Altered Memory T-Cell Responses to Bacillus Calmette-Guerin and Tetanus Toxoid Vaccination and Altered Cytokine Responses to Polyclonal Stimulation in HIV-Exposed Uninfected Kenyan Infants

Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy and T-cell immunity in this vulnerable population is warranted.     

Acceptability and Use of Portable Drinking Water and Hand Washing Stations in Health Care Facilities and Their Impact on Patient Hygiene Practices,Western Kenya

Many health care facilities (HCF) in developing countries lack access to reliable hand washing stations and safe drinking water. To address this problem, we installed portable, low-cost hand washing stations (HWS) and drinking water stations (DWS), and trained healthcare workers (HCW) on hand hygiene, safe drinking water, and patient education techniques at 200 rural HCFs lacking a reliable water supply in western Kenya. We performed a survey at baseline and a follow-up evaluation at 15 months to assess the impact of the intervention at a random sample of 40 HCFs and 391 households nearest to these HCFs. From baseline to follow-up, there was a statistically significant increase in the percentage of dispensaries with access to HWSs with soap (42% vs. 77%, p<0.01) and access to safe drinking water (6% vs. 55%, p<0.01). Female heads of household in the HCF catchment area exhibited statistically significant increases from baseline to follow-up in the ability to state target times for hand washing (10% vs. 35%, p<0.01), perform all four hand washing steps correctly (32% vs. 43%, p = 0.01), and report treatment of stored drinking water using any method (73% vs. 92%, p<0.01); the percentage of households with detectable free residual chlorine in stored drinking water did not change (6%, vs. 8%, p = 0.14). The installation of low-cost, low-maintenance, locally-available, portable hand washing and drinking water stations in rural HCFs without access to 24-hour piped water helped assure that health workers had a place to wash their hands and provide safe drinking water. This HCF intervention may have also contributed to the improvement of hand hygiene and reported safe drinking water behaviors among households nearest to HCFs.     

Factors That Affect Quality of Life among People Living with HIV Attending an Urban Clinic in Uganda: A Cohort Study

Introduction

With the availability of antiretroviral therapy (ART) and primary general care for people living with HIV (PLHIV) in resource limited settings, PLHIV are living longer, and HIV has been transformed into a chronic illness. People are diagnosed and started on treatment when they are relatively well. Although ART results in clinical improvement, the ultimate goal of treatment is full physical functioning and general well-being, with a focus on quality of life rather than clinical outcomes. However, there has been little research on the relationship of specific factors to quality of life in PLHIV. The objective of this study was to investigate factors associated with quality of life among PLHIV in Uganda receiving basic care and those on ART.

Methods

We enrolled 1274 patients attending an HIV outpatient clinic into a prospective cohort study. Of these, 640 received ART. All were followed up at 3 and 6 months. Health related quality of life was assessed with the MOS-HIV Health Survey and the Global Person Generated Index (GPGI). Multivariate linear regression and logistic regression with generalized estimating equations were used to examine the relationship of social behavioral and disease factors with Physical Health Summary (PHS) score, Mental Health Summary (MHS) score, and GPGI.

Results

Among PLHIV receiving basic care, PHS was associated with: sex (p=0.045) - females had lower PHS; age in years at enrollment (p=0.0001) - older patients had lower PHS; and depression (p<0.001) - depressed patients had lower PHS. MHS was only associated with opportunistic infection (p=0.01) - presence of an opportunistic infection was associated with lower MHS. For the GPG the associated variables were age (p=0.03) - older patients had lower GPGI; education (p=0.01) – higher education associated with higher GPGI; and depression - patients with depression had a lower GPGI (p<0.001). Among patients on ART, PHS was associated with: study visit (p=0.01), with increase in time there was better PHS, and this also improved with increase in education level (p=0.002). Patients with WHO disease stage 3&4 had a lower PHS compared to patients at stage 1&2 (p=0.006), and depressed patients had lower PHS (p<0.001). MHS improved from baseline to six month study visit (p<0.001), and females had lower MHS compared to males (p=0.01). GPGI was associated with higher income (p=0.04), alcohol use was associated with lower GPGI (p=0.004), and depressed patients had a lower GPGI (p<0.001).

Conclusion

Quality of life improved over time for PLHIV on ART. Regardless of treatment status, PLHIV with depression or low education level and female gender were at risk of having a poor quality of life. Clinicians and policy makers should be aware of these findings, and address them to improve quality of life for PLHIV.     

