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Background and Objective: The subgluteal approach is common for sciatic nerve block. Although the surface landmarks are clear, the depth of this nerve at this level is difficult to judge. The purpose of this study is to establish a method of estimating the sciatic nerve depth using the anteroposterior (AP) diameter of the thigh as a marker.Methods: The study was undertaken in 2 phases. Phase 1 entailed review of 100 magnetic resonance images (MRIs) of the pelvis and proximal lower extremity of patients. Measurements were taken of the AP diameter of the thigh at the midpoint of the lesser trochanter and then compared with distances of the sciatic nerves from the skin of the posterior aspect of the thigh at the same level. Phase 2 involved enrolling 40 patients undergoing lower-extremity surgery for whom subgluteal sciatic nerve blocks were indicated. The AP diameters of the thighs were measured from the subgluteal groove to the inguinal groove with the patient in the supine position. Placing the patient in the lateral position, the subgluteal sciatic block was then performed by using a stimulating needle. The distances from the skin at which the sciatic nerves were actually found, as estimated by maximum motor response to stimulus, were noted.Results: Phase 1 showed a mean AP diameter of 18.94 cm +/- 2.61 cm (mean +/- standard deviation [SD]), mean nerve depth of 6.51 cm +/- 1.46 cm (mean +/- SD), and a linear regression slope of 0.48. Phase 2 showed a mean AP diameter of 16.28 cm +/- 2.73 cm (mean +/- SD), a mean nerve depth of 6.99 cm +/- 1.39 cm (mean +/- SD), and a linear regression slope of 0.43. The thigh diameters differed (P < .001) between the groups, but there was no difference in the depth to the sciatic nerve between the 2 groups (P = .07).Conclusions: Comparing phase 1 and phase 2 datasets shows the slopes of linear regression lines are nearly parallel. The clinical data from phase 2 verify the anatomical data collected in phase 1 and show that the sciatic nerve depth to AP diameter ratio is 0.43 or the depth of the sciatic nerve is approximately 43% of thigh diameter if the patient is positioned in the lateral decubitus position. [ABSTRACT FROM AUTHOR]

Drawing on three theoretical perspectives (feminist, conflict, and social learning), an integrated analytical model of adolescence sibling violence and abuse is proposed. The model suggests that certain characteristics of the parents' relationship, various aspects of parent-child relations, and characteristics of the sibling relationship are major components in explaining sibling violence and abuse. These are mediated by individual sibling characteristics and sibling verbal conflict. The model should enable researchers to systematically examine, in a more holistic way, the factors related to violence and abuse, and to assess their relative importance in accounting for these phenomena. [ABSTRACT FROM AUTHOR]

Background: Isoxazolines are rarely reported to be associated with neurological adverse events in cats and dogs, but information about the onset and duration of neurological signs is lacking in the summary of product characteristics of these medicines., Methods: The Veterinary Poisons Information Service and the Dutch Poisons Information Center databases were searched using the Veterinary Dictionary for Drug-Related Affairs terms for ataxia, muscle tremor, convulsions or hyperesthesia in cats and dogs exposed to isoxazolines., Results: There were 22 cases with and 57 cases without outcome information, mostly involving fluralaner or sarolaner. In both groups, muscle tremors and convulsions were the most common signs. In dogs, neurological signs occurred with oral therapeutic dose and overdosage. In cats, most fluralaner cases involved therapeutic topical exposure, and all sarolaner cases involved oral exposure. In all cases with outcome information, the animals recovered., Limitations: Cases discussed with poison centres tend to involve more severe signs., Conclusion: The true incidence of neurological adverse effects from isoxazolines remains unclear. The delay between the administration and onset of signs can be long, and the association may be missed. A lack of timing information in the summary of product characteristics could also contribute to missed attribution of adverse effects., (© 2024 British Veterinary Association.)

Background: This retrospective study evaluated the efficacy and safety of intraoperative methadone compared with short-acting opioids., Methods: Patients undergoing cardiac surgery with cardiopulmonary bypass ( n =11 967) from 2018 to 2023 from a single health system were categorised into groups based on intraoperative opioid administration: no methadone (Group O), methadone plus other opioids (Group M+O), and methadone only (Group M)., Results: Patients in Groups M and M+O had lower mean pain scores until postoperative day (POD) 7 compared with Group O after adjusting for covariates ( P <0.01). Both Groups M and M+O had lower total opioid administered compared with Group O for all days POD0-POD6 (all P <0.001). The median number of hours until initial postoperative opioid after surgery was 2.55 (inter-quartile range [IQR]=1.07-5.12), 6.82 (IQR=3.52-12.98), and 7.0 (IQR=3.82-12.95) for Group O, Group M+O, and Group M, respectively. The incidence of postoperative complications did not differ between groups., Conclusions: Intraoperative administration of methadone was associated with better pain control without significant side-effects after cardiac surgery., (© 2024 The Authors.)

