Sensitivity of activated human lymphocytes to cyclosporine and its metabolites

Alloreactive T cells generated as clones from mixed lymphocyte cultures, or propagated from heart or liver transplant biopsies, were tested for secondary proliferation measured in the primed lymphocyte test in the presence of Cyclosporine A and metabolites fractionated from human bile. Significant differences were observed in Cyclosporine A sensitivity between various cell cultures ranging as high as 100-fold. The liver is the primary site of Cyclosporine A metabolism, which yields a number of hydroxylated and N-dimethylated derivatives that are eventually secreted into the bile. Bile was collected from adult liver transplant patients on Cyclosporine A therapy and following extraction with diethyl ether, separated by high pressure liquid chromatography. Thirteen fractions were tested for their effect on lymphocyte proliferation in concanavalin A activation, mixed lymphocyte cultures and primed lymphocyte test assays. The strongest immunosuppressive effect was found with fraction 8, which contained metabolite M17, which has a single hydroxylation in position 1. Only three other fractions 9, 10, and 13, which contained metabolites M1, M18, and M21, respectively, exhibited immunosuppressive activity, albeit much lower than that of Cyclosporine A. Differences in Cyclosporine A sensitivity among alloreactive T cells followed similar patterns with Cyclosporius A metabolites. Thus, the assessment of the Cyclosporine A effect must consider differences in drug sensitivity of lymphocytes involved in transplant immunity and the generation of metabolites with immunosuppressive activity. © 1988

In pursuit of ‘safe’ water: the burden of personal injury from water fetching in 21 low-income and middle income countries

Introduction: Water fetching for household needs can cause injury, but documentation of the burden of harm globally has been limited. We described the frequency, characteristics and correlates of water-fetching injuries in 24 sites in 21 low-income and middle-income countries in Asia, Africa and Latin America and the Caribbean. Methods: In a survey of 6291 randomly selected households, respondents reported whether and how they had experienced water-fetching injuries. Responses were coded for injury type, mechanism, bodily location and physical context. We then identified correlates of injury using a multilevel, mixed-effects logistic regression model. Results: Thirteen per cent of respondents reported at least one water-fetching injury. Of 879 injuries, fractures and dislocations were the most commonly specified type (29.2%), and falls were the most commonly specified mechanism (76.4%). Where specified, 61.1% of injuries occurred to the lower limbs, and dangerous terrain (69.4%) was the most frequently reported context. Significant correlates included being female (OR 1.50, 95% CI 1.15 to 1.96); rural (OR 4.80, 95% CI 2.83 to 8.15) or periurban residence (OR 2.75, 95% CI 1.64 to 4.60); higher household water insecurity scores (1.09, 95% CI 1.07 to 1.10) and reliance on surface water (OR 1.97, 95% CI 1.21 to 3.22) or off-premise water sources that required queueing (OR 1.72, 95% CI 1.19 to 2.49). Conclusion These data suggest that water-fetching injuries are an underappreciated and largely unmeasured public health challenge. We offer guidelines for comprehensive data collection on injuries to better capture the true burden of inadequate water access. Such data can guide the design of interventions to reduce injury risk and promote equitable water access solutions

Nonlinear Control for Reconfiguration of Unmanned-Aerial-Vehicle Formation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76757/1/AIAA-8760-121.pd