Feedback via Ca²⁺-activated ion channels modulates endothelin 1 signaling in retinal arteriolar smooth muscle

PURPOSE: To investigate the role of feedback by Ca²?-sensitive plasma-membrane ion channels in endothelin 1 (Et1) signaling in vitro and in vivo. Methods. Et1 responses were imaged from Fluo-4-loaded smooth muscle in isolated segments of rat retinal arteriole using two-dimensional (2-D) confocal laser microscopy. Vasoconstrictor responses to intravitreal injections of Et1 were recorded in the absence and presence of appropriate ion channel blockers using fluorescein angiograms imaged using a confocal scanning laser ophthalmoscope. Results. Et1 (10 nM) increased both basal [Ca²?](i) and the amplitude and frequency of Ca²?-waves in retinal arterioles. The Ca²?-activated Cl?-channel blockers DIDS and 9-anthracene carboxylic acid (9AC) blocked Et1-induced increases in wave frequency, and 9AC also inhibited the increase in amplitude. Iberiotoxin, an inhibitor of large conductance (BK) Ca²?-activated K?-channels, increased wave amplitude in the presence of Et1 but had no effect on frequency. None of these drugs affected basal [Ca²?](i). The voltage-operated Ca²?-channel inhibitor nimodipine inhibited wave frequency and amplitude and also lowered basal [Ca²?](i) in the presence of Et1. Intravitreal injection of Et1 caused retinal arteriolar vasoconstriction. This was inhibited by DIDS but not by iberiotoxin or penitrem A, another BK-channel inhibitor. Conclusions. Et1 evokes increases in the frequency of arteriolar Ca²?-waves in vitro, resulting in vasoconstriction in vivo. These responses, initiated by release of stored Ca²?, also require positive feedback via Ca²?-activated Cl?-channels and L-type Ca²?-channels.

THE SYNTHESIS, KINETIC CHARACTERIZATION AND APPLICATION OF A NOVEL BIOTINYLATED AFFINITY LABEL FOR CATHEPSIN-B

In this study we report on the synthesis, kinetic characterization and application of a novel biotinylated and active-site-directed inactivator of cathepsin B. Thus the peptidyliazomethane biotinyl-Phe-Ala-diazomethane has been synthesized by a combination of solid-phase and solution methodologies and has been shown to be a very efficient inactivator of bovine and human cathepsin B. The respective apparent second-order rate constants (k0bs./[I]) for the inactivation of the human and bovine enzymes by this reagent, namely approximately 5.4 x 10(4) M-1 and approximately 7.8 x 10(4) M-1, compare very favourably with those values determined for the urethane-protected analogue benzloxycarbonyl-Phe-Ala-chloromethane first described by Green & Shaw [(1981) J.Biol. Chem. 256, 1923-1928], thus demonstrating that the presence of the biotin moiety at the P3 position is compatible with inhibitor effectiveness. The utilization of this reagent for the detection of cathepsin B in electrophoretic gels, using Western blotting and in combination with a streptavidin/alkaline phosphatase detection system, is also demonstrated. Given that the peptidydiazomethanes exhibit a pronounced reactivity towards cysteine proteinases, we feel that the present label may well constitute the archetypal example of a wide range of reagents for the selective labelling of this class of proteinase, even in a complex biological milieu containing additional classes of proteinases.

Pharmacy Students’ Views of Faculty Feedback on Academic Performance

Objective: To investigate students' views on and satisfaction with faculty feedback on their academic performance.

Methods: A 41-item survey instrument was developed based on a literature review relating to effective feedback. All pharmacy undergraduate students were invited via e-mail to complete the self-administered electronic questionnaire relating to their views on feedback, including faculty feedback received to date regarding their academic performance.

Results: A response rate of 61% (343/561) was obtained. Only 32.3% of students (107/331) agreed that they were satisfied with the feedback they received; dissatisfaction with examination feedback was particularly high. The provision of faculty feedback was perceived to be variable in terms of quality and quantity.

Conclusions: There are some inconsistencies relating to provision of feedback within the MPharm degree program at Queen's University Belfast. Further work is needed to close the gap between student expectations and the faculty's delivery of feedback on academic performance.

Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees

OBJECTIVE The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). METHOD The family sample included 2,461 individuals from 631 pedigrees (581 in the primary European-ancestry analyses). Association was tested for single SNPs and genetic pathways. Polygenic scores based on family study results were used to predict case-control status in the Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and consistency of direction of effect with the family study was determined for top SNPs in the PGC GWAS analysis. Within-family segregation was examined for schizophrenia-associated rare CNVs. RESULTS No genome-wide significant associations were observed for single SNPs or for pathways. PGC case and control subjects had significantly different genome-wide polygenic scores (computed by weighting their genotypes by log-odds ratios from the family study) (best p=10-17, explaining 0.4% of the variance). Family study and PGC analyses had consistent directions for 37 of the 58 independent best PGC SNPs (p=0.024). The overall frequency of CNVs in regions with reported associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2, and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous case-control studies. NRXN1 deletions and 16p11.2 duplications (both of which were transmitted from parents) and 22q11.2 deletions (de novo in four cases) did not segregate with schizophrenia in families. CONCLUSIONS Many common SNPs are likely to contribute to schizophrenia risk, with substantial overlap in genetic risk factors between multiply affected families and cases in large case-control studies. Our findings are consistent with a role for specific CNVs in disease pathogenesis, but the partial segregation of some CNVs with schizophrenia suggests that researchers should exercise caution in using them for predictive genetic testing until their effects in diverse populations have been fully studied.

