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Violent releases of space plasma energy from the Earth's magnetotail during substorms produce strong electric currents and bright aurora. But what modulates these currents and aurora and controls dissipation of the energy released in the ionosphere? Using data from the THEMIS fleet of satellites and ground-based imagers and magnetometers, we show that plasma energy dissipation is controlled by field-aligned currents (FACs) produced and modulated during magnetotail topology change and oscillatory braking of fast plasma jets at 10-14 Earth radii in the nightside magnetosphere. FACs appear in regions where plasma sheet pressure and flux tube volume gradients are non-collinear. Faster tailward expansion of magnetotail dipolarization and subsequent slower inner plasma sheet restretching during substorm expansion and recovery phases cause faster poleward then slower equatorward movement of the substorm aurora. Anharmonic radial plasma oscillations build up displaced current filaments and are responsible for discrete longitudinal auroral arcs that move equatorward at a velocity of about 1km/s. This observed auroral activity appears sufficient to dissipate the released energy.

Abstract Background The study aimed to assess the impact of different training modalities on otoscopy performance during a practical exam using a high-fidelity simulator and to determine if objective evaluation of otoscopy is feasible using a simulator that records insertion depth and tympanic membrane coverage. Methods Participants were assigned to one of four groups: control and three intervention groups with varying training approaches. Participants received otoscopy training and then were assessed through a practical exam on a high-fidelity simulator that uses virtual reality to visualize the ear canal and middle ear. Performance was evaluated using a modified Objective Structured Assessment of Technical Skills checklist and Integrated Procedural Performance Instrument checklist. Insertion depth, tympanic membrane coverage, and correct diagnosis were recorded. Data were tested for normal distribution using the Shapiro-Wilk test. One-way ANOVA and, for non-normally distributed data, Kruskal-Wallis test combined with Dunn’s test for multiple comparisons were used. Interrater reliability was assessed using Cohen’s κ and Intraclass correlation coefficient. Results All groups rated their training sessions positively. Performance on the OSATS checklist was similar among groups. IPPI scores indicated comparable patient handling skills. The feedback group examined larger tympanic membrane areas and had higher rates of correct diagnosis. The correct insertion depth was rarely achieved by all participants. Interrater reliability for OSATS was strong. IPPI reliability showed good correlation. Conclusion Regardless of training modality, participants perceived learning improvement and skill acquisition. Feedback improved examination performance, indicating simulator-guided training enhances skills. High-fidelity simulator usage in exams provides an objective assessment of performance.

Abstract Background Students’ ratings of bedside teaching courses are difficult to evaluate and to comprehend. Validated systematic analyses of influences on students’ perception and valuation of bedside teaching can serve as the basis for targeted improvements. Methods Six hundred seventy-two observations were conducted in different surgical departments. Survey items covered the categories teacher’s performance, student’s self-perception and organizational structures. Relevant factors for the student overall rating were identified by multivariable linear regression after exclusion of variable correlations > 0.500. The main target for intervention was identified by the 15% worst overall ratings via multivariable logistic regression. Results According to the students the success of bedside teaching depended on their active participation and the teacher’s explanations of pathophysiology. Further items are both relevant to the overall rating and a possible negative perception of the session. In comparison, negative perception of courses (worst 15%) is influenced by fewer variables than overall rating. Variables that appear in both calculations show slight differences in their weighing for their respective endpoints. Conclusion Relevant factors for overall rating and negative perception in bedside teaching can be identified by regression analyses of survey data. Analyses provide the basis for targeted improvement.

Innovative and decentralized biorefineries are needed in urban areas to contribute to local resource efficiency. In this case study a biorefinery (waste-to-resource-unit, W2RU) is introduced for bioconversion of food waste using heterotrophic microalgae to protein-rich biomass, and for simultaneous extraction of high-value chemicals pigments (e.g., astaxanthin, β-carotene, lycopene, lutein, or riboflavin), vitamins (e.g., retinol, tocopherol, or ascorbic acid), and flavonoids from food waste. The W2RU is a compact and fully automated systems, which is applicable to recycle various biological waste streams. It consists of a module for the extraction of valuable compounds from wasted food. Remaining material will be sent to hydrolysis and hydrolysate applied as nutrient source in heterotrophic microalgae cultivation for production of protein-rich biomass. Such an approach can be integrated in urban infrastructure and the simultaneous production of various products from high-value chemicals to proteins revealed beneficial environmental impacts.

Background: The efficacy and safety of renin angiotensin aldosterone system blockers (RAASB’s) if introduced immediately after renal transplantation have not been extensively investigated. Methods: The medical charts of 142 kidney transplant recipients who received a RAASB in the early postoperative period and of 114 matched controls were analyzed. The RAASB was given primarily for blood pressure control. Results: 117 patients continued to receive and 50 controls remained continuously free of the RAASB in the first year. The RAASB was added on average at postoperative day 8 and the mean duration of follow-up was 5.4 years. Systolic, blood pressure at treatment initiation was increased in the RAASB group (150 ± 17 vs. 141 ± 16, p

Nodular hyperplasia of parathyroid glands (PG) is the most probable cause of medical treatment failure in secondary hyperparathyroidism (sHPT). This prospective cohort study is located at the interface of medical and surgical consideration of sHPT treatment options and identifies risk-factors for nodular hyperplasia of PG.One-hundred-eight resected PG of 27 patients with a broad spectrum of sHPT severity were classified according to the degree of hyperplasia by histopathology. Twenty routinely gathered parameters from medical history, ultrasound findings of PG and laboratory results were analyzed for their influence on nodular hyperplasia of PG by risk-adjusted multivariable binary regression. A prognostic model for non-invasive assessment of PG was developed and used to weight the individual impact of identified risk-factors on the probability of nodular hyperplasia of single PG.Independent risk-factors for nodular hyperplasia of single PG were duration of dialysis in years, PG volume in mm3 determined by ultrasound and serum level of parathyroid hormone in pg/mL. Multivariable analyses computed a model with an Area Under the Receiver Operative Curve of 0.857 (95%-CI:0.773-0.941) when predicting nodular hyperplasia of PG. Theoretical assessment of risk-factor interaction revealed that the duration of dialysis had the strongest influence on the probability of nodular hyperplasia of single PG.The three identified risk-factors (duration of dialysis, PG volume determined by ultrasound and serum level of parathyroid hormone) can be easily gathered in daily routine and could be used to non-invasively assess the probability of nodular hyperplasia of PG. This assessment would benefit from periodically collected data sets of PG changes during the course of sHPT, so that the choice of medical or surgical sHPT treatment could be adjusted more to the naturally changing type of histological PG lesion on an individually adopted basis in the future.

