Xrn1/Pacman affects apoptosis and regulates expression of hid and reaper

Programmed cell death, or apoptosis, is a highly conserved cellular process that is crucial for tissue homeostasis under normal development as well as environmental stress. Misregulation of apoptosis is linked to many developmental defects and diseases such as tumour formation, autoimmune diseases and neurological disorders. In this paper, we show a novel role for the exoribonuclease Pacman/Xrn1 in regulating apoptosis. Using Drosophila wing imaginal discs as a model system, we demonstrate that a null mutation in pacman results in small imaginal discs as well as lethality during pupation. Mutant wing discs show an increase in the number of cells undergoing apoptosis, especially in the wing pouch area. Compensatory proliferation also occurs in these mutant discs, but this is insufficient to compensate for the concurrent increase in apoptosis. The phenotypic effects of the pacman null mutation are rescued by a deletion that removes one copy of each of the pro-apoptotic genes reaper, hid and grim, demonstrating that pacman acts through this pathway. The null pacman mutation also results in a significant increase in the expression of the pro-apoptotic mRNAs, hid and reaper, with this increase mostly occurring at the post-transcriptional level, suggesting that Pacman normally targets these mRNAs for degradation. Our results uncover a novel function for the conserved exoribonuclease Pacman and suggest that this exoribonuclease is important in the regulation of apoptosis in other organisms

Through the looking glass: public and professional perspectives on patient-centred professionalism in modern-day community pharmacy

This paper presents five consultation workshops with 29 community pharmacists, stakeholders and patients that examined "patient-centred professionalism" in terms of pharmacists' working day and environment. The concept is ill-defined in both medical and pharmacy literature and the study aimed to clarify the situated nature of the term for patients and health professionals across settings. Workshops were supported by bio-photographic datasets of "in-situ" practice and Nominal Group Work. The thematic content analyses led to the following aspects: building caring relationships; managing external forces; the effects of space and environment, and different roles and expectations. The study reveals how patient-centred professionalism cannot be defined in any singular or stationary sense, but should be seen as a "moveable feast", best understood through everyday examples of practice and interaction, in relation to whose experience is being expressed, and whose needs considered. The phrase is being mobilised by a whole set of interests and stakeholders to reshape practice, the effect of which remains both uncertain and contested. Whilst patients prioritise a quick and efficient dispensing service from knowledgeable pharmacists, pharmacists rail against increasing public demands and overtly formalised consultations that take them away from the dispensary where the defining aspects of their professionalism lie. URN: urn:nbn:de:0114-fqs100177Unser Beitrag stellt die Ergebnisse aus insgesamt fünf Workshops mit 29 Apotheker/innen, Patient/innen und weiteren Akteuren vor, die sich mit "Patient/innen-zentrierter Versorgung" in der Alltagsarbeit und -umgebung von Apotheker/innen befassten. Dieses Konzept ist in der relevanten Literatur nur ungenügend definiert, und ein Ziel der Studie war, dessen situativen Charakter für Patient/innen und im Gesundheitssystem Tätige zu präzisieren. In den Workshops kamen Fotografien aus der Alltagspraxis und spezifische Gruppenarbeitsverfahren zum Einsatz. Im Beitrag werden nach einer Information über die Teilnehmenden die Ergebnisse der thematischen Inhaltsanalyse zusammengefasst, die die folgenden Schwerpunkte erbrachte: Aufbau von Beziehungen mit Patient/innen, Umgang mit externen Einflussgrößen, (räumliche) Umgebungseffekte und Unterschiedlichkeit von Rollen und Erwartungen. Die Ergebnisse zeigen, dass "Patient/innen-zentrierte Versorgung" nicht in einer singulären oder statischen Weise definiert werden kann, sondern am besten nachvollziehbar ist entlang von Beispielen aus der Alltagspraxis und von Alltagsinteraktionen, abhängig davon, wessen Erfahrungen ausgedrückt und wessen Bedürfnisse im Fokus stehen sollen. Dieses Verständnis trifft für eine Vielzahl an Interessen und Akteuren zu, um Praxis zu rekonzeptualisieren, die zugleich auch fragil und strittig ist: Während Patient/innen möglichst schnelle und effektive Dienstleistungen von sachkundigen Apotheker/innen erwarten, wenden diese sich gegen wachsende öffentliche Ansprüche und zunehmend formalisierte Beratungen, die sie von der Art von Arbeit entfernen, die Kern ihrer professionellen Identität ist. URN: urn:nbn:de:0114-fqs100177Este documento presenta cinco talleres de consulta con 29 farmacéuticos comunitarios, los promotores y los pacientes que examinaron "el profesionalismo centrado en el paciente" en términos de jornada de trabajo de los farmacéuticos y el medio ambiente. El concepto está mal definido, tanto en la literatura médica y farmacéutica, y el estudio tuvo como objetivo aclarar la naturaleza situada del término en los pacientes y en los profesionales de la salud en diferentes contextos. Los talleres fueron apoyados por conjuntos de datos bio-fotográficas de la práctica "in-situ" y el Grupo Nominal de Trabajo. El análisis de contenido temático c a los siguientes aspectos: creación de relaciones afectuosas; gestión de fuerzas externas; los efectos del espacio y el medio ambiente, y roles y expectativas diferentes. El estudio revela cómo el profesionalismo centrado en el paciente no puede definirse en un sentido singular o estacional, pero debe ser visto como “fiesta ambulante”, mejor entendida a través de ejemplos de la vida diaria y la interacción, en relación con cuya experiencia se expresa, y cuyas necesidades considera. La frase está siendo movilizada por un juego entero de intereses y de los promotores para reformar la práctica, el efecto del cual sigue siendo incierto y puesto en debate. Mientras los pacientes priorizan un servicio de distribución rápido y eficiente de parte de farmacéuticos bien informados, los farmacéuticos critican severamente las crecientes demandas públicas y abiertamente formalizan consultas que se los llevan lejos del dispensario donde radican los aspectos de definición de su profesionalismo. URN: urn:nbn:de:0114-fqs10017

