The Flt3-inhibitor quizartinib augments apoptosis and promotes maladaptive remodeling after myocardial infarction in mice.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) targeting fms-like tyrosine kinase 3 (Flt3) such as quizartinib were specifically designed for acute myeloid leukemia treatment, but also multi-targeting TKIs applied to solid tumor patients inhibit Flt3. Flt3 is expressed in the heart and its activation is cytoprotective in myocardial infarction (MI) in mice. OBJECTIVES: We sought to test whether Flt3-targeting TKI treatment aggravates cardiac injury after MI. METHODS AND RESULTS: Compared to vehicle, quizartinib (10 mg/kg/day, gavage) did not alter cardiac dimensions or function in healthy mice after four weeks of therapy. Pretreated mice were randomly assigned to MI or sham surgery while receiving quizartinib or vehicle for one more week. Quizartinib did not aggravate the decline in ejection fraction, but significantly enhanced ventricular dilatation one week after infarction. In addition, apoptotic cell death was significantly increased in the myocardium of quizartinib-treated compared to vehicle-treated mice. In vitro, quizartinib dose-dependently decreased cell viability in neonatal rat ventricular myocytes and in H9c2 cells, and increased apoptosis as assessed in the latter. Together with H2O2, quizartinib potentiated the phosphorylation of the pro-apoptotic mitogen activated protein kinase p38 and augmented H2O2-induced cell death and apoptosis beyond additive degree. Pretreatment with a p38 inhibitor abolished apoptosis under quizartinib and H2O2. CONCLUSION: Quizartinib potentiates apoptosis and promotes maladaptive remodeling after MI in mice at least in part via a p38-dependent mechanism. These findings are consistent with the multi-hit hypothesis of cardiotoxicity and make cardiac monitoring in patients with ischemic heart disease under Flt3- or multi-targeting TKIs advisable.

Defective Desmosomal Adhesion Causes Arrhythmogenic Cardiomyopathy by Involving an Integrin-αVß6/TGF-ß Signaling Cascade.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell-cell adhesion complex, but the underlying mechanisms are not well understood. In the current study, we investigated the relevance of defective desmosomal adhesion for ACM development and progression. METHODS: We mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 on the basis of structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell-cell dissociation assays and force spectroscopy measurements by atomic force microscopy. The DSG2-W2A knock-in mouse model was analyzed by echocardiography, ECG, and histologic and biomolecular techniques including RNA sequencing and transmission electron and superresolution microscopy. The results were compared with ACM patient samples, and their relevance was confirmed in vivo and in cardiac slice cultures by inhibitor studies applying the small molecule EMD527040 or an inhibitory integrin-αVß6 antibody. RESULTS: The DSG2-W2A mutation impaired binding on molecular level and compromised intercellular adhesive function. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function, and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVß6 and subsequent transforming growth factor-ß signaling as driver of cardiac fibrosis. Blocking integrin-αVß6 led to reduced expression of profibrotic markers and reduced fibrosis formation in mutant animals in vivo. CONCLUSIONS: We show that disruption of desmosomal adhesion is sufficient to induce a phenotype that fulfils the clinical criteria to establish the diagnosis of ACM, confirming the dysfunctional adhesion hypothesis. Deregulation of integrin-αVß6 and transforming growth factor-ß signaling was identified as a central step toward fibrosis. A pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM.

NOX1 mediates metabolic heart disease in mice and is upregulated in monocytes of humans with diastolic dysfunction.

AIMS: Microvascular inflammation plays an important role in the pathogenesis of diastolic dysfunction (DD) and metabolic heart disease. NOX1 is expressed in vascular and immune cells and has been implicated in the vascular pathology of metabolic disease. However, its contribution to metabolic heart disease is less understood. METHODS AND RESULTS: NOX1-deficient mice (KO) and male wild-type (WT) littermates were fed a high-fat high-sucrose diet (HFHS) and injected streptozotocin (75 mg/kg i.p.) or control diet (CTD) and sodium citrate. Despite similar weight gain and increase in fasting blood glucose and insulin, only WT-HFHS but not KO-HFHS mice developed concentric cardiac hypertrophy and elevated left ventricular filling pressure. This was associated with increased endothelial adhesion molecule expression, accumulation of Mac-2-, IL-1ß-, and NLRP3-positive cells and nitrosative stress in WT-HFHS but not KO-HFHS hearts. Nox1 mRNA was solidly expressed in CD45+ immune cells isolated from healthy mouse hearts but was negligible in cardiac CD31+ endothelial cells. However, in vitro, Nox1 expression increased in response to lipopolysaccharide (LPS) in endothelial cells and contributed to LPS-induced upregulation of Icam-1. Nox1 was also upregulated in mouse bone marrow-derived macrophages in response to LPS. In peripheral monocytes from age- and sex-matched symptomatic patients with and without DD, NOX1 was significantly higher in patients with DD compared to those without DD. CONCLUSIONS: NOX1 mediates endothelial activation and contributes to myocardial inflammation and remodelling in metabolic disease in mice. Given its high expression in monocytes of humans with DD, NOX1 may represent a potential target to mitigate heart disease associated with DD.

Fms-like tyrosine kinase 3 is a regulator of the cardiac side population in mice.