To accelerate the discovery of novel drug candidates for Coronavirus Disease 2019 (COVID-19) therapeutics, we reported a series of machine learning (ML)-based models to accurately predict the anti-SARS-CoV-2 activities of screening compounds. We explored 6 popular ML algorithms in combination with 15 molecular descriptors for molecular structures from 9 screening assays in the COVID-19 OpenData Portal hosted by NCATS. As a result, the models constructed by k-nearest neighbors (KNN) using the molecular descriptor GAFF+RDKit achieved the best overall performance with the highest average accuracy of 0.68 and relatively high average area under the receiver operating characteristic curve of 0.74, better than other ML algorithms. Meanwhile, The KNN model for all assays using GAFF+RDKit descriptor outperformed using other descriptors. The overall performance of our developed models was better than REDIAL-2020 ( R ). A web server (https://clickff.org/amberweb/covid-19-cp) was developed to enable users to predict anti-SARS-CoV-2 activities of arbitrary compounds using the COVID-19-CP ( P ) models. Besides the descriptor-based machine learning models, we also developed graph-based Attentive FP ( A ) models for the 9 assays. We found that the Attentive FP models achieved a comparable performance to that of COVID-19-CP and outperformed the REDIAL-2020 models. The consensus prediction utilizing both COVID-19-CP and Attentive FP can significantly boost the prediction accuracy as assessed by comparing its performance with other three individual models ( R , P , A ) utilizing the Wilcoxon signed-rank test, thus can ultimately improve the success rate of COVID-19 drug discovery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: The compressional modulus of elasticity is an important mechanical property for understanding stalk lodging, but this property is rarely available for thin-walled plant stems such as maize and sorghum because excised tissue samples from these plants are highly susceptible to buckling. The purpose of this study was to develop a testing protocol that provides accurate and reliable measurements of the compressive modulus of elasticity of the rind of pith-filled plant stems. The general approach was to relying upon standard methods and practices as much as possible, while developing new techniques as necessary., Results: Two methods were developed for measuring the compressional modulus of elasticity of pith-filled node-node specimens. Both methods had an average repeatability of ± 4%. The use of natural plant morphology and architecture was used to avoid buckling failure. Both methods relied up on spherical compression platens to accommodate inaccuracies in sample preparation. The effect of sample position within the test fixture was quantified to ensure that sample placement did not introduce systematic errors., Conclusions: Reliable measurements of the compressive modulus of elasticity of pith-filled plant stems can be performed using the testing protocols presented in this study. Recommendations for future studies were also provided.

Key Points: Current methods do not allow a quantitative description of Ca(2+) movements across the tubular (t-) system membrane without isolating the membranes from their native skeletal muscle fibre. Here we present a fluorescence-based method that allows determination of the t-system [Ca(2+) ] transients and derivation of t-system Ca(2+) fluxes in mechanically skinned skeletal muscle fibres. Differences in t-system Ca(2+) -handling properties between fast- and slow-twitch fibres from rat muscle are resolved for the first time using this new technique. The method can be used to study Ca(2+) handling of the t-system and allows direct comparisons of t-system Ca(2+) transients and Ca(2+) fluxes between groups of fibres and fibres from different strains of animals., Abstract: The tubular (t-) system of skeletal muscle is an internalization of the plasma membrane that maintains a large Ca(2+) gradient and exchanges Ca(2+) between the extracellular and intracellular environments. Little is known of the Ca(2+) -handling properties of the t-system as the small Ca(2+) fluxes conducted are difficult to resolve with conventional methods. To advance knowledge in this area we calibrated t-system-trapped rhod-5N inside skinned fibres from rat and [Ca(2+) ]t-sys , allowing confocal measurements of Ca(2+) -dependent changes in rhod-5N fluorescence during rapid changes in the intracellular ionic environment to be converted to [Ca(2+) ] transients in the t-system ([Ca(2+) ]t-sys (t)). Furthermore, t-system Ca(2+) -buffering power was determined so that t-system Ca(2+) fluxes could be derived from [Ca(2+) ]t-sys (t). With this new approach, we show that rapid depletion of sarcoplasmic reticulum (SR) Ca(2+) induced a robust store-operated Ca(2+) entry (SOCE) in fast- and slow-twitch fibres, reducing [Ca(2+) ]t-sys to < 0.1 mm. The rapid activation of SOCE upon Ca(2+) release was consistent with the presence of STIM1L in both fibre types. Abruptly introducing internal solutions with 1 mm Mg(2+) and [Ca(2+) ]cyto (28 nm-1.3 μm) to Ca(2+) -depleted fibres generated t-system Ca(2+) uptake rates dependent on [Ca(2+) ]cyto with [Ca(2+) ]t-sys reaching final plateaus in the millimolar range. For the same [Ca(2+) ]cyto , t-system Ca(2+) fluxes of fast-twitch fibres were greater than that in slow-twitch fibres. In addition, simultaneous imaging of t-system and SR Ca(2+) signals indicated that both membrane compartments accumulated Ca(2+) at similar rates and that SOCE was activated early during SR Ca(2+) depletion., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

There is a paucity of data to aid in assessing whether postmortem methadone findings in breastfed infants are clinically and/or toxicologically significant. Two cases are reported in which methadone was detected in deceased neonates whose mothers were enrolled in methadone maintenance programs and were breastfeeding. In addition to a complete autopsy and toxicological testing for alcohol, prescription medications, and drugs of abuse, pharmacogenetic analysis was performed for variants in genes related to methadone metabolism and response. In both cases, the postmortem methadone concentration measured in neonatal heart blood was higher than the maximum serum methadone concentration reported in living breastfed infants whose mothers were receiving methadone. However, additional analysis of antemortem blood indicated postmortem redistribution of methadone. Pharmacogenetic results were suggestive of a potential predisposition to methadone toxicity based on studies in adults; the significance of these findings in breastfed neonates requires further research. The medical cause of death was unascertained in both cases., (© 2015 American Academy of Forensic Sciences.)