Home medication management practices and associated factors among patients with selected chronic diseases in a community pharmacy in Uganda

ABSTRACT: BACKGROUND: Chronic diseases are rapidly increasing and are currently the major cause of death and disability worldwide. Patients with chronic diseases experience many challenges including medicine-related problems. However, there is limited information about the home management of medicines among these patients. This study therefore was to determine home medication management practices and associated factors among patients with chronic diseases seeking care in a community pharmacy in Uganda. METHODS: A cross-sectional study was conducted in a community pharmacy in Kampala from June to July 2010. A total of 207 consenting chronic disease patients or caregivers of children with chronic disease were consecutively sampled. The patients were visited at home to evaluate their drug management practices and to check their medical forms for disease types and drugs prescribed. An interviewer-administered questionnaire and an observation checklist were used to collect the data. RESULTS: Overall home medication management was inappropriate for 70% (n = 145) of the participants (95% CI = 63.3-76.2) and was associated with perceived severity of disease (not severe OR =0.40, moderately severe OR = 0.35), duration of disease >5 years (OR = 2.15), and health worker not assessing for response to treatment (OR = 2.53). About 52% (n = 107) had inappropriate storage which was associated with inadequate information about the disease (OR = 2.39) and distance to the health facility >5 kilometres (OR = 2.82). Fifteen percent (n = 31) had no drug administration schedule and this was associated with increasing age (OR = 0.97), inadequate information about the disease (OR = 2.96), and missing last appointment for medical review (OR = 6.55). About 9% (n = 18) had actual medication duplication; 1.4% (n = 3) had expired medicines; while 18.4% (n = 38) had drug hoarding associated with increasing number of prescribers (OR = 1.34) and duration of disease (OR = 2.06). About 51% (n = 105) had multiple prescribers associated with perceiving the disease to be non severe (OR = 0.27), and having more than one chronic disease (OR = 2.37). CONCLUSIONS: Patients with chronic disease have poor home management of medicines. In order to limit the occurrence of poor outcomes of treatment or drug toxicity, health providers need to strengthen the education of patients with chronic disease on how to handle their medicines at home.

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P(combined) = 4.09 × 10(-9); odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P(combined) = 2.74 × 10(-10); OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

The Houses of the Oireachtas:Parliament in Ireland

The Irish parliament - the Oireachtas - is nearing the centenary year of its foundation, making it one of the oldest continuously surviving parliaments in the world. As the most important national institution in the state, it plays an essential role in giving voice to a diversity of views and opinions, providing stable governments, approving law and national budgets and upholding democratic values. For much of its existence, however, and most pointedly in the context of recent banking and economic crises, it has been subject to criticism concerning its ability to adequately hold the executive to account, to act as a coherent policy-making forum, to meet the challenges arising from European Union membership, to embrace wide-ranging reforms and to develop with purpose and ambition.

This comprehensive new volume considers all aspects of the Houses of the Oireachtas - including their evolution, composition, organisation, financing, administration and reform. Contributors include academics, administrators and sitting and former parliamentarians. Contemporary challenges brought about by transformations in media style, increased inter-parliamentarism and the changing character of politics are also addressed. The book questions a number of assumptions about parliament and its work, including the efficacy of the legislative and budgetary processes, the nature of executive-legislative relations and the perceived encroachment of the courts on the legislature. Combined, this wide-ranging and detailed study fills a long-standing void, and provides essential reading not alone for those interested in Irish politics and government, but also for students and scholars of legislative studies.

ALCOHOL-RELATED KNOWLEDGE AND ATTITUDES IN PEOPLE WITH A MILD LEARNING-DISABILITY - THE EFFECTS OF A SENSIBLE DRINKING GROUP

Alcohol-related knowledge and attitudes in people with a mild learning disability, who were either living, or being prepared to live, in relatively independent conditions in the community, were assessed through a structured interview format. Compared with non-learning-disabled teenagers, adults and a hospitalized patient sample, alcohol-related knowledge in the people with a learning disability was found to be significantly poorer, alcohol was reported as having particularly negative effects and susceptibility to social pressure to drink alcohol was greater. A 'sensible drinking' group, taking a social skills and influences approach to alcohol education, was conducted with a subgroup of the individuals with a learning disability. The group format and methods, including in vivo sessions in a public house, are described. Follow-up evaluations suggested some significant positive changes in knowledge, attitudes and sensible drinking skills. It is concluded that this population, which is increasingly living, or being moved into, independent conditions in the community, is at least as vulnerable to social influences on alcohol use and abuse as are young people. As with young people, the usefulness of making available such alcohol-education programmes as described in this study, is discussed.

A.J. Raffles and Arsène Lupin in Literature, Theatre, and Film: On The Transnational Adaptations of Popular Fiction (1905-1930)

As a consequence of the accelerating technological development and the impact of cultural globalisation, the transnational aspects of the process of adaptation have become increasingly crucial in recent years. To go back to the very beginnings of the twentieth century and research the historical connections between popular literature, theatre, and film can shed greater light on the origins of these phenomena. By focusing on two case studies from turn-of-the-century crime fiction, this paper examines the extent to which practices of serialisation, translation, and adaptation of literary works contributed to the formation of a transnational market for popular culture. Ernest W. Hornung’s A. J. Raffles and Maurice Leblanc’s Arsène Lupin were the heroes of two crime series that were immediately translated, imitated, and adapted into countless theatrical plays and films all over the world. Given the resemblance between the two characters, the two franchises frequently ended by overlapping. Their ability to move from a medium to another as well as from a country to another was the result of the logic of ‘recycling, remaking, retelling’ (Brian Naremore) that guides not only the process of adaptation but also the creation of any work of popular culture.