Pneumocystis carinii shows DNA homology with the ustomycetous red yeast fungi

Pneumocystis carinii causes life-threatening pneumonia in T-lymphocyte-immunodeficient subjects in transplant and oncology units or with acquired immune deficiency syndrome (AIDS). Recent DNA homology studies show P. carinii to be a fungus. To investigate the biology and epidemiology of this parasite further, we elected to determine for it a more precise taxonomic assignment within the fungal kingdom. We screened a wide range of organisms representing the major orders of fungi using DNA amplification and subsequently sequenced a portion of the mitochondrial gene encoding the large subunit ribosomal RNA. Our data show that the opportunistic pulmonary pathogen P. carinii is closely related to the ustomycetous red yeast fungi, a group which includes organisms that are extensively distributed throughout the environment and which release many widely dispersed airborne spores.     

A dietary conjugated linoleic acid treatment that slows renal disease progression alters renal cyclooxygenase-2-derived prostanoids in the Han: SPRD-cy rat

A mixture of dietary conjugated linoleic acid (CLA) isomers reduces inflammation and mitigates disease progression in the Han:SPRD-cy rat model of chronic kidney disease. Since cyclooxygenase (COX) activities and prostanoid levels are higher in diseased kidneys in this rat, and dietary CLA can inhibit COX2 and prostanoid production in other tissues, the effects of dietary CLA were investigated. Kidney homogenates from normal and diseased Han:SPRD-cy rats were analyzed for prostanoid levels under various conditions: endogenous levels, steady-state levels (60-min incubations) and produced by COX isoforms. Thromboxane B(2) (TXB(2); TXA(2) metabolite), 6-keto-prostaglandin F(1α) (6-keto-PGF(1α); PGI(2) metabolite) and PGE(2) levels under these conditions were two- to ninefold higher in diseased kidneys. Dietary CLA resulted in ～32%-53% lower levels of prostanoids produced by total COX and COX2 activities in normal and diseased kidneys and partially mitigated alterations in COX2 protein levels associated with disease. The COX1 protein and activity were higher in renal disease, resulting in increased production of TXB(2) and 6-ketoPGF(1α), but not PGE(2). Dietary CLA had no effect on COX1, however. Disease resulted in up to twofold higher ratios of TXB(2)/6-ketoPGF(1α), TXB(2)/PGE(2) and 6-ketoPGF(1α) /PGE(2), and dietary CLA partially mitigated these increases under several conditions. Elevated levels of renal membrane associated cytosolic phospholipase A(2) in diseased kidneys also were reduced by 50% with CLA feeding. The effects of CLA feeding on COX2 protein levels and activity indicate that the beneficial effect of dietary CLA in this renal disorder is mediated in part via effects on COX2-derived prostanoids.     

Immature gannets follow adults in commuting flocks providing a potential mechanism for social learning

Group travel is a familiar phenomenon among birds but the causes of this mode of movement are often unclear. For example, flocking flight may reduce flight costs, enhance predator avoidance or increase foraging efficiency. In addition, naive individuals may also follow older, more experienced conspecifics as a learning strategy. However, younger birds may be slower than adults so biomechanical and social effects on flock structure may be difficult to separate. Gannets are wide‐ranging (100s–1000s km) colonial seabirds that often travel in V or echelon‐shaped flocks. Tracking suggests that breeding gannets use memory to return repeatedly to prey patches 10s–100s km wide but it is unclear how these are initially discovered. Public information gained at the colony or by following conspecifics has been hypothesised to play a role, especially during early life. Here, we address two hypotheses: 1) flocking reduces flight costs and 2) young gannets follow older ones in order to locate prey. To do so, we recorded flocks of northern gannets commuting to and from a large colony and passing locations offshore and used a biomechanical model to test for age differences in flight speeds. Consistent with the aerodynamic hypothesis, returning flocks were significantly larger than departing flocks, while, consistent with the information gathering hypothesis, immatures travelled in flocks more frequently than adults and these flocks were more likely to be led by adults than expected by chance. Immatures did not systematically occupy the last position in flocks and had similar theoretical airspeeds to adults, making it unlikely that they follow, rather than lead, for biomechanical reasons. We therefore conclude that while gannets are likely to travel in flocks in part to reduce flight costs, the positions of immatures in those flocks may result in a flow of information from adults to immatures, potentially leading to social learning.     

Errors-in-variables in joint population pharmacokinetic/pharmacodynamic modeling

Pharmacokinetic (PK) models describe the relationship between the administered dose and the concentration of drug (and/or metabolite) in the blood as a function of time. Pharmacodynamic (PD) models describe the relationship between the concentration in the blood (or the dose) and the biologic response. Population PK/PD studies aim to determine the sources of variability in the observed concentrations/responses across groups of individuals. In this article, we consider the joint modeling of PK/PD data. The natural approach is to specify a joint model in which the concentration and response data are simultaneously modeled. Unfortunately, this approach may not be optimal if, due to sparsity of concentration data, an overly simple PK model is specified. As an alternative, we propose an errors-in-variables approach in which the observed-concentration data are assumed to be measured with error without reference to a specific PK model. We give an example of an analysis of PK/PD data obtained following administration of an anticoagulant drug. The study was originally carried out in order to make dosage recommendations. The prior for the distribution of the true concentrations, which may incorporate an individual's covariate information, is derived as a predictive distribution from an earlier study. The errors-in-variables approach is compared with the joint modeling approach and more naive methods in which the observed concentrations, or the separately modeled concentrations, are substituted into the response model. Throughout, a Bayesian approach is taken with implementation via Markov chain Monte Carlo methods.     

Cell surface protease PRT1 identified in the fungal pathogen Pneumocystis carinii

The subtelomeric regions of the chromosomes of many organisms contain gene families that allow adaptation to a changing environment. In a number of parasites, these subtelomeric gene families encode cell surface proteins that undergo antigenic variation. Proteases are another important virulence determinant in pathogenic microorganisms. We report the localization of the PRT1 protease of the pathogenic fungus Pneumocystis carinii sp. f. carinii, encoded by a subtelomeric gene family, to the cell surface of both the trophozoite and the cyst phase of the organism. Using anti-PRT1 antiserum, we demonstrated specificity to P. carinii sp. f. carinii in sections of infected rat lungs and, using immunofluorescence, we showed that the PRT1 protease has the characteristic distribution of a surface protein. The anti-PRT1 antiserum showed cross-reactivity with a number of P. carinii sp. f. carinii proteins migrating between 185 kDa and 28 kDa, the majority migrating between 42 kDa and 52 kDa, a region that has been shown by serological studies to contain important immunodominant P. carinii proteins. Cross-reactivity was also observed with P. carinii sp. f. hominis proteins. We have also cloned a portion of the catalytic domain of PRT1 from P. carinii sp. f. hominis, P. carinii sp. f. muris and P. carinii sp. f. rattus. Our data suggest that the PRT1 protease plays an important role in the pathogenicity of P. carinii.