Studies of the Depolarization-Induced Release of Beta Adrenergic Receptor Blocking Drugs from in vitro Neural Preparations

The objective of this study was to evaluate the hypothesis that nerve terminals may serve as a site for storage and release of beta adrenergic receptor blocking drugs. Experiments were conducted with two different in vitro neural preparations, cultured superior cervical ganglia from adult rats and synaptosomes prepared from rat cerebral cortex. The release of propranolol by depolarizing stimuli was examined and compared with the release of the more hydrophilic, cardioselective beta receptor antagonist atenolol. In both neuronal models, norepinephrine release was monitored as an index of exocytosis. Cultured superior cervical ganglia of the rat represent an in vitro model for adrenergic neurons which contains no post junctional effector tissue. Ganglia excised from adult rats and maintained in a chemically defined media for 48 hours develop axonal sprouts that have uptake, storage and release mechanisms characteristic of sympathetic nerve endings. Electrical field stimulation of 48-hour cultured ganglia preloaded with either 3H-propranolol or 3H-norepinephrine was found to promote the release of each molecule in a frequency-dependent manner. Stimulation for 30 seconds at a frequency of 15 Hz released 3.00% of the norepinephrine and 0.15% of the propranolol accumulated by the ganglia. Removal of extracellular calcium and elevation of magnesium reduced the stimulation-induced release of norepinephrine (control = 161 ± 31 fmol/30 sec/ganglion) by 60% but did not affect the stimulation-induced release of propranolol (control = 17 ± 5 fmol/30 sec/ ganglion). Norepinephrine release was also inhibited by bretylium and enhanced by phenoxybenzamine, whereas neither agent altered the stimulation-induced release of propranolol. Moreover, reserpine pretreatment almost abolished norepinephrine accumulation and release without affecting the accumulation or release of propranolol. These results demonstrate that propranolol is released from neural tissue in response to electrical stimulation. In addition, the data indicate that propranolol release from cultured ganglia occurs by a different mechanism than that observed for norepinephrine and appears to result from a calcium-independent, presumably nonexocytotic, process. Synaptosomes were prepared by discontinuous sucrose density gradient centrifugation and used as a model of isolated nerve terminals. When incubated at 30°C with radiolabelled drugs (0.1 µM), synaptosomes accumulated 20 pmoles propranolol and 0.6 pmoles atenolol/mg protein. Exposure of 3H-propranolol-loaded synaptosomes to elevated potassium, rubidium or cesium was found to evoke a concentration-dependent increase in drug efflux. The action of these ions to release propranolol was highly correlated with their ability to produce synaptosomal membrane depolarization as estimated with the voltage-sensitive dye diS-C3-(5). When external potassium was increased to 75 mM, 25% of the propranolol accumulated by the synaptosomes was released within 15 seconds. Elevated external potassium also promoted the efflux of 3H-atenolol from preloaded synaptosomes, with 75 mM potassium releasing in three minutes 25% of the atenolol taken up. 3H-Norepinephrine was released by potassium with a time course similar to that found for atenolol. Depolarization of synaptosomes with veratridine was also observed to stimulate the release of both propranolol and atenolol and these effects were antagonized by tetrodotoxin. Under calcium-free conditions, potassium-induced release of propranolol was reduced 37% while atenolol release was decreased 68% and norepinephrine release 82%. Pretreatment of rats with 6-hydroxydopamine to destroy adrenergic nerve terminals failed to alter the steady state accumulation or the potassium-induced release of either propranolol or atenolol from synaptosomes. The results from these studies demonstrate that both polar and nonpolar beta receptor antagonists are accumulated by nerve endings and released in response to membrane depolarization. The data also raise the possibility that these drugs may be released from nonadrenergic as well as adrenergic neurons. The depolarization-induced release of propranolol from cultured sympathetic ganglia and synaptosomes is consistent with previous findings of propranolol release in association with sympathetic nerve stimulation in situ. The release of atenolol extends these observations to include polar beta receptor antagonists as well as the lipophilic propranolol molecule and suggests that this phenomenon may apply to the entire class of these drugs. While atenolol release has the characteristics of an exocytotic event, propranolol release from these preparations appears to be complex and may involve a combination of exocytotic and nonexocytotic mechanisms. The results of the present study support the concept that neural storage and release of beta adrenergic receptor blocking drugs may contribute to their pharmacological actions by modulating drug concentration at localized sites of action

Inspections: Software development process for building defect free software applied in a small-scale software development environment

Inspections is a software management technique designed to produce higher quality software and improve programmer productivity. These improvements are achieved through rigorous examination of the products in each phase of the software development life-cycle. While the process has generally been applied to large-scale mainframe projects, this research demonstrates successful implementation of inspections in a small-scale, micro-processor based software development project

Patients’ Experience of the External Therapeutic Application of Ginger by Anthroposophically Trained Nurses

There has been considerable public debate on a range of complementary health practices throughout the western world, perhaps especially in Australia, United States and Europe. Most often, the research critique of these practices is restricted to quantitative or non-user qualitative research methodologies. Consequently, there is a significant gap in the research profile of complementary health services that needs to be addressed particularly in view of the rapid and ongoing increase in the use of complementary services, even in the face of sometimes adverse media publicity. This paper demonstrates the contribution that phenomenologically based research can make to fill this lacuna by explicating, in detail, the client experience of a complementary health practice. The paper explores patient experience of a ginger compress, as applied by anthroposophically trained nurses, to demonstrate various therapeutic effects. Four key themes emerged including an increase in warmth and internal activity in the major organs of the body, changes in thought-life and sensory perception along with a greater sense of well-being and self-focus with the perception of clearer personal boundaries. These themes, emerging from a patient sample in New Zealand, compared favourably to the Filderklinik Study completed in 1992 in a large German state hospital. Indo-Pacific Journal of Phenomenology, Volume 4, Edition 1 July 200