Der Begriff papierloses Büro ist als Metapher für Reduktion der Verwaltung auf ein notwendiges Minimum zu verstehen. Es werden Hemmnisse und Probleme einer derartigen Entwicklung sowohl auf organisatorischer als auch soziokultureller Ebene diskutiert.

OBJECTIVE:A monoclonal antibody (mAb) against the leukocyte common antigen CD45 (RT7 in rats) could facilitate bone marrow transplantation (BMT). This study in rats evaluates a depletive rat anti-RT7a mAb as isolated tool for BMT conditioning without using irradiation or any chemotherapeutic / immunosuppressive agent. METHODS:The model used a CD45 di-allelic polymorphism (RT7a/RT7b). The anti-RT7a mAb was intravenously administered to LEW.1W rats (RT1uRT7a) at 5, 10 and 15 mg/kg. 1x10(8) BM cells of MHC syngeneic (RT1u), MHC disparate (RT1l) or MHC haploidentical (RT1u/l) donors were transplanted. All BM donor strains carried the RT7b allele so that their CD45+ cells were not affected by the anti-RT7a mAb. Recipients were monitored for reconstitution and donor-chimerism in blood leukocytes. RESULTS:mAb dosages of 5 or 10 mg/kg were myelosuppressive, whereas 15 mg/kg was myeloablative. Multi-lineage donor-chimerism at day 100 indicated engraftment of MHC syngeneic BM after any used mAb dosage (5 mg/kg: 46+/-7%; 10 mg/kg: 62+/-5%; 15 mg/kg: 80+/-4%). MHC disparate BM resulted in autologous reconstitution after conditioning by 10 mg/kg of the mAb and caused transient chimerism ending up in death associated with aplasia after conditioning by 15 mg/kg of the mAb. MHC haploidentical BM (F1 to parental) engrafted only after conditioning by 15 mg/kg (chimerism at day 100: 78+/-7%). Abandonment of α/β TCR+ cell depletion from BM grafts impaired the engraftment process after conditioning using 15 mg/kg of the mAb in the MHC syngeneic setting (2 of 6 recipients failed to engraft) and the MHC haploidentical setting (3 of 6 recipients failed). CONCLUSION:This depletive anti-RT7a mAb is myelosuppressive and conditions for engraftment of MHC syngeneic BM. The mAb also facilitates engraftment of MHC haploidentical BM, if a myeloablative dose is used. RT7b expressing, BM-seeded α/β TCR+ cells seem to impair the engraftment process after myeloablative mAb conditioning.

Background. This is a single center oncological resume overlooking four decades of experience with liver transplantation (LT) for hepatocellular carcinoma (HCC). Methods. All 319 LT for HCC that were performed between 1975 and 2011 were included. Predictors for HCC recurrence (HCCR) and survival were identified by Cox regression, Kaplan-Meier analysis, Log Rank, and χ2-tests where appropriate. Results. HCCR was the single strongest hazard for survival (exp⁡B=10.156). Hazards for HCCR were tumor staging beyond the histologic MILAN (exp⁡B=3.645), bilateral tumor spreading (exp⁡B=14.505), tumor grading beyond G2 (exp⁡B=8.668), and vascular infiltration of small or large vessels (exp⁡B=11.612, exp⁡B=18.324, resp.). Grading beyond G2 (exp⁡B=10.498) as well as small and large vascular infiltrations (exp⁡B=13.337, exp⁡B=16.737, resp.) was associated with higher hazard ratios for long-term survival as compared to liver transplantation beyond histological MILAN (exp⁡B=4.533). Tumor dedifferentiation significantly correlated with vascular infiltration (χ2p=0.006) and intrahepatic tumor spreading (χ2p=0.016). Conclusion. LT enables survival from HCC. HCC dedifferentiation is associated with vascular infiltration and intrahepatic tumor spreading and is a strong hazard for HCCR and survival. Pretransplant tumor staging should include grading by biopsy, because grading is a reliable and easily accessible predictor of HCCR and survival. Detection of dedifferentiation should speed up the allocation process.

Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.

El artículo que se presenta describe una alternativa económica de sistema de adquisición de datos parael monitoreo de una instalación de potencia eléctrica trifásica. El sistema experimental está basado en unmicrocontrolador de Intel StrongARM SA-1110 de 32 bits con CPU RISC, una memoria flash de 16 Mbyte,una memoria SDRAM de 32 Mbyte y un controlador LAN Ethernet de 10/100 Mbps entre otros elementos.El mismo tiene instalado un sistema operativo Linux (kernel versión 2.4) y un servidor web thttpd. Através de un programa CGI se logra el muestreo, procesamiento y transmisión de la información recibidadesde un sistema trifásico de potencia y a partir de un protocolo HTTP se envía toda esta información aun grupo de clientes conectados a una red convencional de computadoras. This work focuses on an economic alternative for developing a data acquisition system which monitors athree-phase power intalation. This experimental system is made up of an Intel StrongARM SA-1110 32-bitRISC microcontroller, a 16-Mbyte flash memory chip, a 32-MByte SDRAM chip, a 10/100 Mbps EthernetLAN controller with 10BASE-T, as well as other hardware elements. The system has an embedded Linuxoperating system (kernel version 2.4), and a thttpd embedded web server. A CGI program was designed inorder to enable the sampling, processing and transmition of information received from the three-phasepower installation. To achieve this, a HTTP protocol was used in order to send all this information to agroup of clients connected to a conventional PC network.