Skeletal muscle fibres are large and highly elongated cells specialized for producing the force required for posture and movement. The process of controlling the production of force within the muscle, known as excitation-contraction coupling, requires virtually simultaneous release of large amounts of Ca(2+) from the sarcoplasmic reticulum (SR) at the level of every sarcomere within the muscle fibre. Here we imaged Ca(2+) movements within the SR, tubular (t-) system and in the cytoplasm to observe that the SR of skeletal muscle is a connected network capable of allowing diffusion of Ca(2+) within its lumen to promote the propagation of Ca(2+) release throughout the fibre under conditions where inhibition of SR ryanodine receptors (RyRs) was reduced. Reduction of cytoplasmic [Mg(2+)] ([Mg(2+)]cyto) induced a leak of Ca(2+) through RyRs, causing a reduction in SR Ca(2+) buffering power argued to be due to a breakdown of SR calsequestrin polymers, leading to a local elevation of [Ca(2+)]SR. The local rise in [Ca(2+)]SR, an intra-SR Ca(2+) transient, induced a local diffusely rising [Ca(2+)]cyto. A prolonged Ca(2+) wave lasting tens of seconds or more was generated from these events. Ca(2+) waves were dependent on the diffusion of Ca(2+) within the lumen of the SR and ended as [Ca(2+)]SR dropped to low levels to inactivate RyRs. Inactivation of RyRs allowed re-accumulation of [Ca(2+)]SR and the activation of secondary Ca(2+) waves in the persistent presence of low [Mg(2+)]cyto if the threshold [Ca(2+)]SR for RyR opening could be reached. Secondary Ca(2+) waves occurred without an abrupt reduction in SR Ca(2+) buffering power. Ca(2+) release and wave propagation occurred in the absence of Ca(2+)-induced Ca(2+) release. These observations are consistent with the activation of Ca(2+) release through RyRs of lowered cytoplasmic inhibition by [Ca(2+)]SR or store overload-induced Ca(2+) release. Restitution of SR Ca(2+) buffering power to its initially high value required imposing normal resting ionic conditions in the cytoplasm, which re-imposed the normal resting inhibition on the RyRs, allowing [Ca(2+)]SR to return to endogenous levels without activation of store overload-induced Ca(2+) release. These results are discussed in the context of how pathophysiological Ca(2+) release such as that occurring in malignant hyperthermia can be generated., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)

Urocortin 2 (Ucn2) is a cardioactive peptide exhibiting beneficial effects in normal and failing heart. In cardiomyocytes, it elicits cAMP- and Ca(2+)-dependent positive inotropic and lusitropic effects. We tested the hypothesis that, in addition, Ucn2 activates cardiac nitric oxide (NO) signaling and elucidated the underlying signaling pathways and mechanisms. In isolated rabbit ventricular myocytes, Ucn2 caused concentration- and time-dependent increases in phosphorylation of Akt (Ser473, Thr308), endothelial NO synthase (eNOS) (Ser1177), and ERK1/2 (Thr202/Tyr204). ERK1/2 phosphorylation, but not Akt and eNOS phosphorylation, was suppressed by inhibition of MEK1/2. Increased Akt phosphorylation resulted in increased Akt kinase activity and was mediated by corticotropin-releasing factor 2 (CRF2) receptors (astressin-2B sensitive). Inhibition of phosphatidylinositol 3-kinase (PI3K) diminished both Akt as well as eNOS phosphorylation mediated by Ucn2. Inhibition of protein kinase A (PKA) reduced Ucn2-induced phosphorylation of eNOS but did not affect the increase in phosphorylation of Akt. Conversely, direct receptor-independent elevation of cAMP via forskolin increased phosphorylation of eNOS but not of Akt. Ucn2 increased intracellular NO concentration ([NO]i), [cGMP], [cAMP], and cell shortening. Inhibition of eNOS suppressed the increases in [NO]i and cell shortening. When both PI3K-Akt and cAMP-PKA signaling were inhibited, the Ucn2-induced increases in [NO]i and cell shortening were attenuated. Thus, in rabbit ventricular myocytes, Ucn2 causes activation of cAMP-PKA, PI3K-Akt, and MEK1/2-ERK1/2 signaling. The MEK1/2-ERK1/2 pathway is not required for stimulation of NO signaling in these cells. The other two pathways, cAMP-PKA and PI3K-Akt, converge on eNOS phosphorylation at Ser1177 and result in pronounced and sustained cellular NO production with subsequent stimulation of cGMP signaling., (Copyright © 2014 the American Physiological Society.)

Cardiac alternans refers to a condition in which there is a periodic beat-to-beat oscillation in electrical activity and the strength of cardiac muscle contraction at a constant heart rate. Clinically, cardiac alternans occurs in settings that are typical for cardiac arrhythmias and has been causally linked to these conditions. At the cellular level, alternans is defined as beat-to-beat alternations in contraction amplitude (mechanical alternans), action potential duration (APD; electrical or APD alternans) and Ca(2+) transient amplitude (Ca(2+) alternans). The cause of alternans is multifactorial; however, alternans always originate from disturbances of the bidirectional coupling between membrane voltage (Vm ) and intracellular calcium ([Ca(2+) ]i ). Bidirectional coupling refers to the fact that, in cardiac cells, Vm depolarization and the generation of action potentials cause the elevation of [Ca(2+) ]i that is required for contraction (a process referred to as excitation-contraction coupling); conversely, changes of [Ca(2+) ]i control Vm because important membrane currents are Ca(2+) dependent. Evidence is mounting that alternans is ultimately caused by disturbances of cellular Ca(2+) signalling. Herein we review how two key factors of cardiac cellular Ca(2+) cycling, namely the release of Ca(2+) from internal stores and the capability of clearing the cytosol from Ca(2+) after each beat, determine the conditions under which alternans occurs. The contributions from key Ca(2+) -handling proteins (i.e. surface membrane channels, ion pumps and transporters and internal Ca(2+) release channels) are discussed., (© 2014 Wiley Publishing Asia Pty Ltd.)

