Inhibition of the HERG potassium channel by the tricyclic antidepressant doxepin.

HERG (human ether-à-go-go-related gene) encodes channels responsible for the cardiac rapid delayed rectifier potassium current, I(Kr). This study investigated the effects on HERG channels of doxepin, a tricyclic antidepressant linked to QT interval prolongation and cardiac arrhythmia. Whole-cell patch-clamp recordings were made at 37 degrees C of recombinant HERG channel current (I(HERG)), and of native I(Kr) 'tails' from rabbit ventricular myocytes. Doxepin inhibited I(HERG) with an IC(50) value of 6.5+/-1.4 microM and native I(Kr) with an IC(50) of 4.4+/-0.6 microM. The inhibitory effect on I(HERG) developed rapidly upon membrane depolarization, but with no significant dependence on voltage and with little alteration to the voltage-dependent kinetics of I(HERG). Neither the S631A nor N588K inactivation-attenuating mutations (of residues located in the channel pore and external S5-Pore linker, respectively) significantly reduced the potency of inhibition. The S6 point mutation Y652A increased the IC(50) for I(HERG) blockade by approximately 4.2-fold; the F656A mutant also attenuated doxepin's action at some concentrations. HERG channel blockade is likely to underpin reported cases of QT interval prolongation with doxepin. Notably, this study also establishes doxepin as an effective inhibitor of mutant (N588K) HERG channels responsible for variant 1 of the short QT syndrome.

Internal Medicine Residents' Beliefs, Attitudes, and Experiences Relating to Palliative Care: A Qualitative Study.

BACKGROUND: Internal medicine residents are frequently called upon to provide palliative care to hospitalized patients, but report feeling unprepared to do so effectively. Curricular development to enhance residents' palliative care skills and competencies requires an understanding of current beliefs, attitudes and learning priorities. METHODS: We conducted a qualitative study consisting of semi-structured interviews with ten internal medicine residents to explore their understanding of and experiences with palliative care. RESULTS: All of the residents interviewed had a sound theoretical understanding of palliative care, but faced many challenges in being able to provide care in practice. The challenges described by residents were system-related, patient-related and provider-related. They identified several priority areas for further learning, and discussed ways in which their current education in palliative care could be enhanced. CONCLUSIONS: Our findings provide important insights to guide curricular development for internal medicine trainees. The top five learning priorities in palliative care that residents identified in our study were: 1) knowing how and when to initiate a palliative approach, 2) improving communication skills, 3) improving symptom management skills, 4) identifying available resources, and 5) understanding the importance of palliative care. Residents felt that their education in palliative care could be improved by having a mandatory rotation in palliative care, more frequent didactic teaching sessions, more case-based teaching from palliative care providers, opportunities to be directly observed, and increased support from palliative care providers after-hours.

Kin competition within groups: the offspring depreciation hypothesis.

Where relatives compete for the same resources (kin competition) and each obtains an equal share, this can favour the evolution of elevated dispersal rates, such that most resource competition is among non-relatives. We show that this effect evaporates as among-sibling dominance increases to the point where the allocation of resources is maximally unequal. We restore a kin-competition effect on emigration rates from dominance-ranked family groups by showing that where siblings form queues to inherit the breeding positions, the length of the queue affects the fitness of all individuals by depreciating the rank of subsequent offspring. Incorporating this 'offspring depreciation' effect decreases optimal queue lengths, increases dispersal rates and explains the otherwise paradoxical use of sinks by cooperatively breeding birds in stable environments. The offspring depreciation effect also favours the evolution of small, but consistent, clutch sizes and high reproductive skew, but constrains the evolution of alloparenting.

Mucopolysaccharide in the blood of a patient with neuroblastoma.

In a case of neuroblastoma the presence of an abnormal blood constituent was suspected from the raised erythrocyte sedimentation rate, sludging of the red cells, marked rouleaux formation, an atypical Leishman stain, increased plasma viscosity, and a distorted protein electrophoresis pattern. The abnormal constituent was shown to be a mucopolysaccharide which was either hyaluronic acid or chondroitin sulphate.

Anxiety sensitivity and response to hyperventilation challenge: physiologic arousal, interoceptive acuity, and subjective distress.

