Background. Very low rates of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) are achievable with use of highly active anti

To derive reliable estimates of the sensitivity of HIV-1 DNA polymerase chain reaction (PCR) in the neonatal period and to quantify the relative contributions of intra-uterine and intra-partum transmission. After reviewing studies on the early diagnosis of HIV-1 infection, investigators were asked to provide published and unpublished PCR test results on prospectively followed, non-breastfed, vertically infected children. Age-specific estimates of the sensitivity of PCR were derived using distribution-free methods for interval-censored data. Data on 271 infected children were combined for analysis. PCR detected HIV-1 DNA in an estimated 38% [90% confidence interval (CD, 29–46] of HIV-infected children tested on the day of, or day after, birth. Sensitivity was observed to rise rapidly in the second week of life, reaching 93% (90% Cl, 76–97) by 14 days of age. The sensitivity of PCR in the neonatal period is higher than previously reported. This affects the clinical interpretation of an early negative test result and encourages the use of PCR as an endpoint for trials to evaluate interventions to reduce vertical transmission in non-breastfed populations. Approximately one-third of vertically acquired HIV-1 infection could be attributable to intra-uterine transmission.

Functional characterization of signaling pathways that critically control mantle cell lymphoma (MCL) cell growth and survival is relevant to designing new therapies for this lymphoma. We herein demonstrate that the constitutive activation of Akt correlates with the expression of the phosphorylated, inactive form of PTEN. Phosphatidyl-inositol-3 kinase (PI3-K)/Akt or mammalian target of rapamycin (mTOR) inhibition decreased the growth of both primary MCL cultures and established cell lines and antagonizes the growth-promoting activity of CD40 triggering and IL-4. These effects are mediated by nuclear accumulation of the p27^Kip1 inhibitor induced by down-regulation of the p45^Skp2 and Cks1 proteins, which target p27^Kip1 for degradation. Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome-dependent degradation driven by GSK-3. Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition. Finally, PI3-K/Akt inhibitors, but not rapamycin, induced variable levels of caspase-dependent apoptosis and reduced telomerase activity. These results indicate that Akt and mTOR activation have distinct functional relevance in MCL and suggest that targeting Akt may result in more effective therapeutic effects compared with mTOR inhibition.

Objective. To describe the natural history of vertically acquired human immunodeficiency virus (HIV) infection. Design. This was a prospective follow-up study. Setting. Ten centers of the European Collaborative Study participated. Subjects. One hundred twenty-four HIV-infected children were born to women known to be infected at or before the time of delivery since 1986. Main outcome measures. Deaths, acquired immunodeficiency syndrome (AIDS), and HIV-related symptoms and signs were assessed. Results. In this cohort, treatment before the onset of AIDS was not universal. Less than 10% of children were treated with Zidovudine or intravenous gamma globulin before 6 months of age, with a steady increase to about 40% after 3 years of life. An estimated 23% (95% confidence interval: 15% to 31%) of infected children develop AIDS before the age of 1 year, and nearly 40% (27% to 50%) by 4 years. Ten percent (5% to 16%) die before age 1 year and 28% (16% to 41%) before age 5 years. Twenty-four months after the AIDS diagnosis, an estimated 48% (36% to 70%) of the children are still alive. Although after the age of 1 year immunologic abnormalities became increasingly common, the proportion of infected children with significant HIV-related symptoms or signs declined. Conclusion. The progression of disease in this cohort of vertically infected children was not as fast as previously suggested, even though treatment was not widespread. Although infected children have a high risk of developing some manifestation of HIV infection early in life, serious HIV-related symptoms became less frequent with increasing age. This has important implications for health planning and care provision.