Critical illness myopathies in patients with sepsis or sustained mechanical ventilation prolong intensive care treatment and threaten both patients and health budgets; no specific therapy is available. Underlying pathophysiological mechanisms are still patchy. We characterized IL-1α action on muscle performance in "skinned" muscle fibers using force transducers and confocal Ca(2+) fluorescence microscopy for force/Ca(2+) transients and Ca(2+) sparks. Association of IL-1α with sarcoplasmic reticulum (SR) release channel, ryanodine receptor (RyR) 1, was investigated with coimmunoprecipitation and confocal immunofluorescence colocalization. Membrane integrity was studied in single, intact fibers challenged with IL-1α. IL-1α reversibly stabilized Mg(2+) inhibition of Ca(2+) release. Low Mg(2+)-induced force and Ca(2+) transients were reversibly abolished by IL-1α. At normal Mg(2+), IL-1α reversibly increased caffeine-induced force and Ca(2+) transients. IL-1α reduced SR Ca(2+) leak via RyR1, as judged by (1) increased SR Ca(2+) retention, (2) increased IL-1α force transients being reproduced by 25 μM tetracaine, and (3) reduced Ca(2+) spark frequencies by IL-1α or tetracaine. Coimmunoprecipitation confirmed RyR1/IL-1 association. RyR1/IL-1 immunofluorescence patterns perfectly colocalized. Long-term, 8-hour IL-1α challenge of intact muscle fibers compromised membrane integrity in approximately 50% of fibers, and confirmed intracellular IL-1α deposition. IL-1α exerts a novel, specific, and reversible interaction mechanism with the skeletal muscle RyR1 macromolecular release complex without the need to act via its membrane IL-1 receptor, as IL-1R membrane expression levels were not detectable in Western blots or immunostaining of single fibers. We present a potential explanation of how the inflammatory mediator, IL-1α, may contribute to muscle weakness in critical illness.

Colorado, Minnesota, and Vermont are pioneering innovative health care pay­ment and delivery system reforms. While the states are pursuing different models, all three are working to align incentives between health care payers and providers to better coordi­nate care, enhance prevention and disease management, reduce avoidable utilization and total costs, and improve health outcomes. Colorado and Minnesota are implementing accountable care models for Medicaid beneficiaries, while Vermont is pursuing multipayer approaches and moving toward a unified health care budget. This synthesis describes the common drivers of reform across the states, lessons learned, and opportunities for federal administrators to help shape, support, and promote expansion of promising state initiatives. It also synthesizes strategies and lessons for other states considering payment and delivery reforms. The accompanying case studies describe the states' efforts in greater detail.

The majority of the skeletal muscle plasma membrane is internalized as part of the tubular (t-) system, forming a standing junction with the sarcoplasmic reticulum (SR) membrane throughout the muscle fiber. This arrangement facilitates not only a rapid and large release of Ca(2+) from the SR for contraction upon excitation of the fiber, but has also direct implications for other interdependent cellular regulators of Ca(2+). The t-system plasma membrane Ca-ATPase (PMCA) and store-operated Ca(2+) entry (SOCE) can also be activated upon release of SR Ca(2+). In muscle, the SR Ca(2+) sensor responsible for rapidly activated SOCE appears to be the stromal interacting molecule 1L (STIM1L) isoform of STIM1 protein, which directly interacts with the Orai1 Ca(2+) channel in the t-system. The common isoform of STIM1 is STIM1S, and it has been shown that STIM1 together with Orai1 in a complex with the partner protein of STIM (POST) reduces the activity of the PMCA. We have previously shown that Orai1 and STIM1 are upregulated in dystrophic mdx mouse muscle, and here we show that STIM1L and PMCA are also upregulated in mdx muscle. Moreover, we show that the ratios of STIM1L to STIM1S in wild-type (WT) and mdx muscle are not different. We also show a greater store-dependent Ca(2+) influx in mdx compared with WT muscle for similar levels of SR Ca(2+) release while normal activation and deactivation properties were maintained. Interestingly, the fiber-averaged ability of WT and mdx muscle to extrude Ca(2+) via PMCA was found to be the same despite differences in PMCA densities. This suggests that there is a close relationship among PMCA, STIM1L, STIM1S, Orai1, and also POST expression in mdx muscle to maintain the same Ca(2+) extrusion properties as in the WT muscle.

An examination of nine hospitals that recently implemented a comprehensive electronic health record (EHR) system finds that clinical and administrative leaders built EHR adoption into their strategic plans to integrate inpatient and outpatient care and provide a continuum of coordinated services. Successful implementation depended on: strong leadership, full involvement of clinical staff in design and implementation, mandatory staff training, and strict adherence to timeline and budget. The EHR systems facilitate patient safety and quality improvement through: use of checklists, alerts, and predictive tools; embedded clinical guidelines that promote standardized, evidence-based practices; electronic prescribing and test-ordering that reduces errors and redundancy; and discrete data fields that foster use of performance dashboards and compliance reports. Faster, more accurate communication and streamlined processes have led to improved patient flow, fewer duplicative tests, faster responses to patient inquiries, redeployment of transcription and claims staff, more complete capture of charges, and federal incentive payments.