Citrulline Malate Fails to Improve Repeated 300 m Swimming Times in Highly Trained Swimmers

Citrulline malate (CM) has been touted as a nutritional ergogenic aid for sports performance, with purported mechanisms of increased muscle blood flow, ammonia clearance, and adenosine triphosphate resynthesis. Combined, these physiological benefits may be best applied to whole-body endurance exercises, such as swimming, though this postulate has not yet been explored. In a double-blind, randomised, and crossover design, 11 national-level swimmers (age: 17 ± 3 years, height: 1.71 ± 0.05 m, body mass: 60.6 ± 8.3 kg) from a high-performance swimming club ingested either 15 g CM or a placebo (PLA) 60 min before six × 300 m freestyle bouts (at 4.5 min intervals). Blood lactate, blood pressure, and ratings of perceived exertion were measured at baseline, 60 min post-ingestion, and immediately post-exercise. Neither mean 300 m swimming time (CM: 212.0 ± 9.6 vs. PLA: 212.8 ± 7.7 s, p = 0.683, g = 0.09) nor any individual swimming bouts (p = 0.679, Pŋ2 = 0.02) were improved with CM ingestion. Moreover, no differences in any physiological or subjective measures were identified between conditions (all p > 0.05). Whether the proposed CM mechanisms were active was unclear as more direct physiological measures (i.e., plasma NO, ammonia) may have been required. Resultantly, these observations do not support an ergogenic effect of acute CM ingestion in highly trained swimmers

Treatments for hyperemesis gravidarum and nausea and vomiting in pregnancy:A systematic review and economic assessment

