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Background Reactions between nitric oxide ( NO), nitrite ( [ABSTRACT FROM AUTHOR]

Aim: To investigate the effect of increases in extracellular Ca2+ entry produced by the L-type Ca2+ channel agonist FPL-64176 (FPL) upon acute atrial arrhythmogenesis in intact Langendorff-perfused mouse hearts and its dependence upon diastolic Ca2+ release from sarcoplasmic reticular Ca2+ stores. Methods: Confocal microscope studies of Fluo-3 fluorescence in isolated atrial myocytes were performed in parallel with electrophysiological examination of Langendorff-perfused mouse hearts. Results: Atrial myocytes stimulated at 1 Hz and exposed to FPL (0.1 μm) initially showed (<10 min) frequent, often multiple, diastolic peaks following the evoked Ca2+ transients whose amplitudes remained close to control values. With continued pacing (>10 min) this reverted to a regular pattern of evoked transients with increased amplitudes but in which diastolic peaks were absent. Higher FPL concentrations (1.0 μm) produced sustained and irregular patterns of cytosolic Ca2+ activity, independent of pacing. Nifedipine (0.5 μm), and caffeine (1.0 mm) and cyclopiazonic acid (CPA) (0.15 μm) pre-treatments respectively produced immediate and gradual reductions in the F/ F0 peaks. Such nifedipine and caffeine, or CPA pre-treatments, abolished, or reduced, the effects of 0.1 and 1.0 μm FPL on cytosolic Ca2+ signals. FPL (1.0 μm) increased the incidence of atrial tachycardia and fibrillation in intact Langendorff-perfused hearts without altering atrial effective refractory periods. These effects were inhibited by nifedipine and caffeine, and reduced by CPA. Conclusion: Enhanced extracellular Ca2+ entry exerts acute atrial arrhythmogenic effects that is nevertheless dependent upon diastolic Ca2+ release. These findings complement reports that associate established, chronic, atrial arrhythmogenesis with decreased overall inward Ca2+ current. [ABSTRACT FROM AUTHOR]

This article explores the career aspirations of thirty individuals with severe psychiatric disabilities who had been employed from 3 to 33 years. We included people in the study who had been hospitalized as adults or had been determined eligible for Social Security Disability benefits due to a psychiatric disability and were currently employed for pay at least 18 hours per week. Some had received assistance from vocational rehabilitation agencies; others had not. Through in-depth interviews, we examined how they view career development and how they set and obtain their long term goals. We found that the sample fell into two groups based upon their attitudes about the future and their employment aspirations over the next five years. Group One, consisting of 17 participants, said they wanted to change jobs or move ahead in their careers and had developed strategies to obtain their specific employment or career goals. The remaining 13 participants, those in Group Two, wanted to remain in the same position or obtain a similar job. We describe the factors Group One participants considered in establishing their career goals and the reasons why Group Two participants wanted to keep their current employment. [ABSTRACT FROM AUTHOR]

Persons who are blind or have low vision face special challenges in obtaining care that is safe, effective, timely, and patient centered. To explore perceptions of care and recommendations for improvements, we conducted 8 interviews with experts and 2 focus groups with 19 persons, all of whom are blind or have low vision. Interviewees perceived that they confront special barriers to care because of being blind or having low vision. Barriers fell into 4 broad categories: basic respect, including concerns about physicians thinking they cannot participate fully in their own care; communication barriers, including difficulties interacting with physicians and office staff; physical access barriers, including difficulties getting to and around physicians' offices; and information barriers, including receiving written materials in inaccessible formats (eg, not in Braille, large print, or audiotape). Using common courtesy and individualized communication techniques, physicians and office staff could improve health care experiences of blind and low-vision patients. [ABSTRACT FROM AUTHOR]

This article presents findings from a comprehensive evaluation of Title VII, Chapter 1, Part C of the Centers for Independent Living (CIL) program funded by the Rehabilitation Services Administration (RSA). These 2001 study results are based upon interviews with 569 consumers about their experiences at CILs. We asked consumers about services received, knowledge or skills gained, and changes in their lives they attributed to the CIL. We also asked consumers about the extent to which they decided upon the services they would receive. This study found that CILs are providing a wide variety of beneficial services and advocacy in their communities. Consumers report a high level of satisfaction with the services they receive and report significant life changes as a result of CIL services. Only 56% of consumers stated that they decided on the services they would receive either by themselves or in conjunction with another staff person. Centers should take steps to insure that consumers are empowered to make or have a voice in decisions about the independent living services they receive. [ABSTRACT FROM AUTHOR]