Mammalian skeletal muscle fibres possess a tubular (t-) system that consists of regularly spaced transverse elements which are also connected in the longitudinal direction. This tubular network provides a pathway for the propagation of action potentials (APs) both radially and longitudinally within the fibre, but little is known about the actual radial and longitudinal AP conduction velocities along the tubular network in mammalian skeletal muscle fibres. The aim of this study was to track AP propagation within the t-system network of fast-twitch rat muscle fibres with high spatio-temporal resolution when the t-system was isolated from the surface membrane. For this we used high speed confocal imaging of AP-induced Ca(2+) release in contraction-suppressed mechanically skinned fast-twitch fibres where the t-system can be electrically excited in the absence of the surface membrane. Supramaximal field pulses normally elicited a synchronous AP-induced release of Ca(2+) along one side of the fibre axis which propagated uniformly across the fibre. In some cases up to 80 or more adjacent transverse tubules failed to be excited by the field pulse, while adjacent areas responded with normal Ca(2+) release. In these cases a continuous front of Ca(2+) release with an angle to the scanning line was observed due to APs propagating longitudinally. From these observations the radial/transversal and longitudinal AP conduction velocities along the tubular network deeper in the fibre under our conditions (19 ± 1°C) ranged between 8 and 11 μm ms(-1) and 5 to 9 μm ms(-1), respectively, using different methods of estimation. The longitudinal propagation of APs appeared to be markedly faster closer to the edge of the fibre, in agreement with the presence of dense longitudinal connections immediately below the surface of the fibre and more sparse connections at deeper planes within the fibre. During long trains of closely spaced field pulses the AP-elicited Ca(2+) releases became non-synchronous along the fibre axis. This is most likely caused by local tubular K(+) accumulation that produces local depolarization and local slowing of AP propagation. Longitudinally propagating APs may reduce such inhomogeneities by exciting areas of delayed AP onset. Clearly, the longitudinal tubular pathways within the fibre for excitation are used as a safety mechanism in situations where a local depolarization obstructs immediate excitation from the sarcolemma. Results obtained from this study also provide an explanation for the pattern of contractures observed in rippling muscle disease.

Background: Ischemic heart disease is a leading cause of mortality. To study this disease, ischemia/reperfusion (I/R) models are widely used to mimic the process of transient blockage and subsequent recovery of cardiac coronary blood supply. We aimed to determine whether the presence of the growth hormone secretagogues, ghrelin and hexarelin, would protect/improve the function of heart from I/R injury and to examine the underlying mechanisms., Methodology/principal Findings: Isolated hearts from adult male mice underwent 20 min global ischemia and 30 min reperfusion using a Langendorff apparatus. Ghrelin (10 nM) or hexarelin (1 nM) was introduced into the perfusion system either 10 min before or after ischemia, termed pre- and post-treatments. In freshly isolated cardiomyocytes from these hearts, single cell shortening, intracellular calcium ([Ca(2+)](i)) transients and caffeine-releasable sarcoplasmic reticulum (SR) Ca(2+) were measured. In addition, RT-PCR and Western blots were used to examine the expression level of GHS receptor type 1a (GHS-R1a), and phosphorylated phospholamban (p-PLB), respectively. Ghrelin and hexarelin pre- or post-treatments prevented the significant reduction in the cell shortening, [Ca(2+)](i) transient amplitude and caffeine-releasable SR Ca(2+) content after I/R through recovery of p-PLB. GHS-R1a antagonists, [D-Lys3]-GHRP-6 (200 nM) and BIM28163 (100 nM), completely blocked the effects of GHS on both cell shortening and [Ca(2+)](i) transients., Conclusion/significance: Through activation of GHS-R1a, ghrelin and hexarelin produced a positive inotropic effect on ischemic cardiomyocytes and protected them from I/R injury probably by protecting or recovering p-PLB (and therefore SR Ca(2+) content) to allow the maintenance or recovery of normal cardiac contractility. These observations provide supporting evidence for the potential therapeutic application of ghrelin and hexarelin in patients with cardiac I/R injury.

Store-operated Ca(2+) entry (SOCE) is a robust mechanism in skeletal muscle, supported by abundant STIM1 and Orai1 in the junctional membranes. The precise role of SOCE in skeletal muscle Ca(2+) homeostasis and excitation-contraction coupling remains to be defined. Regardless, it remains important to determine whether the function and capacity of SOCE changes in aged skeletal muscle. We identified an approximate 40% decline in the expression of the integral SOCE protein, stromal interacting molecule 1 (STIM1), but no such decline in its coupling partner, Orai1, in muscle fibers from aged mice. To determine whether this changed aspects of SOCE functionality in skeletal muscle in aged mice, Ca(2+) in the cytoplasm and t-system were continuously and simultaneously imaged on a confocal microscope during sarcoplasmic reticulum Ca(2+) release and compared to experiments under identical conditions using muscle fibers from young mice. Normal activation, deactivation, Ca(2+) influx, and spatiotemporal characteristics of SOCE were found to persist in skeletal muscle from aged mice. Thus, SOCE remains a robust mechanism in aged skeletal muscle despite the decline in STIM1 protein expression, suggesting STIM1 is in excess in young skeletal muscle., (© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)

Store-operated Ca(2+) entry (SOCE) has been found to be a rapidly activated robust mechanism in skeletal muscle fibres. It is conducted across the junctional membranes by stromal interacting molecule 1 (STIM1) and Orai1, which are housed in the sarcoplasmic reticulum (SR) and tubular (t-) system, respectively. These molecules that conduct SOCE appear evenly distributed throughout the SR and t-system of skeletal muscle, allowing for rapid and local control in response to depletions of Ca(2+) from SR. The significant depletion of SR Ca(2+) required to reach the activation threshold for SOCE could only be achieved during prolonged bouts of excitation-contraction coupling (EC coupling) in a healthy skeletal muscle fibre, meaning that this mechanism is not responsible for refilling the SR with Ca(2+) during periods of fibre quiescence. While Ca(2+) in SR remains below the activation threshold for SOCE, a low-amplitude persistent Ca(2+) influx is provided to the junctional cleft. This article reviews the properties of SOCE in skeletal muscle and the proposed molecular mechanism, assesses its potential physiological roles during EC coupling, namely refilling the SR with Ca(2+) and simple balancing of Ca(2+) within the cell, and also proposes the possibility of SOCE as a potential regulator of t-system and SR membrane protein function.

