Seasonal patterns of body temperature daily rhythms in group-living Cape ground squirrels Xerus inauris

Organisms respond to cyclical environmental conditions by entraining their endogenous biological rhythms. Such physiological responses are expected to be substantial for species inhabiting arid environments which incur large variations in daily and seasonal ambient temperature (T(a)). We measured core body temperature (T(b)) daily rhythms of Cape ground squirrels Xerus inauris inhabiting an area of Kalahari grassland for six months from the Austral winter through to the summer. Squirrels inhabited two different areas: an exposed flood plain and a nearby wooded, shady area, and occurred in different social group sizes, defined by the number of individuals that shared a sleeping burrow. Of a suite of environmental variables measured, maximal daily T(a) provided the greatest explanatory power for mean T(b) whereas sunrise had greatest power for T(b) acrophase. There were significant changes in mean T(b) and T(b) acrophase over time with mean T(b) increasing and T(b) acrophase becoming earlier as the season progressed. Squirrels also emerged from their burrows earlier and returned to them later over the measurement period. Greater increases in T(b), sometimes in excess of 5°C, were noted during the first hour post emergence, after which T(b) remained relatively constant. This is consistent with observations that squirrels entered their burrows during the day to 'offload' heat. In addition, greater T(b) amplitude values were noted in individuals inhabiting the flood plain compared with the woodland suggesting that squirrels dealt with increased environmental variability by attempting to reduce their T(a)-T(b) gradient. Finally, there were significant effects of age and group size on T(b) with a lower and less variable T(b) in younger individuals and those from larger group sizes. These data indicate that Cape ground squirrels have a labile T(b) which is sensitive to a number of abiotic and biotic factors and which enables them to be active in a harsh and variable environment.     

The utility of recovery biopsies in determining donor suitability

Tissue recovery personnel often find themselves in a situation in which, upon donor physical assessment, they discover an unusual or suspicious skin or tissue lesion. Because of the concern about the possibility of recovering tissues from a donor who may have an occult malignancy or infection, the Recovery Team may elect not to recover. Otherwise they may continue with the recovery, documenting their concern on the physical assessment form. At the time of evaluation of donor suitability the Medical Director must determine what the lesion is. This is inherently difficult and sometimes has led to the discard of recovered tissues. In order to optimize the gift of donation and avoid unnecessary deferral or discard of tissues we instituted a recovery biopsy procedure several years ago. Between January, 2005 and March, 2010, 561 biopsies were performed. In 552 donors (98.4%) there was no negative effect on medical suitability. Nine donors (1.6%) were found unsuitable based on the biopsy results. The recovery biopsy has allowed Recovery Teams to better manage their time by quickly identifying and biopsying suspicious lesions without trying to make a determination of donor eligibility and possibly ruling ineligible a qualified donor. The recovery biopsy has allowed the Medical Directors to make suitability decisions to accept or reject based on diagnostic certainty.     

Discovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterials

A series of potential antimicrobial derivatives possessing bioisosteric replacements for the central oxazolidinone ring found in oxazolidinone antibacterials have been prepared. The design concept involved replacement of the requisite sp(3)-hybridized stereogenic center found at the 5-position of the oxazolidinone with a nitrogen atom. The synthesis and antibacterial activity of three such ring systems, the benzisoxazolinones, pyrroles, and isoxazolinones is described.     

Biaryl isoxazolinone antibacterial agents

In an era of increasing resistance to classical antibacterial agents, the synthetic oxazolidinone series of antibiotics has attracted much interest. Zyvoxtrade mark was the first oxazolidinone to be approved for clinical use against infections caused by multi-drug resistant Gram-positive bacteria. In the course of studies directed toward the discovery of novel antibacterial agents, a new series of synthetic phenyl-isoxazolinone agents that displayed potent activity against Gram-positive bacterial strains was recently discovered at Bristol-Myers Squibb. Extensive investigation of various substitutions on the phenyl ring was then undertaken. We report here, the synthesis and antibacterial activity of a series of biaryl isoxazolinone compounds.     