Ecosystem engineering in the Quaternary of the West Coast of South Africa

Despite advances in our understanding of the geographic and temporal scope of the Paleolithic record, we know remarkably little about the evolutionary and ecological consequences of changes in human behavior. Recent inquiries suggest that human evolution reflects a long history of interconnections between the behavior of humans and their surrounding ecosystems (e.g., niche construction). Developing expectations to identify such phenomena is remarkably difficult because it requires understanding the multi‐generational impacts of changes in behavior. These long‐term dynamics require insights into the emergent phenomena that alter selective pressures over longer time periods which are not possible to observe, and are also not intuitive based on observations derived from ethnographic time scales. Generative models show promise for probing these potentially unexpected consequences of human‐environment interaction. Changes in the uses of landscapes may have long term implications for the environments that hominins occupied. We explore other potential proxies of behavior and examine how modeling may provide expectations for a variety of phenomena.     

Marten space use and habitat selection in managed coniferous boreal forests of eastern Canada

Effects of habitat loss and fragmentation on the behavior of individual organisms may have direct consequences on population viability in altered forest ecosystems. The American marten (Martes americana) is a forest specialist considered as one of the most sensitive species to human-induced disturbances. As some studies have shown that martens cannot tolerate >30–40% clear-cuts within their home range, we investigated marten space use (home range size and overlap) and habitat selection in landscapes fragmented by 2 different patterns of timber harvesting in the black spruce boreal forest: dispersed-cut landscapes (10–80 ha cut-blocks) and clustered-cut landscapes (50–200 ha cut-blocks). We installed radio-collars on female martens and determined 20 winter home ranges (100% minimum convex polygons and 60–90% kernels) in dispersed-cut (n = 8) and clustered-cut (n = 12) landscapes. Home range size was not related to the proportion of clear-cuts (i.e., habitat loss), but rather to the proportion of mixedwood stands 70–120 years old. However, female body condition was correlated to habitat condition inside their home ranges (i.e., amount of residual forest and recent clear-cuts). At the home range scale, we determined that mixedwood forests were also among the most used forest stands and the least used were recent clear-cuts and forested bogs, using resource selection functions. At the landscape scale, home ranges included more mixedwood forests than random polygons and marten high activity zones were composed of more residual forest and less human-induced disturbances (clear-cuts, edges, and roads). These results suggest that mixedwood forests, which occupy approximately 10% of the study area, play a critical role for martens in this conifer-dominated boreal landscape. We recommend permanent retention or special management considerations for these isolated stands, as harvesting mixedwood often leads to forest composition conversion that would reduce the availability of this highly used habitat. © The Wildlife Society, 2013     

The Ratio of Monocytes to Lymphocytes in Peripheral Blood Correlates with Increased Susceptibility to Clinical Malaria in Kenyan Children

Background

Plasmodium falciparum malaria remains a major cause of illness and death in sub-Saharan Africa. Young children bear the brunt of the disease and though older children and adults suffer relatively fewer clinical attacks, they remain susceptible to asymptomatic P. falciparum infection. A better understanding of the host factors associated with immunity to clinical malaria and the ability to sustain asymptomatic P. falciparum infection will aid the development of improved strategies for disease prevention.

Methods and Findings

Here we investigate whether full differential blood counts can predict susceptibility to clinical malaria among Kenyan children sampled at five annual cross-sectional surveys. We find that the ratio of monocytes to lymphocytes, measured in peripheral blood at the time of survey, directly correlates with risk of clinical malaria during follow-up. This association is evident among children with asymptomatic P. falciparum infection at the time the cell counts are measured (Hazard ratio (HR)  =  2.7 (95% CI 1.42, 5.01, P  =  0.002) but not in those without detectable parasitaemia (HR  =  1.0 (95% CI 0.74, 1.42, P  =  0.9).

Conclusions

We propose that the monocyte to lymphocyte ratio, which is easily derived from routine full differential blood counts, reflects an individual''s capacity to mount an effective immune response to P. falciparum infection.     

Bioisosteric approach to the discovery of imidazo[1,2-a]pyrazines as potent Aurora kinase inhibitors

Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.     

Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors

A series of substituted imidazo[1,2-a]pyrazin-8-amines were discovered as novel breast tumor kinase (Brk)/protein tyrosine kinase 6 (PTK6) inhibitors. Tool compounds with low-nanomolar Brk inhibition activity, high selectivity towards other kinases and desirable DMPK properties were achieved to enable the exploration of Brk as an oncology target.