Neutrophil depletion increases susceptibility to systemic and vaginal candidiasis in mice, and reveals differences between brain and kidney in mechanisms of host resistance

Infections caused by the yeast Candida albicans represent an increasing threat to debilitated and immunosuppressed patients, and neutropenia is an important risk factor. Monoclonal antibody depletion of neutrophils in mice was used to study the role of these cells in host resistance. Ablation of neutrophils increased susceptibility to both systemic and vaginal challenge. The fungal burden in the kidney increased threefold on day 1, and 100-fold on day 4, and infection was associated with extensive tissue destruction. However, a striking feature of the disseminated disease in neutrophil-depleted animals was the altered pattern of organ involvement. The brain, which is one of the primary target organs in normal mice, was little affected. There was a threefold increase in the number of organisms recovered from the brains of neutrophil-depleted mice on day 4 after infection, but detectable abscesses were rare. In contrast, the heart, which in normal mice shows only minor lesions, developed severe tissue damage following neutrophil depletion. Mice deficient in C5 demonstrated both qualitative and quantitative increases in the severity of infection after neutrophil depletion when compared with C5-sufficient strains. The results are interpreted as reflecting organ-specific differences in the mechanisms of host resistance.

Falling incidence of amputations for peripheral occlusive arterial disease in western Australia between 1980 and 1992

Objectives: To assess temporal trends in the incidence of surgical procedures for peripheral occlusive arterial disease (POAD) and associated changes in outcome as measured by the rate of major lower limb amputations for POAD. Design: a retrospective descriptive population-based study was conducted of the geographically isolated population of Western Austrialia between 1980 and 1992. Methods: Vascular procedures with an accompanying diagnosis of POAD were identified in a computerised system of name-identified records of all discharges from hospital for the population. These procedures were detected using relevant codes from the International Classification of Disease and Procedures. Records of angioplasty and thrombolysis procedures were augmented by searches of hospital-based registers of invasive radiological procedures. The data for the remaining procedures were validated by a review of a random sample of medical records. Results: over the 13 years of the study, rates of major amputations fell significantly for in non-amputation vascular surgery for individuals under the age of 60. In addition, rather than an overall rise in surgery there was shift away from sympathectomy and thromboendarterectomy to angioplasty and bypass surgery. Furthermore, an increasing proportion of all major amputations had a prior attempt at arterial reconstruction. Conclusion: These observations suggest the decrease in major amputations for POAD may reflect a fall in the incidence of POAD, possibly aided by move effective surgery, rather than increased rates of vascular surgery.

Probing the effect of vehicles on topical delivery: Understanding the basic relationship between solvent and solute penetration using silicone membranes

Purpose. In the present study we examined the relationship between solvent uptake into a model membrane (silicone) with the physical properties of the solvents (e.g., solubility parameter, melting point, molecular weight) and its potential predictability. We then assessed the subsequent topical penetration and retention kinetics of hydrocortisone from various solvents to define whether modifications to either solute diffusivity or partitioning were dominant in increasing permeability through solvent-modified membranes. Methods. Membrane sorption of solvents was determined from weight differences following immersion in individual solvents, corrected for differences in density. Permeability and retention kinetics of H-3-hydrocortisone, applied as saturated solutions in the various solvents, were determined over 48 h in horizontal Franz-type glass diffusion cells. Results. Solvent sorption into the membrane could be related to differences in solubility parameters, MW and hydrogen bonding (r(2) = 0.76). The actual and predicted volume of solvent sorbed into the membrane was also found to be linearly related to Log hydrocortisone flux, with changes in both diffusivity and partitioning of hydrocortisone observed for the different solvent vehicles. Conclusions. A simple structure-based predictive model can be applied to the sorption of solvents into silicone membranes. Changes in solute diffusivity and partitioning appeared to contribute to the increased hydrocortisone flux observed with the various solvent vehicles. The application of this predictive model to the more complex skin membrane remains to be determined.