Store-operated Ca(2+) entry (SOCE) is an important mechanism in virtually all cells. In adult skeletal muscle, this mechanism is highly specialized for the rapid delivery of Ca(2+) from the transverse tubule into the junctional cleft during periods of depleting Ca(2+) release. In dystrophic muscle fibers, SOCE may be a source of Ca(2+) overload, leading to cell necrosis. However, this possibility is yet to be examined in an adult fiber during Ca(2+) release. To examine this, Ca(2+) in the tubular system and cytoplasm were simultaneously imaged during direct release of Ca(2+) from sarcoplasmic reticulum (SR) in skeletal muscle fibers from healthy (wild-type, WT) and dystrophic mdx mouse. The mdx fibers were found to have normal activation and deactivation properties of SOCE. However, a depression of the cytoplasmic Ca(2+) transient in mdx compared with WT fibers was observed, as was a shift in the SOCE activation and deactivation thresholds to higher SR Ca(2+) concentrations ([Ca(2+)](SR)). The shift in SOCE activation and deactivation thresholds was accompanied by an approximately threefold increase in STIM1 and Orai1 proteins in dystrophic muscle. While the mdx fibers can introduce more Ca(2+) into the fiber for an equivalent depletion of [Ca(2+)](SR) via SOCE, it remains unclear whether this is deleterious.

Skeletal muscle is highly specialized for the rapid delivery of Ca(2+) to the contractile apparatus during excitation-contraction coupling (EC coupling). Previous studies have shown the presence of a relatively fast-activated store-operated Ca(2+) entry (SOCE) mechanism (<1s) to be present in skeletal muscle, unlike the situation occurring in non-excitable cells. We simultaneously imaged [Ca(2+)] in the t-system and cytoplasm in mechanically skinned fibers during SR Ca(2+) release and observed both cell-wide Ca(2+) release and Ca(2+) waves. SOCE activation followed cell-wide Ca(2+) release from high sarcoplasmic reticulum (SR) [Ca(2+)] ([Ca(2+)](SR)) by seconds, consistent with depletion of [Ca(2+)](SR) to an absolute threshold for SOCE and an unformed SOCE complex at high [Ca(2+)](SR). Ca(2+) waves occurred at low [Ca(2+)](SR), close to the threshold for SOCE, minimizing the time between Ca(2+) release and Ca(2+) influx. Local activation of SOCE during Ca(2+) waves occurred in approximately 27ms following local initiation of SR depletion indicating a steep relationship between [Ca(2+)](SR) and SOCE activation. Most of this delay was due to slow release of Ca(2+) from SR, leaving only milliseconds at most for the activation of Ca(2+) entry following store depletion. SOCE was also observed to deactivate effectively instantly during store refilling at low [Ca(2+)](SR). These rapid kinetics of SOCE persisted as subsequent Ca(2+) waves propagated along the fiber. Thus we show for the first time millisecond activation and deactivation of SOCE during low amplitude [Ca(2+)](SR) oscillations at low [Ca(2+)](SR). To account for the observed Ca(2+) movements we propose the SOCE complex forms during the progressive depletion of [Ca(2+)](SR) prior to reaching the activation threshold of SOCE and this complex remains stable at low [Ca(2+)](SR)., (2010 Elsevier Ltd. All rights reserved.)

1. Here we review evidence obtained recently by us indicating that the poor longevity of isolated mammalian skeletal muscle preparations at temperatures in the normal physiological range is related to the increased production of reactive oxygen species (ROS) in the resting muscle. 2. Temperature-induced ROS production increases markedly above 32 degrees C in isolated, resting skeletal muscle and is associated with the gradual and irreversible functional deterioration of the muscle. 3. The majority of the temperature-induced muscle ROS originates in the mitochondria and acts on various sites involved in excitation-contraction coupling.

The tubular (t) system is essential for normal function of skeletal muscle fibre, acting as a conduit for molecules and ions within the cell. However, t system accessibility and interconnectivity have been mainly assessed in fixed cells where the t system no longer fully represents that of the living cell. Here, fluorescent dyes of different diameter were allowed to equilibrate within the t system of intact fibres from toad, mechanically skinned to trap the dyes, and then imaged using confocal microscopy to investigate t system accessibility and interconnectivity. Dual imaging of rhod-2 and a 500 kDa fluorescein dextran identified regions throughout the t system that differed in the accessibility to molecules of different molecular weight. Restrictions within the t system lumen occurred at the junctions of the longitudinal and transverse tubules and also where a transverse tubule split into two tubules to maintain their alignment with Z-lines of adjacent mis-registered sarcomeres. Thus, three types of tubule, transverse, longitudinal and Z, can be identified by their lumenal diameter in this network. The latter we define for the first time as a tubule with a narrow lumen that is responsible for the change in register. Stretch-induced t system vacuolation showed exclusive access of rhod-2 to these structures indicating their origin was the longitudinal tubules. Exposing the sealed t system to highly hypertonic solution reversed vacuolation of longitudinal tubules and also revealed that these tubules are not collapsible. Fluorescence recovery after photobleaching (FRAP) measurements of t system-trapped fluo-5 N showed interconnectivity through the t system along the axis of the fibre. However, diffusion occurred at a rate slower than expected given the known number of longitudinal tubules linking adjacent transverse tubules. This could be explained by the observed narrow opening to the longitudinal tubules from transverse tubules, reducing the effective cross-sectional area in which molecules could move within the t system.

To find out whether the decrease in muscle performance of isolated mammalian skeletal muscle associated with the increase in temperature toward physiological levels is related to the increase in muscle superoxide (O(2)(*-)) production, O(2)(*-) released extracellularly by intact isolated rat and mouse extensor digitorum longus (EDL) muscles was measured at 22, 32, and 37 degrees C in Krebs-Ringer solution, and tetanic force was measured in both preparations at 22 and 37 degrees C under the same conditions. The rate of O(2)(*-) production increased marginally when the temperature was increased from 22 to 32 degrees C, but increased fivefold when the temperature was increased from 22 to 37 degrees C in both rat and mouse preparations. This increase was accompanied by a marked decrease in tetanic force after 30 min incubation at 37 degrees C in both rat and mouse EDL muscles. Tetanic force remained largely depressed after return to 22 degrees C for up to 120 min. The specific maximum Ca(2+)-activated force measured in mechanically skinned fibers after the temperature treatment was markedly depressed in mouse fibers but was not significantly depressed in rat muscle fibers. The resting membrane and intracellular action potentials were, however, significantly affected by the temperature treatment in the rat fibers. The effects of the temperature treatment on tetanic force, maximum Ca(2+)-activated force, and membrane potential were largely prevented by 1 mM Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl), a membrane-permeable superoxide dismutase mimetic, indicating that the increased O(2)(*-) production at physiological temperatures is largely responsible for the observed depression in tetanic force at 37 degrees C by affecting the contractile apparatus and plasma membrane.

