Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

Efficacy and tolerability of gemtuzumab ozogamicin (anti-CD33 monoclonal antibody, CMA-676, Mylotarg(®)) in children with relapsed/refractory myeloid leukemia

BACKGROUND: Gemtuzumab ozogamicin (GO) is a cytotoxic anti-CD33 monoclonal antibody that has given promising preliminary results in adult myeloid CD33+ AML. We conducted a retrospective multicenter study of 12 children treated with GO on a compassionate basis (median age 5.5 y). Three patients (2 MDS/AML, 1 JMML) were refractory to first-line treatment, 8 patients with de novo AML were in refractory first relapse, and one patient with de novo AML was in 2(nd )relapse after stem cell transplantation (SCT). CD33 expression exceeded 20% in all cases. METHODS: GO was administered alone, at a unit dose of 3–9 mg/m(2), once (3 patients), twice (3 patients), three (5 patients) or five times (1 patient). Mean follow-up was 128 days (8–585 d). RESULTS: There were three complete responses (25%) leading to further curative treatment (SCT). Treatment failed in the other nine patients, and only one patient was alive at the end of follow-up. NCI-CTC grade III/IV adverse events comprised hematological toxicity (n = 12), hypertransaminasemia (n = 2), allergy and hyperbilirubinemia (1 case each). There was only one major adverse event (grade IV allergy). No case of sinusoidal obstruction syndrome occurred. CONCLUSION: These results warrant a prospective trial of GO in a larger population of children with AML

Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial

Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). Patients and methods: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. Results: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. Conclusions: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients

Compromiso organizacional y satisfacción laboral: un estudio exploratorio en unidades de salud familiar portuguesas

Explorou-se a relação entre compromisso organizacional e satisfação laboral nos colaboradores de unidades de saúde familiar. Participaram seis unidades de saúde familiar do norte de Portugal e 105 profissionais (médico, enfermeiros e secretários clínicos). Utilizaram-se as adaptações portuguesas da Escala do Compromisso Organizacional de Meyer & Allen (1997) e do Questionário de Satisfação com o Trabalho (Spector, 1985). Os resultados sugerem associação positiva entre compromisso organizacional e satisfação laboral. Os profissionais estão moderadamente satisfeitos e comprometidos com as unidades de saúde familiar, sendo a natureza do trabalho, a relação com os colegas e a comunicação os aspectos mais satisfatórios, e as recompensas o mais insatisfatório. A componente afetiva do compromisso evidencia-se, salientando o envolvimento e a identificação dos profissionais com o projeto unidades de saúde familiar. O modelo de regressão linear revelou-se significativo, o compromisso organizacional explica 22,7% da variância da satisfação com o trabalho. Para esta amostra, o compromisso organizacional prediz a satisfação com o trabalho.This study explored the relationship between organizational commitment and job satisfaction among workers in family health units. Six family health units in the North of Portugal participated, including 105 health professionals (physicians, nurses, and clinical secretaries). The study used the Portuguese adaptations of the Organizational Commitment Scale by Meyer & Allen (1997) and the Job Satisfaction Survey (Spector, 1985). The results suggest a positive association between organizational commitment and job satisfaction. The professionals are moderately satisfied and committed to the family health units; the most satisfactory aspects are the nature of the work, relationship to coworkers, and communication, while pay is the most unsatisfactory. The affective component of the commitment appears, highlighting the professionals' involvement in (and identification with) the family health units project. The linear regression model proved significant, and organizational commitment explains 22.7% of the variance in job satisfaction. For this sample, organizational commitment predicts job satisfaction.Instituto Nacional de Saúde Dr Ricardo Jorgeinfo:eu-repo/semantics/publishedVersio

Landscape determinants of European roller foraging habitat: implications for the definition of agri-environmental measures for species conservation