Background: Nausea and vomiting in pregnancy (NVP) affects up to 85% of all women during pregnancy, but for the majority self-management suffices. For the remainder, symptoms are more severe and the most severe form of NVP – hyperemesis gravidarum (HG) – affects 0.3–1.0% of pregnant women. There is no widely accepted point at which NVP becomes HG. Objectives: This study aimed to determine the relative clinical effectiveness and cost-effectiveness of treatments for NVP and HG. Data sources: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Cochrane Central Register of Controlled Trials, PsycINFO, Commonwealth Agricultural Bureaux (CAB) Abstracts, Latin American and Caribbean Health Sciences Literature, Allied and Complementary Medicine Database, British Nursing Index, Science Citation Index, Social Sciences Citation Index, Scopus, Conference Proceedings Index, NHS Economic Evaluation Database, Health Economic Evaluations Database, China National Knowledge Infrastructure, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were searched from inception to September 2014. References from studies and literature reviews identified were also examined. Obstetric Medicine was hand-searched, as were websites of relevant organisations. Costs came from NHS sources. Review methods: A systematic review of randomised and non-randomised controlled trials (RCTs) for effectiveness, and population-based case series for adverse events and fetal outcomes. Treatments: vitamins B6 and B12, ginger, acupressure/acupuncture, hypnotherapy, antiemetics, dopamine antagonists, 5-hydroxytryptamine receptor antagonists, intravenous (i.v.) fluids, corticosteroids, enteral and parenteral feeding or other novel treatment. Two reviewers extracted data and quality assessed studies. Results were narratively synthesised; planned meta-analysis was not possible due to heterogeneity and incomplete reporting. A simple economic evaluation considered the implied values of treatments. Results: Seventy-three studies (75 reports) met the inclusion criteria. For RCTs, 33 and 11 studies had a low and high risk of bias respectively. For the remainder (n = 20) it was unclear. The non-randomised studies (n = 9) were low quality. There were 33 separate comparators. The most common were acupressure versus placebo (n = 12); steroid versus usual treatment (n = 7); ginger versus placebo (n = 6); ginger versus vitamin B6 (n = 6); and vitamin B6 versus placebo (n = 4). There was evidence that ginger, antihistamines, metoclopramide (mild disease) and vitamin B6 (mild to severe disease) are better than placebo. Diclectin® [Duchesnay Inc.; doxylamine succinate (10 mg) plus pyridoxine hydrochloride (10 mg) slow release tablet] is more effective than placebo and ondansetron is more effective at reducing nausea than pyridoxine plus doxylamine. Diclectin before symptoms of NVP begin for women at high risk of severe NVP recurrence reduces risk of moderate/severe NVP compared with taking Diclectin once symptoms begin. Promethazine is as, and ondansetron is more, effective than metoclopramide for severe NVP/HG. I.v. fluids help correct dehydration and improve symptoms. Dextrose saline may be more effective at reducing nausea than normal saline. Transdermal clonidine patches may be effective for severe HG. Enteral feeding is effective but extreme method treatment for very severe symptoms. Day case management for moderate/severe symptoms is feasible, acceptable and as effective as inpatient care. For all other interventions and comparisons, evidence is unclear. The economic analysis was limited by lack of effectiveness data, but comparison of costs between treatments highlights the implications of different choices. Limitations: The main limitations were the quantity and quality of the data available. Conclusion: There was evidence of some improvement in symptoms for some treatments, but these data may not be transferable across disease severities. Methodologically sound and larger trials of the main therapies considered within the UK NHS are needed. Study registration: This study is registered as PROSPERO CRD42013006642. Funding: The National Institute for Health Research Health Technology Assessment programme

Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy

Importance Nausea and vomiting affects approximately 85% of pregnant women. The most severe form, hyperemesis gravidarum, affects up to 3% of women and can have significant adverse physical and psychological sequelae.Objective To summarize current evidence on effective treatments for nausea and vomiting in pregnancy and hyperemesis gravidarum.Evidence Review Databases were searched to June 8, 2016. Relevant websites and bibliographies were also searched. Titles and abstracts were assessed independently by 2 reviewers. Results were narratively synthesized; planned meta-analysis was not possible because of heterogeneity and incomplete reporting of findings.Findings Seventy-eight studies (n  = 8930 participants) were included: 67 randomized clinical trials (RCTs) and 11 nonrandomized studies. Evidence from 35 RCTs at low risk of bias indicated that ginger, vitamin B6, antihistamines, metoclopramide (for mild symptoms), pyridoxine-doxylamine, and ondansetron (for moderate symptoms) were associated with improved symptoms compared with placebo. One RCT (n = 86) reported greater improvements in moderate symptoms following psychotherapy (change in Rhodes score [range, 0 {no symptoms} to 40 {worst possible symptoms}], 18.76 [SD, 5.48] to 7.06 [SD, 5.79] for intervention vs 19.18 [SD, 5.63] to 12.81 [SD, 6.88] for comparator [P < .001]). For moderate-severe symptoms, 1 RCT (n = 60) suggested that pyridoxine-doxylamine combination taken preemptively reduced risk of recurrence of moderate-severe symptoms compared with treatment once symptoms begin (15.4% vs 39.1% [P < .04]). One RCT (n = 83) found that ondansetron was associated with lower nausea scores on day 4 than metoclopramide (mean visual analog scale [VAS] score, 4.1 [SD, 2.9] for ondansetron vs 5.7 [SD, 2.3] for metoclopramide [P = .023]) but not episodes of emesis (5.0 [SD, 3.1] vs 3.3 [SD, 3], respectively [P = .013]). Although there was no difference in trend in nausea scores over the 14-day study period, trend in vomiting scores was better in the ondansetron group (P = .042). One RCT (n = 159) found no difference between metoclopramide and promethazine after 24 hours (episodes of vomiting, 1 [IQR, 0-5] for metoclopramide vs 2 [IQR, 0-3] for promethazine [P = .81], VAS [0-10 scale] for nausea, 2 [IQR, 1-5] vs 2 [IQR, 1-4], respectively [P = .99]). Three RCTs compared corticosteroids with placebo or promethazine or metoclopramide in women with severe symptoms. Improvements were seen in all corticosteroid groups, but only a significant difference between corticosteroids vs metoclopramide was reported (emesis reduction, 40.9% vs 16.5% at day 2; 71.6% vs 51.2% at day 3; 95.8% vs 76.6% at day 7 [n = 40, P < .001]). For other interventions, evidence was limited.Conclusions and Relevance For mild symptoms of nausea and emesis of pregnancy, ginger, pyridoxine, antihistamines, and metoclopramide were associated with greater benefit than placebo. For moderate symptoms, pyridoxine-doxylamine, promethazine, and metoclopramide were associated with greater benefit than placebo. Ondansetron was associated with improvement for a range of symptom severity. Corticosteroids may be associated with benefit in severe cases. Overall the quality of evidence was low