Aim To investigate the effect of increases in extracellular Ca2+ entry produced by the L-type Ca2+ channel agonist FPL-64176 (FPL) upon acute atrial arrhythmogenesis in intact Langendorff-perfused mouse hearts and its dependence upon diastolic Ca2+ release from sarcoplasmic reticular Ca2+ stores. Methods: Confocal microscope studies of Fluo-3 fluorescence in isolated atrial myocytes were performed in parallel with electrophysiological examination of Langendorff-perfused mouse hearts. Results: Atrial myocytes stimulated at 1 Hz and exposed to FPL (0.1 μm) initially showed (<10 min) frequent, often multiple, diastolic peaks following the evoked Ca2+ transients whose amplitudes remained close to control values. With continued pacing (>10 min) this reverted to a regular pattern of evoked transients with increased amplitudes but in which diastolic peaks were absent. Higher FPL concentrations (1.0 μm) produced sustained and irregular patterns of cytosolic Ca2+ activity, independent of pacing. Nifedipine (0.5 μm), and caffeine (1.0 mm) and cyclopiazonic acid (CPA) (0.15 μm) pre-treatments respectively produced immediate and gradual reductions in the F/F0 peaks. Such nifedipine and caffeine, or CPA pre-treatments, abolished, or reduced, the effects of 0.1 and 1.0 μm FPL on cytosolic Ca2+ signals. FPL (1.0 μm) increased the incidence of atrial tachycardia and fibrillation in intact Langendorff-perfused hearts without altering atrial effective refractory periods. These effects were inhibited by nifedipine and caffeine, and reduced by CPA. Conclusion: Enhanced extracellular Ca2+ entry exerts acute atrial arrhythmogenic effects that is nevertheless dependent upon diastolic Ca2+ release. These findings complement reports that associate established, chronic, atrial arrhythmogenesis with decreased overall inward Ca2+ current.

A collection of 113 Streptococcus strains from supragingival dental plaque of caries-free individuals were recently tested in vitro for direct antagonism of the dental caries pathogen Streptococcus mutans , and for their capacity for arginine catabolism via the arginine deiminase system (ADS). To advance their evaluation as potential probiotics, twelve strains of commensal oral streptococci with various antagonistic and ADS potentials were assessed in a mouse model for oral (i.e., oral mucosal pellicles and saliva) and dental colonization under four diets (healthy or high-sucrose, with or without prebiotic arginine). Colonization by autochthonous bacteria was also monitored. One strain failed to colonize, whereas oral colonization by the other eleven strains varied by 3 log units. Dental colonization was high for five strains regardless of diet, six strains increased colonization with at least one high-sucrose diet, and added dietary arginine decreased dental colonization of two strains. Streptococcus sp. A12 (high in vitro ADS activity and antagonism) and two engineered mutants lacking the ADS (Δ arcADS ) or pyruvate oxidase-mediated H 2 O 2 production (Δ spxB ) were tested for competition against S. mutans UA159. A12 wild type and Δ arcADS colonized only transiently, whereas Δ spxB persisted, but without altering oral or dental colonization by S. mutans In testing four additional candidates, S. sanguinis BCC23 markedly attenuated S. mutans' oral and dental colonization, enhanced colonization of autochthonous bacteria, and decreased severity of smooth surface caries under highly cariogenic conditions. Results demonstrate the utility of the mouse model to evaluate potential probiotics, revealing little correlation between in vitro antagonism and competitiveness against S. mutans in vivo IMPORTANCE Our results demonstrate in vivo testing of potential oral probiotics can be accomplished and can yield information to facilitate the ultimate design and optimization of novel anti-caries probiotics. We show human oral commensals associated with dental health are an important source of potential probiotics that may be used to colonize patients under dietary conditions of highly varying cariogenicity. Assessment of competitiveness against dental caries pathogen Streptococcus mutans and impact on caries identified strains or genetic elements for further study. Results also uncovered strains that enhanced oral and dental colonization by autochthonous bacteria when challenged with S. mutans , suggesting cooperative interactions for future elucidation. Distinguishing a rare strain that effectively compete with S. mutans under conditions that promote caries further validates our systematic approach to more critically evaluate probiotics for use in humans., (Copyright © 2020 Culp et al.)

This report describes the development of the first national undergraduate interprofessional standardized curriculum in chronic disease prevention for healthcare professionals in the Republic of Ireland. This project brought together for the first time all higher education institutions nationwide in a novel collaboration with the national health service i.e. the Health Service Executive (HSE), to develop a standardized national curriculum for undergraduate health care professions. The curriculum sits within the framework of Making Every Contact Count, the goal of which is to re-orientate health services to embed the ethos of prevention through lifestyle behavior change as part of the routine care of health professionals. The core focus of Making Every Contact Count is chronic disease prevention, targeting four main lifestyle risk factors for chronic disease; tobacco use, alcohol consumption, physical inactivity and unhealthy eating. Making Every Contact Count is a key component of Healthy Ireland, the Irish national framework for health and wellbeing. The aim of the curriculum is to prepare newly qualified health professionals with the skills needed to support patients to achieve lifestyle behavior change delivered as part of routine clinical care.

