Can Volunteer Community Health Workers Decrease Child Morbidity and Mortality in Southwestern Uganda? An Impact Evaluation

Background

The potential for community health workers to improve child health in sub-Saharan Africa is not well understood. Healthy Child Uganda implemented a volunteer community health worker child health promotion model in rural Uganda. An impact evaluation was conducted to assess volunteer community health workers'' effect on child morbidity, mortality and to calculate volunteer retention.

Methodology/Principal Findings

Two volunteer community health workers were selected, trained and promoted child health in each of 116 villages (population ∼61,000) during 2006–2009. Evaluation included a household survey of mothers at baseline and post-intervention in intervention/control areas, retrospective reviews of community health worker birth/child death reports and post-intervention focus group discussions. Retention was calculated from administrative records. Main outcomes were prevalence of recent child illness/underweight status, community health worker reports of child deaths, focus group perception of effect, and community health worker retention. After 18–36 months, 86% of trained volunteers remained active. Post-intervention surveys in intervention households revealed absolute reductions of 10.2% [95%CI (−17.7%, −2.6%)] in diarrhea prevalence and 5.8% [95%CI (−11.5%, −0.003%)] in fever/malaria; comparative decreases in control households were not statistically significant. Underweight prevalence was reduced by 5.1% [95%CI (−10.7%, 0.4%)] in intervention households. Community health worker monthly reports revealed a relative decline of 53% in child deaths (<5 years old), during the first 18 months of intervention. Focus groups credited community health workers with decreasing child deaths, improved care-seeking practices, and new income-generating opportunities.

Conclusions/Significance

A low-cost child health promotion model using volunteer community health workers demonstrated decreased child morbidity, dramatic mortality trend declines and high volunteer retention. This sustainable model could be scaled-up to sub-Saharan African communities with limited resources and high child health needs.     

Activated TLR signaling in atherosclerosis among women with lower Framingham risk score: the multi-ethnic study of atherosclerosis

Background

Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis.

Results

A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis.

Conclusion

Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals.     

Haemolysin II is a Bacillus cereus virulence factor that induces apoptosis of macrophages

Bacillus cereus is a Gram‐positive spore‐forming bacterium causing food poisoning and serious opportunistic infections. These infections are characterized by bacterial accumulation despite the recruitment of phagocytic cells. The precise mechanisms and the bacterial factors allowing B. cereus to circumvent host immune responses remain to be elucidated. We have previously shown that B. cereus induces macrophage cell death by an unknown mechanism. Here we identified the toxic component from the B. cereus supernatant. We report that Haemolysin II (HlyII) provokes macrophage cell death by apoptosis through its pore‐forming activity. The HlyII‐induced apoptotic pathway is caspase 3 and 8 dependent, thus most likely mediated by the death receptor pathway. Using insects and mice as in vivo models, we show that deletion of hlyII strongly reduces virulence. In addition, we show that after infection of Bombyx mori larvae, the immune cells are apoptotic, demonstrating that HlyII induces apoptosis of phagocytic cells in vivo. Altogether, our results clearly unravel HlyII as a novel virulence protein that induces apoptosis in phagocytic cells in vitro and in vivo.     

Mitochondrial DNA variations associated with recurrent pregnancy loss among Indian women

Several genetic factors have been found to be associated with recurrent pregnancy loss (RPL). However, not many attempts have been made to associate the mitochondrial DNA (mtDNA) variations with RPL. Therefore, we have analyzed the complete mtDNA of 100 women with RPL and 12 aborted fetal tissues. Our analysis revealed a total of 681 variations, most of which were in NADH Dehydrogenase (ND) genes that encode mitochondrial enzyme Complex I. Presence of T4216C variation (ND1 gene) in 9% of the RPL women and several pathogenic, and novel mutations suggest the role of mtDNA variations in RPL.     