Air quality and mental health: evidence, challenges and future directions

Background: Poor air quality is associated with poor health. Little attention is given to the complex array of environmental exposures and air pollutants that affect mental health during the life course. // Aims: We gather interdisciplinary expertise and knowledge across the air pollution and mental health fields. We seek to propose future research priorities and how to address them. // Method: Through a rapid narrative review, we summarise the key scientific findings, knowledge gaps and methodological challenges. // Results: There is emerging evidence of associations between poor air quality, both indoors and outdoors, and poor mental health more generally, as well as specific mental disorders. Furthermore, pre-existing long-term conditions appear to deteriorate, requiring more healthcare. Evidence of critical periods for exposure among children and adolescents highlights the need for more longitudinal data as the basis of early preventive actions and policies. Particulate matter, including bioaerosols, are implicated, but form part of a complex exposome influenced by geography, deprivation, socioeconomic conditions and biological and individual vulnerabilities. Critical knowledge gaps need to be addressed to design interventions for mitigation and prevention, reflecting ever-changing sources of air pollution. The evidence base can inform and motivate multi-sector and interdisciplinary efforts of researchers, practitioners, policy makers, industry, community groups and campaigners to take informed action. // Conclusions: There are knowledge gaps and a need for more research, for example, around bioaerosols exposure, indoor and outdoor pollution, urban design and impact on mental health over the life course

Air quality and mental health: evidence, challenges and future directions

Background: Poor air quality is associated with poor health. Little attention is given to the complex array of environmental exposures and air pollutants that affect mental health during the life course. Aims: We gather interdisciplinary expertise and knowledge across the air pollution and mental health fields. We seek to propose future research priorities and how to address them. Method: Through a rapid narrative review, we summarise the key scientific findings, knowledge gaps and methodological challenges. Results: There is emerging evidence of associations between poor air quality, both indoors and outdoors, and poor mental health more generally, as well as specific mental disorders. Furthermore, pre-existing long-term conditions appear to deteriorate, requiring more healthcare. Evidence of critical periods for exposure among children and adolescents highlights the need for more longitudinal data as the basis of early preventive actions and policies. Particulate matter, including bioaerosols, are implicated, but form part of a complex exposome influenced by geography, deprivation, socioeconomic conditions and biological and individual vulnerabilities. Critical knowledge gaps need to be addressed to design interventions for mitigation and prevention, reflecting ever-changing sources of air pollution. The evidence base can inform and motivate multi-sector and interdisciplinary efforts of researchers, practitioners, policy makers, industry, community groups and campaigners to take informed action. Conclusions: There are knowledge gaps and a need for more research, for example, around bioaerosols exposure, indoor and outdoor pollution, urban design and impact on mental health over the life course.Natural Environment Research Council (NERC): NE/V002171/1; Engineering and Physical Sciences Research Council (EPSRC): EP/V052462/1; EP/W001411/1; EP/T003189/

A Pro-Cathepsin L Mutant Is a Luminal Substrate for Endoplasmic-Reticulum-Associated Degradation in C. elegans

Endoplasmic-reticulum associated degradation (ERAD) is a major cellular misfolded protein disposal pathway that is well conserved from yeast to mammals. In yeast, a mutant of carboxypeptidase Y (CPY*) was found to be a luminal ER substrate and has served as a useful marker to help identify modifiers of the ERAD pathway. Due to its ease of genetic manipulation and the ability to conduct a genome wide screen for modifiers of molecular pathways, C. elegans has become one of the preferred metazoans for studying cell biological processes, such as ERAD. However, a marker of ERAD activity comparable to CPY* has not been developed for this model system. We describe a mutant of pro-cathepsin L fused to YFP that no longer targets to the lysosome, but is efficiently eliminated by the ERAD pathway. Using this mutant pro-cathepsin L, we found that components of the mammalian ERAD system that participate in the degradation of ER luminal substrates were conserved in C. elegans. This transgenic line will facilitate high-throughput genetic or pharmacological screens for ERAD modifiers using widefield epifluorescence microscopy