No abstract

Inhibition of phosphodiesterase 10A (PDE10A) promotes cyclic nucleotide signaling, increases striatal activation, and decreases behavioral activity. Enhanced cyclic nucleotide signaling is a well established route to producing changes in gene expression. We hypothesized that chronic suppression of PDE10A activity would have significant effects on gene expression in the striatum. A comparison of the expression profile of PDE10A knockout (KO) mice and wild-type mice after chronic PDE10A inhibition revealed altered expression of 19 overlapping genes with few significant changes outside the striatum or after administration of a PDE10A inhibitor to KO animals. Chronic inhibition of PDE10A produced up-regulation of mRNAs encoding genes that included prodynorphin, synaptotagmin10, phosphodiesterase 1C, glutamate decarboxylase 1, and diacylglycerol Oacyltransferase and a down-regulation of mRNAs encoding choline acetyltransferase and Kv1.6, suggesting long-term suppression of the PDE10A enzyme is consistent with altered striatal excitability and potential utility as a antipsychotic therapy. In addition, upregulation of mRNAs encoding histone 3 (H3) and down-regulation of histone deacetylase 4, follistatin, and claspin mRNAs suggests activation of molecular cascades capable of neuroprotection. We used lentiviral delivery of cAMP response element (CRE)-luciferase reporter constructs into the striatum and live animal imaging of 2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid (TP-10)-induced luciferase activity to further demonstrate PDE10 inhibition results in CRE-mediated transcription. Consistent with potential neuroprotective cascades, we also demonstrate phosphorylation of mitogen-and stress-activated kinase 1 and H3 in vivo after TP-10 treatment. The observed changes in signaling and gene expression are predicted to provide neuroprotective effects in models of Huntington's disease.

The prevalence of asthma was studied in a ice hockey team compared with both a floor ball team and the Swiss population. Lung function, bronchial hyperresponsiveness to methacholine, asthma symptoms and exercise-induced asthma were measured in a cross-sectional prospective study. A positive response to the methacholine bronchial provocation test was found in 34.6% of the ice hockey players and 20.8% of the floor ball players (Swiss population 16.4%). The provocative dose causing a 20% fall in the forced expiratory volume in one second (PD20) was significantly lower in ice hockey players than in floor ball players, but there was no significant difference in the dose-response slopes between the two groups. Asthma was diagnosed in 19.2% of the ice hockey players and in 4.2% of the floor ball players (Swiss population 6.8%), whereas exercise-induced asthma was found in 11.5% of the ice hockey players and in 4.2% of the floor ball players. In conclusion, asthma and bronchial hyperresponsiveness seemed to be more common in ice hockey players than in floor ball players and in the Swiss population. Strenuous exercise at lower temperatures may be a risk factor for the higher prevalence of asthma and bronchial hyperresponsiveness, as well as the increased severity of bronchial hyperresponsiveness, particularly in ice hockey players.

No abstract

The new Swiss Chronic Obstructive Pulmonary Disease (COPD) Guidelines are based on a previous version, which was published 10 years ago. The Swiss Respiratory Society felt the need to update the previous document due to new knowledge and novel therapeutic developments about this prevalent and important disease. The recommendations and statements are based on the available literature, on other national guidelines and, in particular, on the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. Our aim is to advise pulmonary physicians, general practitioners and other health care workers on the early detection and diagnosis, prevention, best symptomatic control, and avoidance of COPD as well as its complications and deterioration.