Dynamics of the microbiota found in the vaginas of dairy cows during the transition period: Associations with uterine diseases and reproductive outcome.

We investigated the microbiota found in the vaginas of Holstein dairy cows during the transition period and described the differences in bacterial composition and total bacterial load (TBL) associated with disease and fertility. Vaginal swabs were collected at -7, 0, 3, and 7 d relative to parturition from 111 dairy cows housed on a commercial dairy farm near Ithaca, New York. Microbiota were characterized by next-generation DNA sequencing of the bacterial 16S rRNA gene, and TBL was determined by real-time quantitative PCR. We applied repeated-measures ANOVA to evaluate the associations of uterine disease and related risk factors with the microbiota and TBL. We estimated phylum-specific bacterial load by multiplying the TBL by the relative abundance of each phylum observed in the metagenomics results. We confirmed the validity of this approach for estimating bacterial load by enumerating the number of bacteria in an artificial sample mixed in vitro and in clinical and healthy vaginal samples. Phyla associated with uterine disease and related risk factors were Proteobacteria, Fusobacteria, and Bacteroidetes. Cows with retained placenta and healthy cows had similar TBL at the day of parturition, but at d 7 postpartum, cows with retained placenta showed a significantly higher TBL, mainly driven by higher estimated loads of Fusobacteria and Bacteroidetes. Cows diagnosed with metritis had a significantly higher estimated load of Proteobacteria at d -7 and at calving and higher estimated loads of Fusobacteria in the postpartum samples. Additionally, the estimated load of Bacteroidetes at d 7 postpartum was higher for cows diagnosed with endometritis at 35 days in milk. Higher estimated loads of Fusobacteria and Bacteroidetes were also evident in cows with postpartum fever, in primiparous cows, in cows with assisted parturition, and in cows that gave birth to twins. Our findings demonstrated that microbiota composition and TBL were associated with known periparturient risk factors of uterine diseases and reproductive failure, including parity, assisted parturition, and retained fetal membranes.

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions.

Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G>A, DRD3 Ser9Gly, HTR2C c.995G>A and ABCB1 1236C>T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G>A, HTR2C c.68G>C (p.C33S), HTR6 c.7154-2542C>T and BDNF c.196G>A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G>C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.