazardous in patients who are already anemic particularly in the presence of cardiac or respiratory insufficiency.