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Abstract:  We investigated the effects of a protein kinase A (PKA) inhibitor, H-89 {N-[2-(p-bromocinnamylamino)ethyl]-5-iso-quinolinesulphonamide}, on Ca2+ regulation in Fura-2-loaded ferret myocytes. H-89 (10 µmol/l) decreased the amplitude of the Fura-2 transient to 28.2±4.3% (P<0.001) of control and prolonged its duration, characterized by a decrease in the rate of decline of Ca2+ to diastolic levels: t 1/2 increased from 311±35 ms to 547±43 ms (P<0.001, n=7). Reduced Ca2+ uptake by the sarcoplasmic reticulum (SR) in the presence of H-89 was also indicated by a decrease in the SR Ca2+ content, as assessed with caffeine. The apparent slowing of the SR Ca2+-ATPase was not caused by changes in phosphorylation of phospholamban (PLB). However, Ca2+ uptake in microsomal vesicles prepared from canine hearts and fast-twitch rat skeletal muscle (which lacks PLB) was decreased by 34.1 and 46.8% (n=3), respectively, suggesting that H-89 has a direct inhibitory effect on the SR Ca2+-ATPase. In electrophysiological experiments, 5.0 µmol/l H-89 decreased the L-type Ca2+ current (I Ca) by 39.5% (n=6) and slowed the upstroke of the action potential and, in some cases, caused loss of excitability without changes in the resting membrane potential. In summary, data show that [Ca2+ ]i regulation, and hence contraction, is sustained by PKA-mediated phosphorylation, even in the absence of β-agonists. However, the use of H-89 as a tool to study the role of this signalling pathway is limited by the non-specific effects of H-89 on the SR Ca2+-ATPase.

When dissolved in N,N-dimethylformamide and then dialyzed against phosphate-buffered saline, A-B-A block copolymers composed of poly [N5-(2-hydroxyethyl)-L-glutamine]-block-poly(gamma-benzyl-L-glutamate)- block-poly [N5-(2-hydroxyethyl)-L-glutamine] form particles. The particles are cage-like structures with average diameters of 300 nm (average polydispersity, 0.3-0.5). They are stable in aqueous solution at 4 degrees C for up to 3 weeks, at which time flocculation becomes apparent. Negative staining and freeze-fracture electron microscopy suggest that cage-like particles are formed by selective association of segregated micelle populations. A model of particle formation is presented in which B blocks form micelles in dimethylformamide. On dialysis against an aqueous solution, the extended A blocks then associate intermolecularly to form rod-shaped micelles, which connect the B block micelles. The result is a meshed cage-like particle. The implications of these observations on the aggregation behavior of polymeric surfactants in dilute solution are discussed.

As act two of the financial crisis begins to unfold, governments across the globe are findingit difficult to finance their debts and raise new money on the markets. The new buzzword is austerity and the UK is not exempt from the coming storm. Cuts in public spending, the likes of which have not been seen for decades, will soon be upon us. With this in mind, talk of financial incentives for public servants may seem ludicrous. However, perhaps there is a way in which departments can save money while still providing a financial reward for those workers interested in increasing efficiency. In this article, we present an idea linking the audit cycle to financial incentives and demonstrate how it could be effective to all parties involved.

Background:The clinical benefit of onabotulinumtoxinA in cervical dystonia (CD) is proven, but its impact on health-related quality of life (HRQoL) is largely unknown. Methods:Multicentre, prospective, observational study (NCT01655862) of CD patients treated with onabotulinumtoxinA at physician discretion (maximum 9 treatments). Patient-reported HRQoL outcomes and work productivity were collected at baseline, 4- or 8-weeks post-treatment, and final visit (prior to 9thtreatment). OnabotulinumtoxinA utilization was assessed. Results:61 patients received ≥1 treatment; 74.1% completed all treatments. Average total dose/treatment was 186.9U. The splenius capitis was most frequently treated (100% patients). Average pain numeric rating scale score was significantly improved at final visit (2.1) versus baseline (4.6; p<0.001) as were CD impact profile questionnaire-58 scores across all subscales (head/neck symptoms, pain/discomfort, sleep, upper limb activities, walking, annoyance, mood, psychosocial functioning; all p<0.001). Fewer patients (16.0%) reported loss of work productivity at final visit versus baseline (48.4%). 121 AEs were reported by 67.2% patients. 62 AEs in 44.3% patients were treatment-related, the most common being neck pain (18%). One serious AE (not treatment-related) was reported by 1 patient. No new safety signals were identified. Conclusions:Long-term use of onabotulinumtoxinA is a safe, effective treatment for CD, improving HRQoL and work productivity.

Background:We assessed long-term health-related quality of life (HRQoL) and functioning in adults receiving onabotulinumtoxinA for CM. Methods:Interim analysis of multicentre, prospective, observational study in adults naïve to botulinum toxin (NCT02502123). Mean change from baseline in Migraine-Specific Quality of Life (MSQ) score (primary); healthcare resource utilization (HRU) and work productivity (secondary) assessed in patients receiving 4 of 7 onabotulinumtoxinA treatments (Tx4; ~10 months). Results:Across treatments (baseline, n=196, post-Tx2, n=173, post-Tx4, n=137), the mean (SD) between-session interval and onabotulinumtoxinA dose was 13.1 weeks and 170.4 (17.2) U, respectively. MSQ scores increased significantly (P<0.0001) (baseline to post-Tx4; all role function domains). Patient percentages declined from baseline to post-Tx2 and post-Tx4 for emergency room visits (17.3%; 9.3%; 6.6%), hospital admissions (3.6%; 2.9%; 1.5%), and headache-related diagnostic testing (35.9%; 15.9%; 8.1%). The percentages of patients employed at baseline (73.5%) and post-Tx4 (72.3%) were similar. Hours worked increased slightly from baseline to post-Tx4 (28.0 [SD=15.4]; 29.4 [SD=16.0]). Headache-related missed work hours decreased (5.9 [SD=9.5]; 2.5 [SD=5.9]). Patients reported less headache-related impact on work productivity from baseline to post-Tx4 (5.4 [SD=2.1] vs 3.9 [SD=2.6]) and ability to perform daily activities (6.1 [SD=2.1] vs 4.2 [SD=2.8]). Conclusions:OnabotulinumtoxinA for CM improved HRQoL and work productivity and reduced HRU.