Mammalian skeletal muscles generate marked amounts of superoxide (O(2)(.-)) at 37 degrees C, but it is not well understood which is the main source of O(2)(.-) production in the muscle fibers and how this interferes with muscle function. To answer these questions, O(2)(.-) production and twitch force responses were measured at 37 degrees C in mechanically skinned muscle fibers of rat extensor digitorum longus (EDL) muscle. In mechanically skinned fibers, the sarcolemma is removed avoiding potential sources of O(2)(.-) production that are not intrinsically part of the muscle fibers, such as nerve terminals, blood cells, capillaries and other blood vessels in the whole muscle. O(2)(.-) production was also measured in split single EDL muscle fibers, where part of the sarcolemma remained attached, and small bundles of intact isolated EDL muscle fibers at rest, in the presence and absence of modifiers of mitochondrial function. The results lead to the conclusion that mitochondrial production of O(2)(.-) accounts for most of the O(2)(.-) measured intracellularly or extracellularly in skeletal muscle fibers at rest and at 37 degrees C. Muscle fiber excitability at 37 degrees C was greatly improved in the presence of a membrane permeant O(2)(.-) dismutase mimetic (Tempol), demonstrating a direct link between O(2)(.-) production in the mitochondria and muscle fiber performance. This implicates mitochondrial O(2)(.-) production in the down-regulation of skeletal muscle function, thus providing a feedback pathway for communication between mitochondria and plasma membranes that is not directly related to the main function of mitochondria as the power plant of the mammalian muscle cell.

Paracetamol (acetaminophen) is the most common drug taken in overdose in the UK, accounting for 48% of poisoning admissions to hospital and being involved in an estimated 100-200 deaths per year. In 1998, the UK government introduced legislation that reduced the maximum pack size of all non-effervescent tablets and capsules containing aspirin (acetylsalicylic acid) or paracetamol that can be sold or supplied from outlets other than registered pharmacies from 25 to 16 tablets or capsules. This article reviews the literature to determine the effectiveness of the legislation, focusing specifically on paracetamol poisoning. Seventeen studies on this subject were identified. Three studies found reductions in mortality rates; one study found an increase in mortality rates, while one found an initial reduction followed by an eventual increase; three found no significant difference in mortality rates before and after introduction of the legislation. Five studies found reductions in admissions to liver units, three of these finding a reduction in liver transplantation rates; two further studies found no change in liver function tests and rates of paracetamol-induced acute liver injury or failure. Four studies found a sustained decrease in hospital admissions, while two found an initial decrease followed by an eventual increase. One study found a decline in admissions for paracetamol poisoning and an increase in admissions for non-paracetamol poisoning. Sales data are conflicting, with two studies finding no significant difference in paracetamol sales before and after the introduction of the legislation and one reporting a decline. The severity of overdose appears to have decreased since the maximum permitted packet size was reduced, with five studies reporting a reduction in the number of severe overdoses (measured by numbers of tablets ingested, serum paracetamol concentrations and usage of antidotes). Only two studies reported an increase in the number of severe overdoses.Paracetamol-associated mortality rates, admissions to liver units/liver transplants, hospital admissions and the severity of paracetamol overdose appear to have been decreasing since 1998. However, one study showed that the reductions in mortality and hospital admissions began in 1997; therefore, the contribution of the 1998 legislation to the observed changes is unclear. Most of the studies are based on short-term follow-up so it is difficult to draw any conclusions regarding long-term trends. Many of the studies were also restricted to relatively small areas of the UK; this, combined with a variety of outcome measures, makes it difficult to distinguish any conclusive trends. The studies also suffer from a lack of comparison and control groups. Some studies do not clearly differentiate between the paracetamol preparations covered by the legislation and those not. The limited number of studies to date, combined with a variety of outcome measures, make it difficult to determine with accuracy whether or not the legislation has been a success. More long-term studies are needed to fully assess the impact of the legislation.

New analysis of the 2003 Commonwealth Fund Biennial Health Insurance Survey reveals that an estimated 77 million Americans age 19 and older--nearly two of five (37%) adults--have difficulty paying medical bills, have accrued medical debt, or both. Working-age adults incur significantly higher rates of medical bill and debt problems than adults 65 and older, with rates highest among the uninsured. Even working-age adults who are continually insured have problems paying their medical bills and have medical debt. Unpaid medical bills and medical debt can limit access to health care: two-thirds of people with a medical bill or debt problem went without needed care because of cost--nearly three times the rate of those without these financial problems.

A 2003 Commonwealth Fund/Health Research and Educational Trust survey of 576 New York State firms found that, in order to manage rising health costs, employers are increasing the share of the insurance premium that employees pay, delaying the start of benefits, and increasing cost-sharing at the point of service. This has enabled employers to preserve health benefits, but has raised costs for workers and their families. On average, workers' contributions for family coverage rose 54 percent, from $1,392 per year in 2001 to $2,148 per year in 2003. During that time period, fewer workers selected family coverage. Employers are receptive to a wide range of approaches to make coverage more available and affordable for their employees, but they have limited familiarity with public programs that could cover their lower-wage workers, such as Healthy New York, Family Health Plus, or Child Health Plus.

