Genes for the majority of group A streptococcal virulence factors and extracellular surface proteins do not confer an increased propensity to cause invasive disease

Background. The factors behind the reemergence of severe, invasive group A streptococcal (GAS) diseases are unclear, but it could be caused by altered genetic endowment in these organisms. However, data from previous studies assessing the association between single genetic factors and invasive disease are often conflicting, suggesting that other, as-yet unidentified factors are necessary for the development of this class of disease. Methods. In this study, we used a targeted GAS virulence microarray containing 226 GAS genes to determine the virulence gene repertoires of 68 GAS isolates (42 associated with invasive disease and 28 associated with noninvasive disease) collected in a defined geographic location during a contiguous time period. We then employed 3 advanced machine learning methods (genetic algorithm neural network, support vector machines, and classification trees) to identify genes with an increased association with invasive disease. Results. Virulence gene profiles of individual GAS isolates varied extensively among these geographically and temporally related strains. Using genetic algorithm neural network analysis, we identified 3 genes with a marginal overrepresentation in invasive disease isolates. Significantly, 2 of these genes, ssa and mf4, encoded superantigens but were only present in a restricted set of GAS M-types. The third gene, spa, was found in variable distributions in all M-types in the study. Conclusions. Our comprehensive analysis of GAS virulence profiles provides strong evidence for the incongruent relationships among any of the 226 genes represented on the array and the overall propensity of GAS to cause invasive disease, underscoring the pathogenic complexity of these diseases, as well as the importance of multiple bacteria and/ or host factors.

Remodeling of extracellular matrix at ovulation of the bovine ovarian follicle

Using immunohistochemistry and RNA analyses we examined the fate of components of a newly identified matrix that develops between granulosa cells (focimatrix, abbreviated from focal intraepithelial matrix) and of the follicular basal lamina in ovulating bovine ovarian follicles. Pre- and postovulatory follicles were generated by treatment with estradiol (Day 1), progesterone (Days 1-10), and prostaglandin analogue (Day 9) with either no further treatment (Group 1, n = 6) and or with 25 mg porcine LH (Day 11, Group 2, n = 8 or Day 10, Group 3, n = 8) and ovariectomy on Day 12 (12-14 hr post LH in Group 2, 38-40.5 hr in Group 3). In the time frame examined no loss of follicular basal lamina laminin chains beta 2 and gamma 1 or nidogen 1 was observed. In the follicular basal lamina collagen type IV alpha 1 and perlecan were present prior to ovulation; after ovulation collagen type IV alpha 1 was discontinuously distributed and perlecan was absent. Versican in the theca interna adjacent to the follicular basal lamina in preovulatory follicles was not observed post ovulation, however, the granulosa cells then showed strong cytoplasmic staining for versican. Expression of versican isoforms V0, V1, and V3 was detected at all stages. Focimatrix was observed in preovulatory follicles. It contained collagen type IV alpha 1, laminins beta 2 and gamma 1, nidogen 1 and perlecan and underwent changes in composition similar to that of the follicular basal lamina. In conclusion focimatrix and the follicular basal lamina are degraded at ovulation. Individual components are lost at different times.

The DVD animal model of schizophrenia: Effects of low maternal vitamin D on brain dopamine

Background: We have previously shown that the offspring of vitamin D3 depleted rats have enlarged ventricles and altered neurotrophin profiles (reduced NGF and GDNF). These findings enhance the biological plausibility that low prenatal vitamin D may be a risk factor for schizophrenia. Our recent behavioural studies have found that adult rats with developmental vitamin D deficiency (DVD) have a subtle increase in baseline locomotor activity and a heightened response to dopamine (DA) antagonists. The aim of this study was to investigate brain DA neurochemistry in the DVD model. Methods: We examined cerebrums and striatal tissue from neonates and a variety of brain tissues from the remaining littermates at adulthood. DA, DOPAC, HVA, serotonin and 5HIAA were analysed by HPLC. Single point comparisons for DA1, DA2 and NMDA receptors were also assessed in these tissues. Results: Significant increases in DA and HVA were found in brains from DVD deplete neonates (P=0.01). However, DA and its metabolites were not increased in either the neonate or adult striatum, however there was a trend towards increased DA and its metabolites in the accumbens (P=0.1). Receptor densities were unaffected by prenatal vitamin D levels. Conclusions: Although the effect of maternal diet appears to increase DA production and turnover in neonatal brain, this does not persist into adulthood. Thus other factors must underlie the increased locomotor activity noted in these animals. Future experiments will concentrate on monitoring accumbens and striatal DA release and turnover using microdialysis in pharmacologically challenged behavioural paradigms. References: Eyles D, Brown J; Mackay-Sim A, McGrath J, Feron F. (2003) Vitamin D3 and brain development. Neuroscience 118 (3) 641–653. Burne T, McGrath J, Eyles D, Mackay-Sim A. Behavioural characterization of vitamin D receptor knockout mice. (2005) Behavioural Brain Res: 157 299–308.

The influence of dopamine on semantic activation in Parkinson's disease: Evidence from a multipriming task

Research has suggested that semantic processing deficits in Parkinson's disease (PD) are related to striatal dopamine deficiency. As an investigation of the influence of dopamine on semantic activation in PD, 7 participants with PD performed a lexical-decision task when on and off levodopa medication. Seven healthy controls matched to the participants with PD in terms of sex, age, and education also participated in the study. By use of a multipriming paradigm, whereby 2 prime words were presented prior to the target word, semantic priming effects were measured across stimulus onset asynchronies (SOAs) of 250 Ins and 1,200 Ins. The results revealed a similar pattern of priming across SOAs for the control group and the PD participants on medication. In contrast, within-group comparisons revealed that automatic semantic activation was compromised in PD participants when off medication. The implications of these results for the neuromodulatory influence of dopamine on semantic processing in PD are discussed.

Arthritic disease suppression and cartilage protection with glycosaminoglycan polypeptide complexes (Peptacans) derived from the cartilage extracellular matrix: A novel approach to therapy

Molecular fragments of cartilage are antigenic and can stimulate an autoimmune response. Oral administration of type II collagen prevents disease onset in animal models of arthritis but the effects of other matrix components have not been reported. We evaluated glycosaminoglycan polypeptides (GAG-P) and matrix proteins (CaP) from cartilage for a) mitigating disease activity in rats with collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) and b) stimulating proteoglycan (PG) synthesis by chondrocytes in-vitro. CIA and AIA were established in Wistar rats using standard methods. Agents were administered orally (10–200 mg/kg), either for seven days prior to disease induction (toleragenic protocol), or continuously for 15 days after injecting the arthritigen (prophylactic protocol). Joint swelling and arthritis scores were determined on day 15. Histological sections of joint tissues were assessed post-necropsy. In chondrocyte cultures, CaP + / − interleukin-1 stimulated PG biosynthesis. CaP was also active in preventing arthritis onset at 3.3, 10 or 20 mg/kg in the rat CIA model using the toleragenic protocol. It was only active at 20 and 200 mg/kg in the CIA prophylactic protocol. GAG-P was active in the CIA toleragenic protocol at 20 mg/kg but chondroitin sulfate and glucosamine hydrochloride or glucosamine sulfate were all inactive. The efficacy of CaP in the rat AIA model was less than in the CIA model. These findings lead us to suggest that oral CaP could be used as a disease-modifying anti-arthritic drug.