Antiserum detection of reactive carbonyl species-modified DNA in human colonocytes

Polyunsaturated fats have been linked to occurrences of sporadic colon cancer. One possible cause may be degradation of polyunsaturated fats during cooking, resulting in multiple reactive carbonyl species (RCS) that can damage nuclear DNA and proteins, particularly in rapidly dividing colon crypt cells. This study describes a novel antiserum against RCS-modified DNA, with apparent order of reactivity to DNA modified with 4-hydroxy-trans-2-nonenal > glyoxal > acrolein > crotonaldehyde > malondialdehyde; some reactivity was also observed against conjugated Schiff base-type structures. Anti-(RCS-DNA) antiserum was successfully utilised to demonstrate formation of RCS-DNA in a human colon cell model, exposed to RCS insult derived from endogenous and exogenous lipid peroxidation sources. Further utilisation of the antiserum for immunohistochemical analysis confirmed RCS-modified DNA in crypt areas of ‘normal’ colon tissue. These results fully support a potential role for dietary lipid peroxidation products in the development of sporadic colon cancer.     

Preclinical evaluation of the Aurora kinase inhibitors AMG 900, AZD1152-HQPA,and MK-5108 on SW-872 and 93T449 human liposarcoma cells

Liposarcoma is a malignant soft tissue tumor that originates from adipose tissue and is one of the most frequently diagnosed soft tissue sarcomas in humans. There is great interest in identifying novel chemotherapeutic options for treating liposarcoma based upon molecular alterations in the cancer cells. The Aurora kinases have been identified as promising chemotherapeutic targets based on their altered expression in many human cancers and cellular roles in mitosis and cytokinesis. In this study, we investigated the effects of an Aurora kinase A inhibitor (MK-5108), an Aurora kinase B inhibitor (AZD1152-HQPA), and a pan-Aurora kinase inhibitor (AMG 900) on undifferentiated SW-872 and well-differentiated 93T449 human liposarcoma cells. Treatment of the SW-872 and 93T449 cells with MK-5108 (0–1000 nM), AZD1152-HQPA (0–1000 nM), and AMG 900 (0–1000 nM) for 72 h resulted in a dose-dependent decrease in the total viable cell number. Based upon the EC₅₀ values, the potency of the three Aurora kinase inhibitors in the SW-872 cells was as follows: AMG 900 (EC₅₀ = 3.7 nM) > AZD1152-HQPA (EC₅₀ = 43.4 nM) > MK-5108 (EC₅₀ = 309.0 nM), while the potency in the 93T449 cells was as follows: AMG 900 (EC₅₀ = 6.5 nM) > AZD1152-HQPA (EC₅₀ = 74.5 nM) > MK-5108 (EC₅₀ = 283.6 nM). The percentage of polyploidy after 72 h of drug treatment (0–1000 nM) was determined by propidium iodide staining and flow cytometric analysis. AMG 900 caused a significant increase in polyploidy starting at 25 nM in the SW-872 and 93T449 cells, and AZD1152-HQPA caused a significant increase starting at 100 nM in the SW-872 cells and 250 nM in the 93T449 cells. The Aurora kinase A inhibitor MK-5108 did not significantly increase the percentage of polyploid cells at any of the doses tested in either cell line. The expression of Aurora kinase A and B was evaluated in the SW-872 cells versus differentiated adipocytes and human mesenchymal stem cells by real-time RT-PCR and Western blot analysis. Aurora kinase A and B mRNA expression was significantly increased in the SW-872 cells versus the differentiated adipocytes and human mesenchymal stem cells. Western blot analysis revealed a ~ 48 kDa immunoreactive band for Aurora kinase A that was not present in the differentiated adipocytes or the human mesenchymal stem cells. A ~ 39 kDa immunoreactive band for Aurora kinase B was detected in the SW-872 cells, differentiated adipocytes, and human mesenchymal stem cells. A smaller immunoreactive band for Aurora kinase B was detected in the SW-872 cells but not in the differentiated adipocytes and human mesenchymal stem cells, and this may reflect the expression of a truncated splice variant of Aurora kinase B that has been associated with poor patient prognosis. The 93T449 cells demonstrated decreased expression of Aurora kinase A and B mRNA and protein compared to the SW-872 cells, and also expressed the truncated form of Aurora kinase B. The results of these in vitro studies indicate that Aurora kinase inhibitors should be further investigated as possible chemotherapeutic agents for human liposarcoma.