Identification of elicited muscle twitches while performing infraclavicular block of the brachial plexus is often confusing but is critical for success of the block. An easily defined endpoint when evaluating these motor responses to neurostimulation is essential, as it is necessary to block the appropriate cord or cords. In addition to an extensive review of the motor and sensory neuroanatomy of the upper extremity, we describe an easy method to learn and remember the motor response to stimulation of each of the cords of the brachial plexus. If the arm is positioned in the anatomical position, the 5th digit (pinkie) moves laterally (pronation of the forearm) when the lateral cord is stimulated, posteriorly (extension) when the posterior cord is stimulated, and medially (flexion) when the medial cord is stimulated. The pinkie thus moves "toward" the cord that is stimulated.

The State Children's Health Insurance Program (SCHIP), passed by Congress in 1997, has been implemented by states in many different forms, thus creating many natural experiments about insurance coverage for low-income children. In Georgia, SCHIP children are enrolled in a Medicaid look-alike program, PeachCare for Kids, with nearly the same administrative rules and providers as in the Medicaid program. Comparing the experiences of PeachCare and Medicaid children thus allows us to examine the impact of population differences on utilization and satisfaction. We find that Medicaid children, controlling for many demographic characteristics, report both less use of services and lower satisfaction with services used. Evidence presented here supports three possible explanations for these differences: Medicaid families are less familiar with and supportive of systems requiring use of an assigned primary care physician, the families face more nonprogram barriers to using care, and physicians have different responses to the two programs.

Objectives: Individuals without health insurance in general receive fewer health services and are more likely than insured patients to experience poor outcomes. The main goal of this research was to study whether physicians' clinical recommendations vary for insured and uninsured patients, implying that physicians' choices of care may mediate insurance-related differences in health care use., Methods: The authors designed clinical scenarios that describe routine decisions encountered by primary care physicians in ambulatory settings. Scenarios were designed to include discretionary, nondiscretionary, preventive, and diagnostic/therapeutic services. Insurance status of patients was indicated as either insured or uninsured for the service under consideration. Scenarios were presented to a nationally representative sample of primary care physicians (n = 1182) as part of the American Medical Association 1992 Socio-economic Monitoring System Survey. Physicians were assigned randomly to receive eight scenarios in which patients were either insured or uninsured. For each scenario, physicians were asked to indicate the percentage of patients for whom they would recommend a given service., Results: After controlling for variables associated with nonresponse, we found that physicians who were presented scenarios with insured patients recommended service for 72% of patients, and physicians who were presented scenarios with uninsured patients recommended the same services for 67% of patients (P < 0.001). Physicians recommended both discretionary services (50% versus 42%; P < 0.001) and nondiscretionary services more often for insured than uninsured patients (93% versus 91%; P < 0.05)., Conclusions: In self-reports, physicians are more likely to recommend services for insured than for uninsured patients, and more so when services are discretionary. This provides evidence that physicians' recommendations may be important mediators of insurance-related variation in the use of health-care services. Higher rates of use among the insured may not always reflect higher quality of care, particularly when the service is discretionary in nature.

This paper examines the effect of one form of chronic stress--household crowding--on psychological well-being, as measured by multiple inverse indicators of psychological well-being. We rely on data from a large (n = 2017) random sample of households in Bangkok, Thailand, a context that has a higher level and broader range of crowding than typically found in the United States. Objective household crowding is found to be detrimental to psychological well-being, controlling for a number of background characteristics. The effect of objective crowding is mediated by subjective crowding, which has strong, consistent and direct detrimental effects on well-being. There is no evidence of a gender effect. Extended family households are not uncommon in Bangkok, but the effects of objective and subjective crowding are similar in both two- and three-generation households, as well as in one- and multiple-couple households. The argument that subjective crowding is an effect, rather than a cause, of psychological well-being is examined and rejected. The findings suggest that crowding, as a chronic source of stress, constitutes a major threat to psychological well-being. Although the empirical analyses are based on data from one city, we frame the issue of household crowding in a historical and theoretical context in order to suggest in which cultural settings household crowding is most likely to have detrimental effects on psychological well-being.

Solutions A and B (15.8% ferrous sulfate in 0.3% citric acid and 6% sodium carbonate, respectively) have been available as a first-aid treatment for cyanide ingestion for many decades. Controversy surrounding the efficacy of solutions A and B has existed for much of that time, the main protagonists being in the UK. The current opinion in the UK is that solutions A and B should no longer be used as a first-aid measure in the management of cyanide poisoning. Similarly, oral sodium thiosulfate or activated charcoal should not be used. The recommended first-aid treatment of symptomatic cyanide poisoning is 100% oxygen and amyl nitrite, irrespective of the route of exposure.

In Thailand, like the U.S., women's higher rates of illness and health service use imply that they are "sicker." But, as in the U.S., females live longer than males. Based on a large representative sample of Bangkokians, we find that married women report more sickness, are more likely to utilize health services and, according to self-reports, have poorer health. Western literature suggests five prominent explanations for gender differences in health: biological risks, acquired risks, psychosocial aspects of symptoms and care, health-reporting behavior, and prior health care and caretakers. However, analyses show that these explanations largely fail to account for morbidity differences between Thai men and women. The observed gender differences in health among Thais remain significant after eliminating pregnant women and new mothers, and after controlling for several aspects of acquired risk. Problems associated with the reproductive system among Thai women, along with greater psychological distress, appear to account for most of the gender differences in health. The theoretical implications of these findings are discussed. As for the apparent contradiction between gender differences in health and mortality in Thailand, the evidence indicates that Thai men, like their American counterparts, suffer from more serious chronic ailments that may explain their higher mortality rates.