Twenty-four female undergraduates, 12 high on anxiety sensitivity and 12 low on anxiety sensitivity, were subjected to a hyperventilation challenge task. Physiologic and subjective measures of arousal and distress were obtained before, during, and after the hyperventilation challenge. Alternating between the eight 15-second intervals of hyperventilation, participants engaged in a heartbeat-tracking task for eight 10-second intervals to assess interoceptive acuity. Although the hyperventilation challenge produced phase main effects for physiologic arousal, and group and time main effects for subjective distress, there were no significant interaction effects. Results revealed no significant interoceptive acuity differences across the low and high anxiety sensitivity groups. However, subjective ratings of physiological sensations during hyperventilation were significantly greater for the high anxiety sensitivity group. Hierarchical multiple regression analyses revealed that anxiety sensitivity accounted for additional variance beyond trait anxiety in explaining subjective ratings of arousal and distress in this nonclinical sample in response to a hyperventilation challenge.

Case control study of risk factors for toxic mastitis in 26 dairy herds.

A retrospective case control study of farm level risk factors for toxic mastitis was carried out in November and December 1996. Twenty-six farms from mid-Somerset were visited: 13 case farms (had had a cow with toxic mastitis in the previous year) and 13 geographically matched controls (no case of toxic mastitis). The farmers were interviewed and the buildings were examined. Information was collected on the type and quality of housing, usual milking routines, milk quality and mastitis prevalence in the previous year. All the data were collected on to pretested recording sheets and loaded into a database. Simple and complex analysis was done. The following variable were significantly (P < 0.05) associated with an increased risk of toxic mastitis in the simple analysis: housing cows in October rather than November; a low number of calving boxes per cow; a high proportion of cows with intermediate body condition and low herd bulk milk somatic cell counts (HBMSCC). In the final model low HBMSCC and a high proportion of cows with intermediate body condition remained significant. The authors conclude that, despite the small size sample, the results of this study are consistent, plausible and support the information from previous experimental and observational studies about the role of somatic cell counts in toxic mastitis.

A consecutive series of adults with brain injury treated with a washing and dressing retraining program.

OBJECTIVES: Single-case reports indicate that behavioral methods can assist persons with brain injury to redevelop self-care skills. However, the proportion of patients who could benefit from these interventions is unknown. The present study used a specific retraining protocol to treat all patients admitted to a single facility over a 3-year period who were unable to wash and dress independently. METHOD: Four patients out of 48 met the study criteria and were treated with the washing and dressing protocol. Three had traumatic brain injury, and one had brain injury after cerebral bleed. The training program involved behavioral observation, task analysis, consistent practice, and cue fading. The Adaptive Behavior Scale was used to measure behavior change. RESULTS: Three subjects achieved rapid independence in washing and dressing (20 days, 37 days, and 11 days of treatment), and one did not show significant clinical improvement. CONCLUSION: All patients admitted to the facility during a 3-year period who required washing and dressing retraining were treated with the same protocol. The consecutive series design prevented researchers from selecting patients who they believed were good treatment candidates; therefore, the findings support the general applicability of the training program.

The exercise-during-hemodialysis program: report on a pilot study.

Dialysis saves lives. However, dialysis alone cannot make those lives active and meaningful. Exercise, in particular, is critical in the rehabilitation of many individuals with chronic renal insufficiency The purpose of this pilot study was to: 1) examine changes in participants' physical capacity and quality of life with the intervention of a 12-week exercise program; 2) investigate whether erythropoietin (EPO) and antihypertensive medication dosages were reduced in the participants; 3) examine the feasibility of incorporating exercise into the London Health Sciences Centre (LHSC) hemodialysis program. A quasi-experimental one-group pre- and post-test design was utilized. Eight subjects completed the 12-week study. The exercise program involved a warm-up, stretching, strengthening, and cardiovascular training. The results demonstrated improvements in the participants'physical capacity, quality of life, and ability to perform activities of daily living (ADLs). There were no discernable trends in the participants' hemoglobin levels or EPO dosages. Although there were no statistically significant changes in participants' blood pressures, five out of the six participants who began the program on antihypertensive medications either had the dosages decreased or the drug(s) discontinued. Data from this small prospective study supports previous research that an exercise during dialysis program is safe and has the potential to result in positive patient outcomes.

Framing the work: development of a renal nursing professional practice model.

