Feasibility of 'parkrun' for people with knee osteoarthritis: A mixed methods pilot study.

Objective: To investigate the feasibility of 'parkrun' for people with knee osteoarthritis (OA) and examine its potential to improve symptoms and increase physical activity. Design: This uncontrolled mixed methods pilot study enrolled people with knee OA not meeting physical activity guidelines. Participants were asked to walk in four consecutive parkrun events supervised by an exercise physiologist/physiotherapist. Feasibility was assessed by recruitment data (numbers screened and time to enrol 15 participants), adherence to the protocol, acceptability (measured by confidence, enjoyment, difficulty ratings and qualitative interviews), and safety (adverse events). Secondary measures were changes in knee pain, function, stiffness, and physical activity levels. Results: Participants (n â€‹= â€‹17) were enrolled over 11 months and recruitment was slower than anticipated. Fourteen participants attended all four parkruns and three of these participants shortened the 5 â€‹km course to ∼3 â€‹km. Across all four parkruns, 75% of participants reported high confidence that they could complete the upcoming parkrun and the majority (87%) enjoyed participating. Most participants rated parkrun either "slightly difficult" (38.5%) or "moderately difficult" (35%) and two mild adverse events were reported. Participants showed improvements in knee pain, function, stiffness, and physical activity levels. Conclusions: This pilot study demonstrates parkrun's feasibility, acceptability, safety and, its potential to improve knee OA symptoms and physical activity levels. Participating in parkrun was acceptable and enjoyable for some, but not all participants. The scalability, accessibility and wide appeal of parkrun supports the development of larger programs of research to evaluate the use of parkrun for people with knee OA.

The effects of neuropsychiatric drugs on glycogen synthase kinase-3 signaling.

Glycogen synthase kinase-3 (GSK-3) has been implicated in the action of antipsychotics, mood stabilizers, and antidepressants. Given that only antipsychotics are able to alleviate the positive symptoms of schizophrenia, the regulation of GSK-3 by antipsychotics would be expected to differ from other neuropsychiatric drugs if GSK-3 is involved in the alleviation of psychosis. Consequently, the current study examined the effects of antipsychotics (haloperidol and clozapine), mood stabilizers (lithium and valproic acid), and antidepressants (imipramine and fluoxetine) on GSK-3, as well as Akt and Wnt in the prefrontal cortex and striatum. Western blotting and co-immunoprecipitation experiments showed that only antipsychotic treatment increased Dvl-3, GSK-3, and ß-catenin levels and enhanced the association of GSK-3 at the dopamine D2 receptor (D2DR) complex in the rat prefrontal cortex. In the striatum, haloperidol had the same effect on Wnt signaling as observed in the prefrontal cortex, whereas clozapine did not affect Dvl-3, GSK-3 or ß-catenin levels. All three classes of drugs were able to activate Akt signaling as shown by the increased phosphorylated Akt and phosphorylated GSK-3 protein levels in the prefrontal cortex and/or striatum. In conclusion, regulation of the Wnt pathway is specific to antipsychotics, whereas antipsychotics, mood stabilizers, and antidepressants all affect Akt.

Antipsychotics affect multiple calcium calmodulin dependent proteins.

Calcineurin is a calmodulin (CaM) dependent protein phosphatase recently found to be altered in the brains of patients suffering from schizophrenia and by repeated antipsychotic treatment in rats. Some data suggest, however, that antipsychotics and schizophrenia may have a more widespread effect on the CaM signaling axis than calcineurin alone. In the current study, the effects of selected psychoactive drugs were investigated using Western blotting, in situ hybridization and immunocytochemistry to determine if they target CaM, calmodulin-dependent protein kinases (CaMK) or calcineurin. Results indicated that repeated treatment with haloperidol, clozapine or risperidone increased CaM protein and CaMII mRNA levels but decreased calmodulin-dependent protein kinase IIalpha (CaMKIIalpha) IV (CaMKIV), kinase alpha (CaMKKalpha), kinase beta (CaMKKbeta) and calcineurin protein levels in the striatum of Sprague-Dawley rats (Rattus Norvegicus). Closer examination of CaMKIV, CaMKKalpha and CaMKKbeta revealed that the observed decreases in protein levels were short-lived following antipsychotic treatment and reversed (i.e. upregulated) 24 h post-treatment similar to what was previously reported for calcineurin. The D(2)/D(3)dopamine receptor antagonist raclopride mimicked the decreases in CaMKIV, CaMKKalpha, CaMKKbeta and calcineurin observed following antipsychotic treatment whereas increases in these proteins were observed in an amphetamine model of the positive symptoms of schizophrenia. Mood stabilizers such as lithium and valproic acid or the antidepressant fluoxetine had no effect on CaMKIV, CaMKKalpha, CaMKKbeta and calcineurin with the exception of an increase in CaMKKbeta following lithium treatment. The results collectively suggest that antipsychotic specifically target several proteins associated with CaM signaling.

Preferential induction of apoptosis in the rainbow trout macrophage cell line, RTS11, by actinomycin D, cycloheximide and double stranded RNA.

The rainbow trout macrophage cell line RTS11 was found to be considerably more sensitive than rainbow trout fibroblast (RTG-2) and Chinook salmon epithelial (CHSE-214) cell lines to killing by macromolecular synthesis inhibitors, actinomycin D (AMD) and cycloheximide (CHX), a synthetic double stranded RNA (dsRNA), polyinosinic:polycytidylic acid (poly IC), and combinations of poly IC with AMD or CHX. Exposures of 24-30 h to AMD or CHX alone killed RTS11, but not CHSE-214 and RTG-2, in basal medium, L-15, with or without fetal bovine serum (FBS) supplementation. A two-week exposure to poly IC killed RTS11 in L-15, whereas RTG-2 and CHSE-214 remained viable. At concentrations that caused very little or no cell death, CHX or AMD pretreatments or co-treatments sensitized RTS11 to poly IC, causing death within 30 h. In all cases death was by apoptosis as judged by two criteria. H33258 staining revealed a fragmented nuclear morphology, and genomic degradation into oligonucleosomal fragments was seen with agarose gel electrophoresis. With AMD- or CHX-induced death, killing seemed caspase-independent as the pan caspase inhibitor, z-VAD-fmk, failed to block killing. By contrast, z-VAD-fmk almost completely abrogated killing by co-treatments of poly IC and low concentrations of AMD or CHX, suggesting caspase dependence. Killing by both types of treatments was blocked by 2 aminopurine (2-AP), which suggests the involvement of dsRNA-dependent protein kinase (PKR). The sensitizing of RTS11 to poly IC killing by AMD or CHX could be explained by a decrease in the level of a short-lived anti-apoptotic protein(s) and/or by the triggering of a ribotoxic stress.