Abstract Introduction Most underlying diseases for abdominal pain in children are not dangerous. However some require rapid diagnosis and treatment, such as acute ovarian torsion or appendicitis. Since reaching a diagnosis can be difficult, and delayed treatment of potentially dangerous diseases might have significant consequences, exploratory laparoscopy is a diagnostic and therapeutic option for patients who have unclear and potentially hazardous abdominal diseases. Here we describe a case where the anomaly could not be identified using a laparoscopy in an adolescent girl with acute abdomen. Case presentation A 13-year old postmenarchal caucasian female presented with an acute abdomen. Emergency sonography could not exclude ovarian torsion. Accurate diagnosis and treatment were achieved only after an initial laparoscopy followed by a laparotomy and after a magnetic resonance imaging scan a further laparotomy. The underlying disease was hematometra of the right uterine horn in a uterus didelphys in conjunction with an imperforate right cervix. Conclusion This report demonstrates that the usual approach for patients with acute abdominal pain may not be sufficient in emergency situations.

Irradiation of [Ru(GaCp*) 3 (SiEt 3 )H 3 ] (1) at 350 nm induces reductive elimination of dihydrogen and triethylsilane and generates unsaturated Ru/Ga species. This photochemically induced cascading reductive elimination processes generate the reactive intermediate [Ru(GaCp*) 3 ], which can be trapped by diphosphine coordination to yield the stable complex [(dppe)Ru(GaCp*) 3 ] (4). The photochemically generated RuGa 3 species is catalytically active in the hydrogenation of alkynes, which is further investigated by 1 H NMR and mass spectrometry. Formation of intermetallic Ru/Ga clusters is observed as a competing and for the catalytic activity of the species limiting side reaction.

Emerging adults with diabetes, particularly in underserved communities, represent a growing but less studied population whose needs may differ from older adults. This study investigated perspectives of underserved emerging adults regarding diabetes self-management influences and provider interactions. Focus groups and interviews with emerging adults in a safety-net health care setting were conducted to identify perspectives regarding self-management influences and patient-provider interactions. Diabetes was perceived as a psychological burden complicated by busy lifestyles and competing responsibilities. Lack of resources, especially financial barriers, also limited self-management. Participants often perceived diabetes visits as standardized encounters providing access to diabetes supplies but desired additional guidance appropriate to their needs and life-stage. Participants valued encouragement and positive ongoing provider relationships for tailored informational and emotional support and support from family and peers. Providers and health care systems adapting to provide or facilitate this support will be better able to optimize diabetes management at and between visits.

The increasing number of emerging adults with diabetes (EAWD) being cared for in adult health care settings requires a better understanding of the needs of EAWD and their interactions with adult health care providers (HCPs). This article describes findings from interviews with endocrinologists and diabetes nurses from a safety-net health care system to investigate HCPs' perspectives regarding influences on EAWD self-management and HCP interactions with EAWD. HCPs frequently perceived lower EAWD engagement in diabetes management, which was complicated by barriers such as the emotional burden of diabetes, busy lives and multiple responsibilities, and limited access to resources; however, HCPs valued the role of information and communication at visits in tailoring care for EAWD. Measures to tailor care should address the psychosocial burden related to the life stage goals and priorities of EAWD, identification of resources for EAWD and HCPs, and further elucidation of effective self-management guidance and communication strategies to support EAWD in safety-net settings., (© 2022 by the American Diabetes Association.)

Background and Objectives: Previous studies have shown gender disparities in physician pay in various specialties. This retrospective, cross-sectional study evaluated data from the American Academy of Neurology (AAN) Compensation and Productivity Survey for differences in neurologist compensation by gender., Methods: Of the 3,268 completed surveys submitted, 2,719 were from neurologists and 1,466 had sufficient data for analysis (551 women, 951 men respondents). We calculated an hourly wage from full-time equivalent (FTE) status and weeks worked per year. We evaluated differences in men and women neurologist compensation with multivariable generalized linear models adjusting for race, ethnicity, geographic region, practice setting, years in practice, call status, leadership role, straight salary, and subspecialty., Results: Baseline characteristics for men and women neurologists were similar with the exception of subspecialty distribution. More men were practicing in higher-wage subspecialties compared to women ( p < 0.05). Mean FTE annual salary for all neurologists was $280,315, and mean standardized hourly compensation was $131. Estimated annual salary for women was 10.7% less ( p ≤ 0.001, 95% confidence interval -4% to -16%) after controlling for race, region, years of practice, practice setting, call status, leadership role, and subspecialty-wage category. FTE annual salary for women neurologists in high-compensation specialties ($281,838) was lower than the mean annual salary for men neurologists in both high-compensation ($365,751) and low-compensation subspecialties ($282,813). When broken down by years of practice, the highest earning women neurologists' mean hourly wage (11-20 years of practice, $128/h) was less than that of all men neurologists except those with 0 to 5 years of practice ($125/h)., Discussion: This study, using convenience sample data, adds to the existing body of evidence demonstrating that, despite adjustment for multiple confounding variables, ongoing disparities exist in physician compensation. Despite efforts by professional societies such as the AAN, ongoing systemic issues and barriers exist. Further research into underlying causes and mitigation strategies is recommended; use of probability sampling methods in future research will be important to decrease potential bias and to increase generalizability., (© 2022 American Academy of Neurology.)

Telehealth services complement in-person neurologic care. The American Academy of Neurology supports patient access to telehealth services regardless of location, coverage for telehealth services by all subscriber benefits and insurance, equitable provider reimbursement, simplified state licensing requirements easing access to virtual care, and expanding telehealth research and quality initiatives. The roles and responsibilities of providers should be clearly delineated in telehealth service models., (© 2021 American Academy of Neurology.)

