Modeling the Influence of Local Environmental Factors on Malaria Transmission in Benin and Its Implications for Cohort Study

Malaria remains endemic in tropical areas, especially in Africa. For the evaluation of new tools and to further our understanding of host-parasite interactions, knowing the environmental risk of transmission—even at a very local scale—is essential. The aim of this study was to assess how malaria transmission is influenced and can be predicted by local climatic and environmental factors

The genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by the interaction of genetic susceptibility and environmental influences. There is increasing evidence that genes link to disease pathogenesis and heterogeneity by causing variation in protease anti-protease systems, defence against oxidative stress and inflammation. The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation

Skin Barrier Homeostasis in Atopic Dermatitis: Feedback Regulation of Kallikrein Activity

Atopic dermatitis (AD) is a widely spread cutaneous chronic disease characterised by sensitive reactions (eg. eczema) to normally innocuous elements. Although relatively little is understood about its underlying mechanisms due to its complexity, skin barrier dysfunction has been recognised as a key factor in the development of AD. Skin barrier homeostasis requires tight control of the activity of proteases, called kallikreins (KLKs), whose activity is regulated by a complex network of protein interactions that remains poorly understood despite its pathological importance. Characteristic symptoms of AD include the outbreak of inflammation triggered by external (eg. mechanical and chemical) stimulus and the persistence and aggravation of inflammation even if the initial stimulus disappears. These characteristic symptoms, together with some experimental data, suggest the presence of positive feedback regulation for KLK activity by inflammatory signals. We developed simple mathematical models for the KLK activation system to study the effects of feedback loops and carried out bifurcation analysis to investigate the model behaviours corresponding to inflammation caused by external stimulus. The model analysis confirmed that the hypothesised core model mechanisms capture the essence of inflammation outbreak by a defective skin barrier. Our models predicted the outbreaks of inflammation at weaker stimulus and its longer persistence in AD patients compared to healthy control. We also proposed a novel quantitative indicator for inflammation level by applying principal component analysis to microarray data. The model analysis reproduced qualitative AD characteristics revealed by this indicator. Our results strongly implicate the presence and importance of feedback mechanisms in KLK activity regulation. We further proposed future experiments that may provide informative data to enhance the system-level understanding on the regulatory mechanisms of skin barrier in AD and healthy individuals

Epidemiology of malaria in the forest-savanna transitional zone of Ghana.

BACKGROUND: Information on the epidemiology of malaria is essential for designing and interpreting results of clinical trials of drugs, vaccines and other interventions. As a background to the establishment of a site for anti-malarial drugs and vaccine trials, the epidemiology of malaria in a rural site in central Ghana was investigated. METHODS: Active surveillance of clinical malaria was carried out in a cohort of children below five years of age (n = 335) and the prevalence of malaria was estimated in a cohort of subjects of all ages (n = 1484) over a 12-month period. Participants were sampled from clusters drawn around sixteen index houses randomly selected from a total of about 22,000 houses within the study area. The child cohort was visited thrice weekly to screen for any illness and a blood slide was taken if a child had a history of fever or a temperature greater than or equal to 37.5 degree Celsius. The all-age cohort was screened for malaria once every eight weeks over a 12-month period. Estimation of Entomological Inoculation Rate (EIR) and characterization of Anopheline malaria vectors in the study area were also carried out. RESULTS: The average parasite prevalence in the all age cohort was 58% (95% CI: 56.9, 59.4). In children below five years of age, the average prevalence was 64% (95% CI: 61.9, 66.0). Geometric mean parasite densities decreased significantly with increasing age. More than 50% of all children less than 10 years of age were anaemic. Children less than 5 years of age had as many as seven malaria attacks per child per year. The attack rates decreased significantly with increasing cut-offs of parasite density. The average Multiplicity of Infection (MOI) was of 6.1. All three pyrimethamine resistance mutant alleles of the Plasmodium falciparum dhfr gene were prevalent in this population and 25% of infections had a fourth mutant of pfdhps-A437G. The main vectors were Anopheles funestus and Anopheles gambiae and the EIR was 269 infective bites per person per year. CONCLUSION: The transmission of malaria in the forest-savanna region of central Ghana is high and perennial and this is an appropriate site for conducting clinical trials of anti-malarial drugs and vaccines

Tethered ligand-derived peptides of proteinase-activated receptor 3 (PAR(3)) activate PAR(1) and PAR(2) in Jurkat T cells

Proteinase-activated receptors (PARs) can activate a number of signalling events, including T-cell signal-transduction pathways. Recent data suggest that the activation of PARs 1, 2 and 3 in Jurkat T-leukaemic cells induces tyrosine phosphorylation of the haematopoietic signal transducer protein, VAV1. To activate the PARs, this study used the agonist peptides SFLLRNPNDK, SLIGKVDGTS and TFRGAPPNSF, which are based on the sequences of the tethered ligand sequences of human PARs 1, 2 and 3, respectively. Here, we show that peptides based on either the human or murine PAR(3)-derived tethered ligand sequences (TFRGAP-NH(2) or SFNGGP-NH(2)) do not activate PAR(3), but rather activate PARs 1 and 2, either in Jurkat or in other PAR-expressing cells. Furthermore, whilst thrombin activates only Jurkat PAR(1), trypsin activates both PARs 1 and 2 and also disarms Jurkat PAR(1) for thrombin activation. We conclude therefore that in Jurkat or related T cells, signalling via PARs that can affect VAV1 phosphorylation is mediated via PAR 1 or 2, or both, and that distinct serine proteinases may potentially differentially affect T-cell function in the settings of inflammation