In 1997, a nursing care model task group was formed to develop a framework to guide the development of the nursing care delivery system in a newly merged hospital corporation. A collective group of experienced and motivated nurses in the renal program met to develop an integrated renal nursing professional practice model. In addition it was recognized that a city-wide model involving the two acute care renal centres would be advantageous. The challenge was to clearly articulate the professional roles and relationships of nurses and nurse practitioner/clinical nurse specialists in a constantly changing environment. This process provided the opportunity to identify key trends influencing renal care and possibilities for changing practice. Networking across the corporations was enhanced, partnerships were formed, and a sense of value for the work that was being undertaken developed. The group's endeavours resulted in an integrated nursing professional practice model that emphasizes accountability and continuity and places value on therapeutic relationships. Another strength of the model is the acknowledgement of the collaborative nature of the multidisciplinary team. After two years of development, the model was implemented. A city-wide Renal Nursing Professional Practice Council has been established in order to provide leadership in evaluating the model. This will include assessing the success of implementation, impact on patient/family care, and collaborative rewards experienced by staff. Future planning will address the potential need for a multidisciplinary focus within the practice council.

How five advanced practice nurses in nephrology spend their time.

The purpose of this paper is to report the results of a descriptive study undertaken to examine the scope of practice of five Masters-prepared nephrology nurse practitioner/clinical nurse specialists (NP/CNS) in a mid-size university teaching hospital program. Four of the NP/CNSs practised in three acute care sites, and one in the regional dialysis program. Impetus for the study came from two sources. First, a sixth person practising in the role was retiring and was not to be replaced. Second, the current three-site model for acute care was being transformed into a two-site model, thus creating opportunities to reduce variability in practice among the NP/CNSs. The study examined the activities of the NP/CNS role through the completion of a time documentation tool (TDT) by five nurse practitioners on each of 10 consecutive days of practice. The TDT was adapted from Ackerman's Model of Advanced Practice (1996). The model outlines five domains of practice for advanced practice nurses (APN): direct comprehensive care, support of systems, research, education, and publication and professional leadership. The NP/CNSs spent an average of 9.21 hours at work daily with a range of 8.6 to 10.3 hours. The TDT captured an average of 8.6 hours of working time with a range of 7.3 to 9.9 hours. An average of 72% of time was spent in clinical practice (range 64-83%). An average of 16% (range 11-20%) of time was spent in support of systems. Research (average 4%, range 3-7%), education (average 6%, range 3-16%), and publication and professional leadership (average 2%, range 0-6%) figured less prominently. The major activities performed within the clinical practice domain and the support of systems domain showed less variability across sites than was anticipated. The results of the study have helped the NP/CNSs and their management colleagues analyze and adapt the role to changing clinical requirements and economic realities.

Application of regional climate models to the Indian winter monsoon over the western Himalayas.

The Himalayan region is characterized by pronounced topographic heterogeneity and land use variability from west to east, with a large variation in regional climate patterns. Over the western part of the region, almost one-third of the annual precipitation is received in winter during cyclonic storms embedded in westerlies, known locally as the western disturbance. In the present paper, the regional winter climate over the western Himalayas is analyzed from simulations produced by two regional climate models (RCMs) forced with large-scale fields from ERA-Interim. The analysis was conducted by the composition of contrasting (wet and dry) winter precipitation years. The findings showed that RCMs could simulate the regional climate of the western Himalayas and represent the atmospheric circulation during extreme precipitation years in accordance with observations. The results suggest the important role of topography in moisture fluxes, transport and vertical flows. Dynamical downscaling with RCMs represented regional climates at the mountain or even event scale. However, uncertainties of precipitation scale and liquid-solid precipitation ratios within RCMs are still large for the purposes of hydrological and glaciological studies.

Modulation by testosterone of an endogenous hERG potassium channel current.

hERG (human ether-a-go-go-related gene) potassium (K+) channels are expressed in a range of tissue types including neuroblastoma cells and the heart, in which hERG K+ current is important for action potential repolarization. Whilst gender differences in cardiac repolarization and the QT interval of the cardiac electrocardiogram are well-established, comparatively little is known about regulation of hERG channels by sex hormones. In this study, whole-cell patch-clamp recordings were made at 37 degrees C from SH-SY5Y human neuroblastoma cells to investigate modulation of endogenous hERG K+ channel current (I(hERG)) by testosterone. Acutely applied testosterone at a physiologically relevant concentration (10 nM) produced a modest (approximately 13-15 %) increase in I(hERG) amplitude, whilst a high concentration (1 microM) slightly decreased I(hERG). The stimulatory effect of testosterone was inhibited by the androgen receptor antagonist flutamide (10 microM) and the PI-3 kinase inhibitor wortmannin (1 microM). Chronic (24 h) application of testosterone also augmented IhERG via flutamide-sensitive receptor activation, without modulation of the current's voltage-dependence. These results demonstrate for the first time that testosterone can stimulate (hERG) K+ channels via activation of classical androgen receptors and implicate PI-3 kinase in the acute response.