Aims: There is limited information characterizing young adults (18-35 years) (YA) with diabetes, especially those admitted for hyperglycemic emergencies. The study aims were to examine associations of patient-level characteristics with hyperglycemic emergency hospitalization and to identify variations based on diabetes type and glycemic control., Methods: We conducted retrospective analysis of 273 YA admitted to an inner-city hospital with diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic nonketotic syndrome (HHS). T-tests, Chi-Square tests, and ANOVA identified differences in demographics, diabetes history, clinical indicators, complications/comorbidities, and hospital admission stratified separately by diabetes type (1 vs 2) and admission HbA1c < 9% (75 mmol/mol), ≥9% to 12% (108 mmol/mol), ≥12%)., Results: Mean admission HbA1c was 12.4% (112 mmol/ml). HbA1c was ≥9.0% for 90.5%. The main DKA/HHS trigger was medication nonadherence (57.9%), with 35.6% presenting with new-onset type 2 diabetes. Only 3.7% utilized outpatient diabetes clinics, 38.8% were re-hospitalized within the year, and 69% lacked insurance. Diabetes complications (44.7%) and psychiatric co-morbidities (35.5%) were common. Significantly more YA with type 1 diabetes had insurance, whereas YA with type 2 diabetes had higher admission HbA1c. YA with HbA1c ≥12% were more likely to be Black and lack insurance., Conclusions: YA hospitalized for DKA/HHS in an inner-city hospital tended to have severely uncontrolled diabetes. Many already had comorbidities and diabetes complications, high use of acute care services and low use of diabetes specialty services. YA characteristics varied by diabetes type and HbA1c. Overall, a substantial percentage lacked insurance, potentially impacting healthcare utilization patterns and medication adherence, and leading to DKA/HHS admissions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Effects of scattering of electrons from whistler chorus waves and of ions due to field line curvature on diffuse precipitating particle fluxes and ionospheric conductance during the large 17 March 2013 storm are examined using the self-consistent Rice Convection Model Equilibrium (RCM-E) model. Electrons are found to dominate the diffuse precipitating particle integrated energy flux, with large fluxes from ~21:00 magnetic local time (MLT) eastward to ~11:00 MLT during the storm main phase. Simulated proton and oxygen ion precipitation due to field line curvature scattering is sporadic and localized, occurring where model magnetic field lines are significantly stretched on the night side at equatorial geocentric radial distances r 0 ≳8 R E and/or at r 0 ~5.5 to 6.5 R E from dusk to midnight where the partial ring current field has perturbed the magnetic field. The precipitating protons likewise contribute sporadically to the storm time Hall and Pedersen conductance in localized regions whereas the precipitating electrons are the dominate storm time contributor to enhanced Hall and Pedersen conductance at auroral magnetic latitudes on the night and morning side. The RCM-E model can reproduce general features of the Van Allen Probe/MagEIS observed trapped electron differential flux spectrograms over energies of ~37 to 150 keV. The simulations with a parameterized electron loss model also reproduce reasonably well the storm time Defense Meteorological Satellite Program integrated electron energy flux at 850 km at satellite crossings from predawn to midmorning. However, model-data agreement is not as good from dusk to premidnight where there are large uncertainties in the electron loss model.

Background: Rifaximin has demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D)., Aim: To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility., Methods: Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods., Results: Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin (n = 37) or placebo (n = 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase, Clostridium difficile was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008-1 µg/mL] and rifampin (MIC range 0.004-0.25 µg/mL). Following double-blind rifaximin treatment, Staphylococcus isolates remained susceptible to rifaximin at all visits (MIC 50 range ≤0.06-32 µg/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested., Conclusions: In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics. CLINICALTRIALS., Gov Identifier: NCT01543178.

The use of low-cost interactive game technology for balance rehabilitation has become more popular recently, with generally good outcomes. Very little research has been undertaken to determine whether this technology is appropriate for balance assessment. The Wii balance board has good reliability and is comparable to a research-grade force plate; however, recent studies examining the relationship between Wii Fit games and measures of balance and mobility demonstrate conflicting findings. This study found that the Wii Fit was feasible for community-dwelling older women to safely use the balance board and quickly learn the Wii Fit games. The Ski Slalom game scores were strongly correlated with several balance and mobility measures, whereas Table Tilt game scores were not. Based on these findings, the Ski Slalom game may have utility in the evaluation of balance problems in community-dwelling older adults.

The prognosis of most leukemia patients treated with BCR-ABL tyrosine kinase inhibitors (TKIs) is favorable, and a more precise understanding of serious and potentially irreversible treatment-related toxicities is essential to properly inform treatment choice. Few cases of pulmonary arterial hypertension (PAH) have been reported in patients with leukemia treated with dasatinib, a second-generation BCR-ABL TKI. To better understand characteristics and outcomes of dasatinib-treated patients with PAH, all clinical cases of PAH confirmed by right-heart catheterization in the Bristol-Myers Squibb pharmacovigilance database (N = 41), including 22 previously unpublished cases, were examined for previous treatments for leukemia, patient characteristics, time to PAH onset, and outcomes. Our analysis shows that compared with PAH due to other etiologies, dasatinib-related PAH is atypical, in that it is associated with partial to complete reversibility upon treatment discontinuation. The incidence of dasatinib-related PAH appears to be low. Most PAH cases were observed in patients who had received prior treatments for leukemia. No specific patient attributes appear to be associated with an increased risk of developing PAH while receiving dasatinib. Symptoms of PAH in dasatinib-treated leukemia patients should prompt a thorough workup, including consideration of confirmatory right-heart catheterization. In cases of confirmed PAH, dasatinib should be discontinued., (© 2015 Wiley Periodicals, Inc.)

