Publications

RATIONALE

Induced pluripotent stem (iPS) cells can differentiate into multiple cell types, including cardiomyocytes and have tremendous potential for drug discovery and regenerative therapies. However, it is unknown how much variability exists between differentiated lineages from independent iPS cell lines and, specifically, how similar iPS cell-derived cardiomyocytes (iPS-CMs) are to embryonic stem (ES) cell-derived cardiomyocytes (ES-CMs).

OBJECTIVE

We investigated how much variability exists between differentiated lineages from independent iPS cell lines and how similar iPS-CMs are to ES-CMs.

METHODS AND RESULTS

We generated mouse iPS cells in which expression of NKX2-5, an early cardiac transcription factor, was marked by transgenic green fluorescent protein (GFP). Isolation of iPS- and ES-derived NKX2-5-GFP(+) cardiac progenitor pools, marked by identical reporters, revealed unexpectedly high similarity in genome-wide mRNA expression levels. Furthermore, the variability between cardiac progenitors derived from independent iPS lines was minimal. The NKX2-5-GFP(+) iPS cells formed cardiomyocytes by numerous induction protocols and could survive upon transplantation into the infarcted mouse heart without formation of teratomas.

CONCLUSIONS

Despite the line-to-line variability of gene expression in the undifferentiated state of ES and iPS cells, the variance narrows significantly in lineage-specific iPS-derived cardiac progenitors, and these progenitor cells can be isolated and used for transplantation without generation of unwanted cell types.

BACKGROUND

Diarrhoea is a major cause of morbidity and mortality among infants and children worldwide, especially in low- and middle-income countries. Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is a condition that similarly disproportionately affects low- and middle-income countries; of the nearly 2.1 million children under age 15 years living with HIV/AIDS, the large majority reside in sub-Saharan Africa. Infants and children with HIV infection have more frequent and more severe diarrhoea than children without HIV. Interventions including vitamin A, zinc and cotrimoxazole may contribute substantially to preventing diarrhoea in children with HIV infection or exposure to HIV.

OBJECTIVES

We perform a systematic review of randomised controlled trials and nonrandomised studies that examine the effectiveness of vitamin A, zinc and cotrimoxazole on mortality and morbidity from diarrhoea in HIV-infected and -exposed infants and children.

SEARCH STRATEGY

Electronic databases including Pubmed, Central and EMBASE were searched without limits to language from 1980 to April 2010. Conference database searches were performed, experts were contacted and bibliographies were handsearched.

SELECTION CRITERIA

Randomised controlled trials (RCTs) and nonrandomised studies (NRSs) that examined the effectiveness of the three interventions were included.

DATA COLLECTION AND ANALYSIS

Two reviewers independently assessed citations for eligibility and double-extracted included studies. Assessment of bias of individual studies was performed independently by both reviewers. Only two summary estimates were performed due to heterogeneity in study design and interventions.

MAIN RESULTS

Four RCTs were identified for vitamin A. One RCT was identified for zinc. One RCT and two NRSs were identified for cotrimoxazole. Vitamin A reduced mortality overall in children with HIV infection (four studies). A pooled estimate of three studies for reduction in mortality from vitamin A compared to placebo had a relative risk (DerSimonian and Laird method, random effects) of 0.50 (95% confidence interval (CI): 0.31 to 0.79) in 267 patients. Diarrheoa-specific mortality did not reach statistical significance and diarrhoeal morbidity outcomes were variable in three trials. Zinc supplementation reduced the number of physician visits for watery diarrhoea in one trial. Cotrimoxazole reduced mortality and hospitalisations compared to placebo in one RCT, although diarrhoea-specific morbidities were not significant.

AUTHORS' CONCLUSIONS

Vitamin A shows benefits in reduction of mortality in HIV-infected children. The effect of vitamin A on children with HIV exposure is not clear and needs further review. Zinc and combination vitamin A, zinc and micronutrient supplementation did not show an effect compared to vitamin A alone in children with HIV infection. Cotrimoxazole reduced mortality and some morbidity in children with HIV infection. Further research may clarify the effects of these interventions on morbidity from diarrhoea and in the population of children with HIV exposure.