The IL-17 family cytokines IL-17A and IL-17C drive the pathogenesis of psoriatic skin inflammation, and anti-IL-17A Abs were recently approved to treat human psoriasis. Little is known about mechanisms that restrain IL-17 cytokine-mediated signaling, particularly IL-17C. In this article, we show that the endoribonuclease MCP-1-induced protein 1 (MCPIP1; also known as regnase-1) is markedly upregulated in human psoriatic skin lesions. Similarly, MCPIP1 was overexpressed in the imiquimod (IMQ)-driven mouse model of cutaneous inflammation. Mice with an MCPIP1 deficiency (Zc3h12a +/- ) displayed no baseline skin inflammation, but they showed exacerbated pathology following IMQ treatment. Pathology in Zc3h12a +/- mice was associated with elevated expression of IL-17A- and IL-17C-dependent genes, as well as with increased accumulation of neutrophils in skin. However, IL-17A and IL-17C expression was unaltered, suggesting that the increased inflammation in Zc3h12a +/- mice was due to enhanced downstream IL-17R signaling. Radiation chimeras demonstrated that MCPIP1 in nonhematopoietic cells is responsible for controlling skin pathology. Moreover, Zc3h12a +/- Il17ra -/- mice given IMQ showed almost no disease. To identify which IL-17RA ligand was essential, Zc3h12a +/- Il17a -/- and Zc3h12a +/- Il17c -/- mice were given IMQ; these mice had reduced but not fully abrogated pathology, indicating that MCPIP1 inhibits IL-17A and IL-17C signaling. Confirming this hypothesis, Zc3h12a -/- keratinocytes showed increased responsiveness to IL-17A and IL-17C stimulation. Thus, MCPIP1 is a potent negative regulator of psoriatic skin inflammation through IL-17A and IL-17C. Moreover, to our knowledge, MCPIP1 is the first described negative regulator of IL-17C signaling., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Background: Inappropriate use of antibiotics for viral upper respiratory infections (URI) directly contributes to antibiotic resistance. Educational interventions reduce antibiotic prescriptions written for viral (URI) symptoms and antibiotic resistance. Objective: This study aims to ascertain whether provider education will reduce antibiotic prescriptions. The study also aims to change provider prescribing practices through education on antibiotic resistance. Methods: Simple random sampling was used to review charts of patients pre- and postintervention in a single provider primary care practice for patients aged 18-64 years with URI diagnosis and/or symptoms. Results: Preintervention, 85% received an antibiotic for URI symptoms compared to 79% in the postintervention group ( p = .514). Chi-square analysis comparing the 2 groups indicated there was no statistical significance between the proportion of antibiotics prescribed within these timeframes ( p = .58). Conclusion: Morbidity and mortality will continue to increase without aggressive antibiotic stewardship. Although the results did not reach statistical significance, there was still a 6% reduction in the amount of antibiotics prescribed by the single provider. The decrease, albeit small, has the potential for clinical significance, and further studies should be pursued.

Recent advances in electrocardiographic monitoring and waveform analysis have significantly improved the ability to detect drug-induced changes in cardiac repolarization manifested as changes in the QT/corrected QT interval. These advances have also improved the ability to detect drug-induced changes in cardiac conduction. This White Paper summarizes current opinion, reached by consensus among experts at the Cardiac Safety Research Consortium, on the assessment of electrocardiogram-based safety measurements of the PR and QRS intervals, representing atrioventricular and ventricular conduction, respectively, during drug development., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Development of pediatric medications and devices is complicated by differences in pediatric physiology and pathophysiology (both compared with adults and within the pediatric age range), small patient populations, and practical and ethical challenges to designing clinical trials. This article summarizes the discussions that occurred at a Cardiac Safety Research Consortium-sponsored Think Tank convened on December 10, 2010, where members from academia, industry, and regulatory agencies discussed important issues regarding pediatric cardiovascular safety of medications and cardiovascular devices. Pediatric drug and device development may use adult data but often requires additional preclinical and clinical testing to characterize effects on cardiac function and development. Challenges in preclinical trials include identifying appropriate animal models, clinically relevant efficacy end points, and methods to monitor cardiovascular safety. Pediatric clinical trials have different ethical concerns from adult trials, including consideration of the subjects' families. Clinical trial design in pediatrics should assess risks and benefits as well as incorporate input from families. Postmarketing surveillance, mandated by federal law, plays an important role in both drug and device safety assessment and becomes crucial in the pediatric population because of the limitations of premarketing pediatric studies. Solutions for this wide array of issues will require collaboration between academia, industry, and government as well as creativity in pediatric study design. Formation of various epidemiologic tools including registries to describe outcomes of pediatric cardiac disease and its treatment as well as cardiac effects of noncardiovascular medications, should inform preclinical and clinical development and improve benefit-risk assessments for the patients. The discussions in this article summarize areas of emerging consensus and other areas in which consensus remains elusive and provide suggestions for additional research to further our knowledge and understanding of this topic., (Copyright © 2012 Mosby, Inc. All rights reserved.)