Background: Although epinephrine is the treatment of choice for anaphylaxis, it remains underused., Objective: This study was designed to describe anaphylactic events and epinephrine autoinjector (EAI) use in U.S. schools enrolled in the EpiPen4Schools program., Methods: This exploratory, cross-sectional, Web-based survey of 6019 schools that participated in the EpiPen4Schools program assessed anaphylactic events and EAI use at responding schools during the 2013-2014 school year., Results: A total of 919 anaphylactic events were reported in 607 schools. Of the 852 anaphylactic events with data on those who experienced an event, most 88.8% (n = 757) occurred in students, and 21.9% of events (n = 187) occurred in individuals with no known allergies. Of the 851 events with data on EAI use, 74.7% (n = 636) were treated with EAIs and 8.5% (n = 54) received a second epinephrine injection. Of the 204 individuals not treated with an EAI, 77.0% (n = 157) received antihistamines, 12.7% (n = 26) received another treatment, and 8.3% (n = 17) received no treatment. Of the 850 events with data on hospital transport, 79.6% of individuals (n = 677) were transported to the hospital. Common triggers varied seasonally, with food listed most frequently overall (62.5%)., Conclusion: More than one in ten schools that participated in the EpiPen4Schools survey reported an anaphylactic event. Approximately 25% of individuals with anaphylactic events were not treated with EAIs, and 20.4% of patients were not taken to the hospital after an anaphylactic event. Analysis of these data supports the value of stocking EAIs and of providing continuing education regarding the recognition and proper treatment of anaphylaxis for school personnel.

Although delivery of medications through nebulization is effective for patients with COPD, nebulization is often perceived negatively. This survey evaluated patient and caregiver attitudes and perceptions related to the use of nebulization for the management of COPD. A total of 400 patients and a separate population of 400 caregivers were randomly selected and interviewed via telephone. Responses were assessed on the basis of 4 domains: health of patients with COPD, satisfaction with nebulization therapy, benefits and challenges, and the caregiver role. Most patients (58%) self-classified their COPD as "mild to moderate," with shortness of breath upon minimal to moderate exertion; caregivers reported similar findings. The majority of patients and caregivers (89% and 92%, respectively) were "generally satisfied with their (or their friend's or family member's) current nebulized treatment." Based on their personal experiences, 80% of patients and caregivers reported that using a nebulizer was better than using only an inhaler. Patients and caregivers agreed (79% and 85%, respectively) that the benefits of nebulization therapy outweighed the difficulties or inconveniences. Patients believed that their overall quality of life had improved since beginning nebulization (75%) and that nebulization better enabled their caregiver to provide care (77%); caregivers echoed this sentiment. Overall, this survey demonstrated that an overwhelming majority of patients and caregivers were satisfied with nebulization therapy, reporting benefits in symptom relief, ease of use, and improved quality of life.

Purpose: The aim of this study was to evaluate if men with varying degrees of bother from a similar number of nocturia episodes differ with respect to self-rated sleep characteristics and fatigue., Materials and Methods: As part of the baseline assessments during a nocturia treatment trial, 55 participants reported frequency and bother of nocturia using the AUA Symptom Inventory and completed 7-day sleep diaries prior to treatment. Participants who reported moderate nocturia (either two or three episodes nightly) were further grouped into categories of LOW (nocturia is no problem or a very small problem) or HIGH bother (nocturia is a big problem). Information from the participant completed sleep diaries was abstracted, including information on daytime napping, total sleep time, mean time needed to return to sleep, nighttime ratings of fatigue, and daytime ratings of fatigue., Results: Of the 55 individuals who completed the pilot study, 24 study participants reported two or three episodes of nocturia and had either HIGH (n = 11) or LOW (n = 13) bother. Participants categorised with HIGH bother were significantly more likely than those with LOW bother to report difficulty initiating sleep (47.7 ± 34.4 vs. 23.5 ± 13.6 min, p = 0.05), difficulty returning to sleep after an awakening (28.9 ± 16.1 vs. 15.4 ± 9.6 min, p = 0.03) and greater morning fatigue (3.3 ± 0.7 vs. 2.5 ± 1.0, p = 0.04 on a 7-point scale)., Conclusions: Since bother related to nocturia is linked to sleep quality, interventions targeting fatigue and sleep maintenance may provide useful targets in the management of nocturia in men., (Published 2012. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Neoadjuvant chemoradiation before surgery is an emerging treatment modality for pancreatic ductal adenocarcinoma (PDAC). However, analysis of prognostic factors is limited for patients with PDAC treated with neoadjuvant chemoradiation and pancreaticoduodenectomy (PD)., Methods: The study population was comprised of 240 consecutive patients with PDAC who received neoadjuvant chemoradiation and PD and was compared with 60 patients who had no neoadjuvant therapy between 1999 and 2007. Clinicopathologic features were correlated with disease-free survival (DFS) and overall survival (OS)., Results: Among the 240 treated patients, the 1-year and 3-year DFS rates were 52% and 32%, with a median DFS of 15.1 months. The 1-year and 3-year OS rates were 95% and 47%, with a median OS of 33.5 months. By univariate analysis, DFS was associated with age, post-therapy tumor stage (ypT), lymph node status (ypN), number of positive lymph nodes, and American Joint Committee on Cancer (AJCC) stage, whereas OS was associated with intraoperative blood loss, margin status, ypT, ypN, number of positive lymph nodes, and AJCC stage. By multivariate analysis, DFS was independently associated with age, number of positive lymph nodes, and AJCC stage, and OS was independently associated with differentiation, margin status, number of positive lymph nodes, and AJCC stage. In addition, the treated patients had better OS and lower frequency of lymph node metastasis than those who had no neoadjuvant therapy., Conclusions: In patients with PDAC who received neoadjuvant chemoradiation and subsequent PD, post-therapy pathologic AJCC stage and number of positive lymph nodes are independent prognostic factors., (Copyright © 2011 American Cancer Society.)