What First-Year Teachers Really Want From Principals During Their Induction Year: A Beginning Teacher Study Group\u27s Shared Inquiry

University teacher educators have a role to play in helping their graduates manage the transition from formal teacher preparation to independent teaching. This study focuses on a shared inquiry that five first-year elementary teachers conducted while participating in a monthly study group facilitated by two teacher educators from their teaching preparation program. The novices regularly perceived a lack of support from their campus administrator, including failing to give the beginning teachers permission to carry out teacher research projects they had designed. After analyzing the degree and kinds of support that they did or did not receive from their principals, the beginning teachers developed four recommendations for principals to help novices feel well-supported during their initial year of teaching, including (1) developing productive relationships with novices, (2) helping novices becoming insiders to the campus, (3) being a visible presence in beginning teachers’ classrooms, and (4) establishing and/or sustaining a professional learning community on the campus

Acts of Commission: Lessons from an Informal Study - Discussion Guide

This discussion guide is designed to help you think through the concepts presented in Janice Nittoli's paper, Acts of Commission: Lessons from an Informal Study, and consider how you might apply them in the everyday practice of philanthropy.The guide contains four exercises:The first exercise provides a role-play to explore the match between a commission strategy and foundation goals and mission.The second exercise presents a template to plan a commission's membership, and assure that it contains a balanced and diverse group of decisionmakers.The third exercise involves creating a "History of the Future" to identify the combination of elements that lead to a successful commission.The fourth exercise offers a series of questions to help a foundation staff person prepare to work with a media consultant to promote a commission's work.Following the exercises, a resource page contains Nittoli's checklist to help funders assess their readiness to launch a policy commission

Taking the Mentoring of New Teacher Educators Seriously: Lessons From a Clinically-Intensive Teacher Preparation Program

The challenges facing teacher educators entering their first faculty position in a clinically intensive teacher preparation program reflect similar difficulties that novice teachers encounter upon entry to their own classroom. Just as new teachers must learn the ropes while performing the work of teaching (Feiman-Nemser, 2001; Wildman, Niles, Magliaro, & McLaughlin, 1989), so, too, must novice teacher educators learn to create clinically based learning opportunities for teacher candidates (American Association of Colleges for Teacher Education, 2018; Grossman, Hammerness & McDonald, 2009) while learning to navigate the university system, establish their practice as field-based practitioners, earn strong student/course evaluations (Ramsden, 2003) and address the realities of publish or perish (Russell & Korthagen, 1995)

Reactive hyperemia is associated with adverse clinical outcomes in heart failure

© 2016 Elsevier Inc. All rights reserved. Introduction Impaired endothelial function, as assessed by brachial artery flow-mediated dilation (FMD), is an established risk factor for cardiovascular events. FMD is impaired in heart failure (HF) patients, but less is known about hyperemic brachial artery flow. We investigated the relationship between FMD and hyperemic flow with adverse clinical outcomes in HF patients. Methods Brachial artery FMD and hyperemic flow were assessed in 156 patients (70.5 % Male; 45.5% Caucasian; mean age (± SD) = 56.2 (±12.4) years) with HF and reduced left ventricular ejection fraction (LVEF). Cox proportional hazard models were used to assess the potential explanatory association of FMD and hyperemic flow with the composite outcome of death or cardiovascular hospitalization over a median 5-year follow-up period. Results Both FMD and hyperemic flow were negatively correlated with age, but unrelated to sex, race, body mass index, LVEF or N-terminal pro-B-Type natriuretic peptide (NT-ProBNP). Reduced hyperemic flow, but not FMD, was associated with an increased risk of death or cardiac hospitalization after controlling for traditional risk factors. Conclusion The association of reduced hyperemic flow with increased risk of adverse clinical outcomes suggests that micro-vascular function may be an important prognostic marker in patients with HF

Between Metropole and Province: circulating botany in British museums, 1870–1940

Exchange of duplicate specimens was an important element of the relationship between metropolitan and regional museums in the period 1870–1940. Evidence of transfers of botanical museum objects such as economic botany specimens is explored for the Royal Botanic Gardens, Kew, and six museums outside the capital: Cambridge University Botanical Museum, National Museum Wales, Glasgow Museums, Liverpool World Museum, Manchester Museum and Warrington Museum. Botany became an important element in these museums soon after their foundation, sometimes relying heavily on Kew material as in the case of Glasgow and Warrington, and usually with a strong element of economic botany (except in the case of Cambridge). Patterns of exchange depended on personal connections and rarely took the form of symmetrical relationships. Botanical displays declined in importance at various points between the 1920s and 1960s, and today only Warrington Museum has a botanical gallery open to the public. However, botanical objects are finding new roles in displays on subjects such as local history, history of collections, natural history and migration

Effects of Coping Skills Training on Quality of Life, Disease Biomarkers and Clinical Outcomes in Patients with Heart Failure: A Randomized Clinical Trial

Heart failure (HF) is a chronic disease that compromises patients’ quality of life (QoL). Interventions designed to reduce distress and improve disease self-management are needed. We evaluated the efficacy of a telephone-based coping skills training (CST) intervention