Calcineurin is implicated in a myriad of human diseases as well as homeostasis and virulence in several major human pathogenic microorganisms. The fungus Aspergillus fumigatus is a leading cause of infectious death in the rapidly expanding immunocompromised patient population. Current antifungal treatments for invasive aspergillosis are often ineffective, and novel therapeutic approaches are urgently needed. We demonstrate that a mutant of A. fumigatus lacking the calcineurin A (cnaA) catalytic subunit exhibited defective hyphal morphology related to apical extension and polarized growth, which resulted in drastically decreased filamentation. The ⌬cnaA mutant lacked the extensive lattice of invading hyphae seen with the wild-type and complemented strains. Sporulation was also affected in the ⌬cnaA mutant, including morphological conidial defects with the absence of surface rodlets and the added presence of disjunctors creating long conidial chains. Infection with the ⌬cnaA mutant in several distinct animal models with different types of immunosuppression and inoculum delivery led to a profound attenuation of pathogenicity compared to infection with the wild-type and complemented strains. Lung tissue from animals infected with the ⌬cnaA mutant showed a complete absence of hyphae, in contrast to tissue from animals infected with the wild-type and complemented strains. Quantitative fungal burden and pulmonary infarct scoring confirmed these findings. Our results support the clinical observation that substantially decreasing fungal growth can prevent disease establishment and decrease mortality. Our findings reveal that calcineurin appears to play a globally conserved role in the virulence of several pathogenic fungi and yet plays specialized roles in each and can be an excellent target for therapeutic intervention.
Abstract. Griesshammer M, Bangerter M, Sauer T, Wennauer R, Bergmann L, Heimpel H (University of Ulm, Germany). Aetiology and clinical significance of thrombocytosis: analysis of 732 patients with an elevated platelet count. J Intern Med 1999; 245: 295±300.Objective. To determine the aetiology and clinical significance of an elevated platelet count (thrombocytosis) in a large cohort of patients. Design. A retrospective review of the medical records was performed on all patients, who had at least one platelet count $ 500 3 10 9 L -1 . Setting.
Normal retina contains neuroretina and retinal pigment epithelium. The neuroretina consists of outer and inner segments of photoreceptors (rods and cones), external limiting membrane, outer nuclear layer, outer plexiform layer, inner nuclear layer, inner plexiform layer, ganglion cell layer, nerve fiber layer and internal limiting membrane. There is a broad spectrum of retinal pathology including congenital abnormalities, dystrophies, degenerations (notably age-related macular degeneration), retinal vascular diseases, toxicities, inflammatory diseases, neoplasms, retinal detachment, trauma and retinal involvement of systemic diseases. This chapter presents a few major pathological processes in retinal diseases, especially processes that are amenable to pharmacotherapeutics.
Scientific research on and natural resource damage assessments (NRDA) of oil spill incidents require the appropriate selection and application of analytical chemical and data interpretation techniques. Estimates of injuries to natural resources (surface waters, geological resources, biological resources), determinations of pathways of exposure, and assessment of recoverability and recovery of injured resources should, in part, be based on methods that are scientifically. defensible and acceptable in their application to the regulatory and legal communities. Recent spill incidents underline the need for significant revision of regulatory methods (such as EPA-approved procedures), so as to target the spilled material (petroleum) and its specific chemical composition. Standard operating procedures for the determination of the saturate and aromatic hydrocarbon concentrations and compositions (normal alkanes and polynuclear aromatic hydrocarbons) of environmental samples have been drafted for use in oil spill assessments. These methods rely on the use of gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS) methods that target specific indicators of source material composition and weathering processes. These proposed methods for analysis of oil spill assessment environmental samples are contrasted with EPA methods such as EPA Method 418.1 (total petroleum hydrocarbons), EPA Methods 625 and 8270 (GC/MS analyses of semivolatile priority pollutant organics), and other methods. Using data from three recent oil spills as examples, this paper examines the current “approved” methods for the analysis of environmental samples, and contrasts the scientific rigor and defensibility of the recommended GC (saturated hydrocarbons) and GC/MS (polynuclear aromatic hydrocarbons and heterocyclics) methods for oil spill chemical analyses in NRDA programs. The approaches presented are recommended as important elements of future technical guidance documents relating to the NRDA federal regulations, in contrast with the inappropriate methods now suggested for use in the existing regulations.
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