Objectives: The primary purpose of this study was to determine the acute and long-term hemodynamic and clinical effects of irbesartan in patients with heart failure., Background: Inhibition of angiotensin II production by angiotensin-converting enzyme (ACE) inhibitors reduces morbidity and mortality in patients with heart failure. Irbesartan is an orally active antagonist of the angiotensin II AT1 receptor subtype with potential efficacy in heart failure., Methods: Two hundred eighteen patients with symptomatic heart failure (New York Heart Association [NYHA] class II-IV) and left ventricular ejection fraction < or = 40% participated in the study. Serial hemodynamic measurements were made over 24 h following randomization to irbesartan 12.5 mg, 37.5 mg, 75 mg, 150 mg or placebo. After the first dose of study medication, patients receiving placebo were reallocated to one of the four irbesartan doses, treatment was continued for 12 weeks and hemodynamic measurements were repeated., Results: Irbesartan induced significant dose-related decreases in pulmonary capillary wedge pressure (average change -5.9+/-0.9 mm Hg and -5.3+/-0.9 mm Hg for irbesartan 75 mg and 150 mg, respectively) after 12 weeks of therapy without causing reflex tachycardia and without increasing plasma norepinephrine. The neurohormonal effects of irbesartan were highly variable and none of the changes was statistically significant. There was a significant dose-related decrease in the percentage of patients discontinuing study medication because of worsening heart failure. Irbesartan was well tolerated without evidence of dose-related cough or azotemia., Conclusions: Irbesartan, at once-daily doses of 75 mg and 150 mg, induced sustained hemodynamic improvement and prevented worsening heart failure.

Background: The epicardial electrocardiogram (ECG) is a sensitive marker for cardiac ischemia and has been used as a measure of ischemia in clinical trials. We sought to examine the utility of a central ECG laboratory for determining ischemic-type ST-segment shifts from epicardial ECG recordings obtained from multiple clinical sites., Hypothesis: We speculated that an operator-assisted digital ECG core laboratory is feasible, reliable, and efficient, with the ability for rapid and accurate interpretation of the epicardial ECG., Methods: The epicardial ECG was recorded via an angioplasty guidewire placed in a coronary artery of a patient undergoing angioplasty. Site investigators visually determined the time-to-onset of 0.1 and 0.3 mm ST-segment elevation, and the maximal ST-segment elevation during balloon inflation, and then compared the measurements with those made at an operator-assisted digital ECG core laboratory., Results: Agreement between the two methods occurred in 78% of the time-to-onset measurements, but in only 39% of the maximal ST-segment measurements. Overall, the visual measurements of the clinical investigators of time-to-onset differed from the digital core laboratory by 11.8 +/- 11.6 s for 0.1 mV, and 15.8 +/- 20.6 s for 0.3 mV. Recorded maximal ST-segment shifts differed by a mean of 0.47 +/- 0.69 mV., Conclusion: The magnitude of inconsistency between the ECG core laboratory results using an operator-assisted digital method and the interpretations of clinical investigators using manual caliper-type analysis was surprisingly large. These results support the need for an ECG core laboratory in clinical trials where ECG ST-segment shifts are used as a response variable.

Exposure of adult ventricular myocytes to exogenous natural phosphatidic acid results in the production of inositol phosphates by unknown mechanism(s). We characterized stimulation of myocytic phosphoinositide-specific phospholipase C (PLC) by synthetic dioleoyl phosphatidic acid (PA) as a potential mechanism for modulation of inositol phosphate production. Our data demonstrate that exogenous PA, at 10(-8)-10(-5) M, caused a concentration-dependent increase in inositol 1,4,5-trisphosphate in adult rabbit ventricular myocytes. PA also caused a concentration-dependent increase in in vitro activity of myocytic PLC in the presence or absence of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA). PLC-delta 1, the predominant isozyme of PLC expressed in adult rabbit ventricular myocytes, bound to liposomes of PA with high affinity in the presence of EGTA. The phosphomonoester group of PA was critical to in vitro stimulation of myocytic PLC activity and high-affinity binding of PLC-delta 1. We propose that binding of PLC-delta 1 to phosphatidic acid may be a novel mechanism for dynamic membrane association and modulation of PLC in adult ventricular myocytes.

Objective: The aim was to assess whether noradrenaline and endothelin-1 can stimulate endogenous production of phosphatidic acid in adult ventricular myocytes., Methods: After stimulation of rabbit ventricular myocytes with noradrenaline and endothelin-1, total lipids were extracted using the Bligh and Dyer procedure and separated by thin layer chromatography, and phosphatidic acid was quantified using photodensitometric analysis of visualised lipids with CuSO4/H3PO4., Results: Noradrenaline (10(-5) M) elicited a rapid increase in phosphatidic acid at 2 min, followed by a decrease at 5 min. A second delayed and sustained increase in phosphatidic acid occurred at 10 min. The response to noradrenaline (10(-9) to 10(-5) M) was concentration dependent with a half maximum response (EC50) of 3.1 x 10(-8) M and the maximum effect at 10(-6) M. The increase in phosphatidic acid production in response to noradrenaline was abolished by an alpha 1 adrenergic receptor blocking agent (2-[beta-(4-hydroxyphenyl)-ethylaminomethyl]tetralone) but unaffected by the beta adrenergic blocking agent L-propranolol. An increase in phosphatidic acid was also elicited in rabbit ventricular myocytes in response to endothelin-1. The response was time and concentration dependent with the maximal increase at 12 min, EC50 5.3 x 10(-9) M, and maximum effect at 10(-6) M. Both noradrenalin and endothelin-1 stimulated phosphatidylbutanol production in the presence of butanol (100 mM), indicating that both agonists activate phospholipase D., Conclusions: Noradrenaline at physiological concentrations elicits both a rapid and a delayed increase in phosphatidic acid in adult rabbit ventricular myocytes. Endothelial-1, at physiological concentrations, also stimulates an increase in the mass of phosphatidic acid in myocytes, but the increase induced by endothelin-1 is monophasic, in contrast to the biphasic response seen during stimulation with noradrenaline. Activation of phospholipase D contributes to the increase in phosphatidic acid seen during stimulation of myocytes with either noradrenaline or endothelin-1. These are the first data to characterise endogenous production of phosphatidic acid in isolated adult ventricular myocytes.