Across much of Europe, farmland birds are declining more than those in other habitats. From a conservation perspective, identifying the primary preferred habitats could help improve the foraging conditions of target species and, consequently, enhance their breeding success and survival. Here, we investigated the ranging behaviour and foraging habitat selection of the European roller (Coracias garrulus) during the breeding season in an agricultural landscape of South Iberia. The occurrence of foraging rollers was predicted to gradually increase with decreasing distance from the nest and increasing availability of perches, such as fences and electric wires. Traditional olive groves and stubble fields were positively and negatively associated with the occurrence of rollers, respectively. Additionally, analysis of hunting strikes showed that rollers highly prefer foraging in fallows rather than cereal or stubble fields. Prey surveys revealed that fallows had the highest abundance of grasshoppers, rollers’ preferred prey during chick-rearing. Pair home-ranges, obtained from 95% fixed Kernel estimators averaged 70.9 ha (range = 34–118 ha) and most foraging trips (80%) occurred in the close vicinity of the nest (<500 m). Number of chicks fledged was not affected by mean foraging distances travelled during the chick-rearing period. Overall, our results suggest that traditional extensive practices of cereal cultivation, with large areas of low-intensity grazed fallows, represent a high-quality foraging habitat for rollers and should be promoted through agri-environmental schemes within at least 1-km radius from the nest. These recommendations are targeted at the roller, but have been shown to apply broadly to several other steppe-bird species

Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia

BACKGROUND: There are few validated fluid biomarkers in frontotemporal dementia (FTD). Glial fibrillary acidic protein (GFAP) is a measure of astrogliosis, a known pathological process of FTD, but has yet to be explored as potential biomarker. METHODS: Plasma GFAP and neurofilament light chain (NfL) concentration were measured in 469 individuals enrolled in the Genetic FTD Initiative: 114 C9orf72 expansion carriers (74 presymptomatic, 40 symptomatic), 119 GRN mutation carriers (88 presymptomatic, 31 symptomatic), 53 MAPT mutation carriers (34 presymptomatic, 19 symptomatic) and 183 non-carrier controls. Biomarker measures were compared between groups using linear regression models adjusted for age and sex with family membership included as random effect. Participants underwent standardised clinical assessments including the Mini-Mental State Examination (MMSE), Frontotemporal Lobar Degeneration-Clinical Dementia Rating scale and MRI. Spearman's correlation coefficient was used to investigate the relationship of plasma GFAP to clinical and imaging measures. RESULTS: Plasma GFAP concentration was significantly increased in symptomatic GRN mutation carriers (adjusted mean difference from controls 192.3 pg/mL, 95% CI 126.5 to 445.6), but not in those with C9orf72 expansions (9.0, -61.3 to 54.6), MAPT mutations (12.7, -33.3 to 90.4) or the presymptomatic groups. GFAP concentration was significantly positively correlated with age in both controls and the majority of the disease groups, as well as with NfL concentration. In the presymptomatic period, higher GFAP concentrations were correlated with a lower cognitive score (MMSE) and lower brain volume, while in the symptomatic period, higher concentrations were associated with faster rates of atrophy in the temporal lobe. CONCLUSIONS: Raised GFAP concentrations appear to be unique to GRN-related FTD, with levels potentially increasing just prior to symptom onset, suggesting that GFAP may be an important marker of proximity to onset, and helpful for forthcoming therapeutic prevention trials

Predicting participation of people with impaired vision in epidemiological studies

The characteristics of the target group and the design of an epidemiologic study, in particular the recruiting methods, can influence participation. People with vision impairment have unique characteristics because those invited are often elderly and totally or partially dependent on help to complete daily activities such as travelling to study sites. Therefore, participation of people with impaired vision in studies is less predictable than predicting participation for the general population.This study was supported by FCT (COMPETE/QREN) grant reference PTDC/DPT-EPI/0412/2012 in the context of the Prevalence and Costs of Visual Impairment in Portugal: a hospital based study (PCVIP-study). PLR is funded by FCT (COMPETE/QREN) grant reference SFRH/BD/119420/2016