Nutritional considerations in the pathogenesis of hepatic veno-occlusive disease in captive cheetahs

Veno-occlusive disease (VOD) of the liver has been diagnosed in a large number of captive cheetahs. Some ingredients or contaminants present in the diet were suspected as possible causes for this noninfectious disease with high incidence. Eight different diets fed to cheetahs kept in North American zoos were analyzed for vitamin A levels and the presence or absence of plant estrogens, nitro-saminines, nitrites, and aflatoxins. Three of the eight diets were considered to contain toxic amounts of vitamin A. In humans and rats, hypervitaminosis A has been associated with hepatic vascular lesions, mainly perisinusoidal fibrosis, which progress eventually to occlusive lesions similar to VOD. Plant estrogens were detected in appreciable amounts only in one of the exotic carnivore diets. The role of plant estrogens in the pathogenesis of VOD in captive cheetahs is not clear at this time and needs further investigation. Based on the liver pathology and diet analyses, nitrosamines or their dietary precursors and aflatoxins can be excluded as possible causes of VOD in cheetahs kept in North American zoos.     

The effect of elastase-specific monoclonal and polyclonal antibodies on the virulence ofAspergillus fumigatus in immunocompromised mice

Elastase has been implicated as a potential virulence factor involved in the invasion process of the opportunistic pathogen,Aspergillus fumigatus. Monoclonal and polyclonal antibodies, known to inhibit elastase in vitro, were employed in an immunocompromised mouse model of invasive aspergillosis to determine if the antibodies could protect mice from fatal infection. Individual monoclonal antibodies, known to inhibit elastase partially (13 to 23%), or combinations of monoclonal antibodies, known to inhibit elastase 70 to 100%, were tested in the mouse model. No individual nor combination of monoclonal antibodies protected immunosuppressed, infected mice in the doses tested. Similarly, elastase-specific polyclonal antibodies, raised in mice or rabbits, did not exhibit a protective effect, nor did immunization of mice with elastase prior to immunosuppression and infection. Histological examination of the lungs of immunosuppressed, infected mice showed no amelioration of fungal invasiveness by treatment with elastase-specific monoclonal or polyclonal antibodies. However, immunocompetent mice, instilled with a spore inoculum much higher than used in the preceding studies and treated with antibodies, survived, while control mice not treated with antibodies were overwhelmed by the massive spore dose and died. Nevertheless, overall evidence suggests that elastase may not be the primary virulence factor involved in invasive pulmonary aspergillosis.     

Conserved fungal genes as potential targets for broad-spectrum antifungal drug discovery

The discovery of novel classes of antifungal drugs depends to a certain extent on the identification of new, unexplored targets that are essential for growth of fungal pathogens. Likewise, the broad-spectrum capacity of future antifungals requires the target gene(s) to be conserved among key fungal pathogens. Using a genome comparison (or concordance) tool, we identified 240 conserved genes as candidates for potential antifungal targets in 10 fungal genomes. To facilitate the identification of essential genes in Candida albicans, we developed a repressible C. albicans MET3 (CaMET3) promoter system capable of evaluating gene essentiality on a genome-wide scale. The CaMET3 promoter was found to be highly amenable to controlled gene expression, a prerequisite for use in target-based whole-cell screening. When the expression of the known antifungal target C. albicans ERG1 was reduced via down-regulation of the CaMET3 promoter, the CaERG1 conditional mutant strain became hypersensitive, specifically to its inhibitor, terbinafine. Furthermore, parallel screening against a small compound library using the CaERG1 conditional mutant under normal and repressed conditions uncovered several hypersensitive compound hits. This work therefore demonstrates a streamlined process for proceeding from selection and validation of candidate antifungal targets to screening for specific inhibitors.