Objective: The aims were (1) to determine whether thrombin, which is increased in the presence of coronary thrombosis, can directly stimulate the production of lysophosphatidylcholine, which has arrhythmogenic properties, in ventricular myocytes; (2) whether the effect is dependent upon extracellular [Ca2+]; and (3) whether it is mediated directly through stimulation of the thrombin receptor., Methods: Lipids were extracted from isolated adult rabbit ventricular myocytes and lysophosphatidylcholine was isolated by HPLC and quantified using a recently developed radiometric assay employing 3H-acetic anhydride., Results: Thrombin (0.05 U.ml-1) stimulation of ventricular myocytes resulted in a nearly sixfold increase in lysophosphatidylcholine levels [0.26(SEM 0.03) to 1.61(0.42) nmol.mg-1 protein] within 1 min. The increase in myocytic lysophosphatidylcholine content was prevented by preincubation of thrombin with the proteolytic site inhibitors phenyly-prolyl-arginyl-chloromethyl ketone (PPACK) and dansylarginine N-(3-ethyl-1,5-pentanediyl)amide. The increase in lysophosphatidylcholine content in response to thrombin was not present at an extracellular calcium concentration ([Ca2+)]o) = 500 microM, but was marked at a physiological level of [Ca2+]o = 1.8 mM. Stimulation of myocytes with the thrombin receptor activating peptide SFLLRNPNDKYEPF (100 microM for 1 min) resulted in a similar increase in lysophosphatidylcholine content [1.61(0.27) nmol.mg-1 protein]., Conclusions: The marked increase in lysophosphatidylcholine content in cardiac myocytes in response to thrombin has important implications as an arrhythmogenic mechanism during early myocardial ischaemia.

The cellular content of phosphatidic acid can increase in response to several agonists either by phosphorylation of diacylglycerol after phospholipase C-catalyzed hydrolysis of phospholipids or directly through activation of phospholipase D. Although previous findings indicated that the generation of phosphatidic acid was exclusively a means of regulation of the cellular concentration of diacylglycerol, more recent studies have indicated that phosphatidic acid may also directly regulate several cellular functions. Accordingly, the present study was performed to assess whether phosphatidic acid could stimulate cardiac phospholipase C in intact adult rabbit ventricular myocytes. The mass of inositol 1,4,5-trisphosphate [Ins (1,4,5)P3] was determined by a specific and sensitive binding protein assay and by direct mass measurement using anion exchange chromatography for separation of selected inositol phosphates and gas chromatography and mass spectrometry for quantification of inositol monophosphate (IP1), inositol bisphosphate (IP2), inositol trisphosphate (IP3), and inositol tetrakisphosphate (IP4). Phosphatidic acid (10(-9)-10(-6) M) elicited a rapid concentration-dependent increase in Ins (1,4,5)P3 accumulation, with the peak fourfold to fivefold increase at 30 seconds of stimulation; the concentration required for 50% of maximal stimulation was 4.4 x 10(-8) M. The time course of individual inositol phosphates indicated a successive increase in the mass of IP3, IP4, IP2, and IP1 in response to stimulation with phosphatidic acid. The production of Ins (1,4,5)P3 in response to phosphatidic acid was not altered in the absence of extracellular calcium or in the presence of extracellular EGTA (10(-3) M). Thus, these findings indicate that phosphatidic acid is a potent activator of inositol phosphate production in adult ventricular myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial synthesis of phosphatidylinositol 4,5-bisphosphate (PIP2) is highly compartmentalized in the sarcolemmal membrane. Sarcolemmal vesicles contain endogenous phospholipase C (PLC), but the identity of sarcolemmal PLC and its relationship to soluble PLC have not been determined previously. Sarcolemmal and cytosolic PLC were prepared from canine myocardium and characterized by DEAE-cellulose chromatography and by immunoblotting with monoclonal and polyclonal antibodies to isoenzymes of PLC (PLC beta, PLC gamma, and PLC delta). DEAE-cellulose chromatography resolved two forms of cytosolic PLC that were identified as an 85-kDa form of PLC delta and a 145-kDa form of PLC gamma. In contrast, DEAE-cellulose chromatography resolved a single form of sarcolemmal PLC that was identified as an 85-kDa form of PLC delta. These data demonstrate that PLC gamma and PLC delta are expressed in canine myocardium and that an 85-kDa form of PLC delta is selectively associated with sites of PIP2 synthesis in a highly enriched preparation of sarcolemma. These data do not exclude the existence of additional isoenzymes of sarcolemmal PLC that may have been removed during isolation of sarcolemmal membranes.

Compartmentation of phosphoinositide synthesis and transfer of endogenous phosphatidylinositol (PI) were characterized in membrane fractions prepared from rabbit myocardium. De novo synthesis of PI was highly enriched in free sarcoplasmic reticulum (551 pmol.mg-1. min-1) compared with that in sarcolemma (26.8 pmol.mg-1. min-1) and junctional sarcoplasmic reticulum (178 pmol.mg-1. min-1). In contrast, PI phosphorylation was highly enriched in sarcolemma (2.69 nmol.mg-1.min-1) compared with that in free sarcoplasmic reticulum (0.22 nmol.mg-1.min-1) and junctional sarcoplasmic reticulum (0.38 nmol.mg-1.min-1). Phosphorylation of endogenous phosphatidylinositol 4-phosphate to phosphatidylinositol 4,5-bisphosphate was also enriched in sarcolemma (38.5 pmol.mg-1.min-1) compared with that in free sarcoplasmic reticulum (less than 5.0 pmol.mg-1.min-1) and junctional sarcoplasmic reticulum (6.5 pmol.mg-1.min-1). Transfer of endogenous PI was characterized as a mechanism to overcome compartmentation of PI synthesis in cardiac membranes. A 29-kDa PI transfer protein was purified 1,500-fold from cytosol of rabbit myocardium. Both cytosol and purified PI transfer protein catalyzed the transfer of endogenous PI from microsomal sites of synthesis to sarcolemma. In conclusion, synthesis of PI is highly enriched in free sarcoplasmic reticulum, whereas phosphorylation of phosphoinositides is highly enriched in sarcolemma. A 29-kDa PI transfer protein in myocardial cytosol can mediate in vitro transfer of de novo-synthesized PI to the sarcolemma.

There is experimental and clinical evidence that i.v. injection of bovine testicular hyaluronidase (BTH) reduces the extent of necrosis during myocardial infarction. The fate of i.v. administered BTH has not been described. In this study, serum kinetics of BTH enzyme activity in dogs, rats and humans were determined. Tissue distribution of BTH was determined with an 125I-labeled preparation of purified BTH. Serum BTH activity initially decreased exponentially with half-life 2.0 +/- 0.1 min in dogs with coronary artery occlusion (n = 8; 500 U of BTH/kg); 3.2 min in humans with acute myocardial infarction (n = 2; 500 U of BTH/kg); and 3.2 +/- 0.3 min in rats (n = 5; 5,000 U of BTH/kg). In dogs BTH disappearance showed two distinct phases. After injection of high dose BTH (5,000 U of BTH/kg), during the first 7 min serum half-life of BTH was 2.1 +/- 0.2 min (n = 8), but increased to 9.4 min in later serum samples. After the injection of 125I-labeled BTH into the rat, protein-bound 125I disappeared from serum with a half-life (3.4 min) that is similar to the serum half-life of BTH enzyme activity (3.2 min). Twenty minutes after injection of 125I-labeled BTH, 30% of the label was recovered in the liver. It is concluded that BTH activity has a short serum half-life of less than 10 min in dogs, rats and humans. In the rat model, the disappearance of serum BTH activity results from physical removal of circulating BTH molecules rather than serum inhibition or inactivation of BTH enzymatic activity.

Bovine testicular hyaluronidase (BTH) reduces experimental myocardial infarct size and ameliorates electrocardiographic signs of ischemia. This study was done to determine if heparin, an in vitro inhibitor of hyaluronidase activity, blocks the action of BTH in the myocardium of dogs after coronary artery occlusion. BTH was administered intravenously as 5,000 NF units/kg at 0.5 and 2.5 hours after coronary occlusion. Heparin was administered intravenously as a 150-unit/kg loading dose, followed by 10 units/kg per hour i.v., beginning 15 minutes before coronary occlusion. The area of myocardial ischemia at risk was assessed by a radiolabeled microsphere technique; the area that developed necrosis was assessed by a histochemical technique. In vivo activity of BTH was assessed by a colorimetric analysis of the BTH substrate, i.e., hyaluronic acid (HA), extracted from myocardial tissue. For biochemical analysis of HA, the heart was divided into anterior myocardium, which included ischemic tissue and posterior nonischemic myocardium. The myocardial HA content of dogs treated with BTH plus heparin (anterior, 3.44 +/- 0.40 micrograms HA/mg protein; posterior, 3.69 +/- 0.33 micrograms HA/mg protein) was not significantly different from control (anterior, 3.61 +/- 0.29 micrograms HA/mg protein; posterior, 3.55 +/- 0.23 micrograms HA/mg protein). In contrast, BTH lowered myocardial HA content (anterior, 2.16 +/- 0.21 micrograms HA/mg protein; posterior, 2.08 +/- 0.14 micrograms HA/mg protein) compared with either BTH plus heparin or control groups in both anterior myocardium (p = 0.006) and posterior myocardium (p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphatidylinositol-specific phospholipase C was characterized in the soluble phase and in membrane fractions prepared from rabbit myocardium. Four subforms of soluble phospholipase C were identified and characterized. Activity of one subform was inhibited 80% when cardiolipin was present in substrate vesicles, whereas three subforms were stimulated 2- to 10-fold by cardiolipin. A cationic subform, molecular mass 67 kDa, was stimulated threefold when cardiolipin comprised 2% of the total phospholipid and fivefold when it comprised 12%. The major mechanism for the cardiolipin effect was a decrease in the apparent Michaelis constant (Km) of this subform for substrate. Competition experiments were consistent with binding of this subform to cardiolipin. Phospholipase C activity was present in mitochondrial, microsomal, and sarcolemmal membrane fractions that were essentially free of contamination by cytosol. Detection of membrane-associated phospholipase C was facilitated by cardiolipin. Thus rabbit myocardium contains multiple subforms of soluble phospholipase C that differ substantially in surface charge, molecular mass, and sensitivity to cardiolipin. Anionic phospholipids may be important determinants of intracellular distribution of phospholipase C in myocardial tissue.

Four previously healthy homosexual men contracted Pneumocystis carinii pneumonia, extensive mucosal candidiasis, and multiple viral infections. In three of the patients these infections followed prolonged fevers of unknown origin. In all four cytomegalovirus was recovered from secretions. Kaposi's sarcoma developed in one patient eight months after he presented with esophageal candidiasis. All patients were anergic and lymphopenic; they had no lymphocyte proliferative responses to soluble antigens, and their responses to phytohemagglutinin were markedly reduced. Monoclonal-antibody analysis of peripheral-blood T-cell subpopulations revealed virtual elimination of the Leu-3 / helper/inducer subset, an increased percentage of the Leu-2 + suppressor/cytoxic subset, and an increased percentage of cells bearing the thymocyte-associated antigen T10. The inversion of the T/ helper to suppressor/cytotoxic ratio suggested that cytomegalovirus infection was an important factor in the pathogenesis of the immunodeficient state. A high level of exposure of male homosexuals to cytomegalovirus-infected secretions may account for the occurrence of this immune deficiency.