Fms-like tyrosine kinase 3 (Flt3) is a regulator of hematopoietic progenitor cells and a target of tyrosine kinase inhibitors. Flt3-targeting tyrosine kinase inhibitors can have cardiovascular side effects. Flt3 and its ligand (Flt3L) are expressed in the heart, but little is known about their physiological functions. Here, we show that cardiac side population progenitor cells (SP-CPCs) from mice produce and are responsive to Flt3L. Compared with wild-type, flt3L-/- mice have less SP-CPCs with less contribution of CD45-CD34+ cells and lower expression of genes related to epithelial-to-mesenchymal transition, cardiovascular development and stem cell differentiation. Upon culturing, flt3L-/- SP-CPCs show increased proliferation and less vasculogenic commitment, whereas Akt phosphorylation is lower. Notably, proliferation and differentiation can be partially restored towards wild-type levels in the presence of alternative receptor tyrosine kinase-activating growth factors signaling through Akt. The lower vasculogenic potential of flt3L-/- SP-CPCs reflects in decreased microvascularisation and lower systolic function of flt3L-/- hearts. Thus, Flt3 regulates phenotype and function of murine SP-CPCs and contributes to cellular and molecular properties that are relevant for their cardiovasculogenic potential.

Professional exhaustion, quality and intentions among family health nurses.

OBJECTIVE: to analyze how family health nurses assess quality of care; check if they have any intention of leaving their current job and nursing; estimate prevalence of professional exhaustion; and correlate these variables. METHOD: cross-sectional and correlational study with 198 nurses. The Maslach Burnout Inventory was applied, as it has questions for characterizing nurses, assessing perception on quality of care and of material and human resources, and verifying intention of leaving current work and nursing. RESULTS: most nurses assess quality of care as good, 28.0% present emotional exhaustion, there is intention of leaving current work and nursing. CONCLUSIONS: family health nurses experience professional exhaustion, which in turn presents correlation with decreased quality of care and increased intentions of leaving current work and nursing.

Professional exhaustion, quality and intentions among family health nurses / Agotamiento profesional, calidad e intenciones entre enfermeros de salud de la familia / Esgotamento profissional, qualidade e intenções entre enfermeiros de saúde da família

ABSTRACT Objective: to analyze how family health nurses assess quality of care; check if they have any intention of leaving their current job and nursing; estimate prevalence of professional exhaustion; and correlate these variables. Method: cross-sectional and correlational study with 198 nurses. The Maslach Burnout Inventory was applied, as it has questions for characterizing nurses, assessing perception on quality of care and of material and human resources, and verifying intention of leaving current work and nursing. Results: most nurses assess quality of care as good, 28.0% present emotional exhaustion, there is intention of leaving current work and nursing. Conclusions: family health nurses experience professional exhaustion, which in turn presents correlation with decreased quality of care and increased intentions of leaving current work and nursing.

RESUMEN Objetivo: analizar como enfermeros de salud de la familia evalúan la calidad del cuidado; verificar si tienen intención de dejar el trabajo actual y la enfermería; estimar la prevalencia de agotamiento profesional y correlacionar variables. Método: estudio transversal y correlacional con 198 enfermeros. Se utilizó el Maslach Burnout Inventory, cuestiones para caracterizar a los enfermeros, para evaluar percepción sobre la calidad del cuidado y de recursos materiales y humanos, así como para verificar intenciones de dejar el trabajo actual y la enfermería. Resultados: la mayoría de los enfermeros evalúa la calidad del cuidado como buena, el 28,0% presenta agotamiento emocional, con intención de dejar el trabajo actual y la enfermería. Conclusión: enfermeros de salud de la familia experimentan agotamiento profesional que presenta correlación con disminución de la calidad del cuidado y con aumento de las intenciones de dejar el trabajo actual y la enfermería.

RESUMO Objetivo: analisar como enfermeiros de saúde da família avaliam qualidade do cuidado; verificar se têm intenção de deixar o trabalho atual e a enfermagem; estimar prevalência de esgotamento profissional e correlacionar variáveis. Método: estudo transversal e correlacional com 198 enfermeiros. Foi utilizado o Maslach Burnout Inventory, questões para caracterizar os enfermeiros, para avaliar percepção sobre a qualidade do cuidado e de recursos materiais e humanos e para verificar intenções de deixar o trabalho atual e a enfermagem. Resultados: a maioria dos enfermeiros avalia a qualidade do cuidado como boa, 28,0% apresenta exaustão emocional, há intenção de deixar o trabalho atual e a enfermagem. Conclusão: enfermeiros de saúde da família vivenciam esgotamento profissional que apresenta correlação com diminuição da qualidade do cuidado e com aumento das intenções de deixar o trabalho atual e a enfermagem.

Polo-Like Kinase 2 is Dynamically Regulated to Coordinate Proliferation and Early Lineage Specification Downstream of Yes-Associated Protein 1 in Cardiac Progenitor Cells.

BACKGROUND: Recent studies suggest that adult cardiac progenitor cells (CPCs) can produce new cardiac cells. Such cell formation requires an intricate coordination of progenitor cell proliferation and commitment, but the molecular cues responsible for this regulation in CPCs are ill defined. METHODS AND RESULTS: Extracellular matrix components are important instructors of cell fate. Using laminin and fibronectin, we induced two slightly distinct CPC phenotypes differing in proliferation rate and commitment status and analyzed the early transcriptomic response to CPC adhesion (<2 hours). Ninety-four genes were differentially regulated on laminin versus fibronectin, consisting of mostly downregulated genes that were enriched for Yes-associated protein (YAP) conserved signature and TEA domain family member 1 (TEAD1)-related genes. This early gene regulation was preceded by the rapid cytosolic sequestration and degradation of YAP on laminin. Among the most strongly regulated genes was polo-like kinase 2 (Plk2). Plk2 expression depended on YAP stability and was enhanced in CPCs transfected with a nuclear-targeted mutant YAP. Phenotypically, the early downregulation of Plk2 on laminin was succeeded by lower cell proliferation, enhanced lineage gene expression (24 hours), and facilitated differentiation (3 weeks) compared with fibronectin. Finally, overexpression of Plk2 enhanced CPC proliferation and knockdown of Plk2 induced the expression of lineage genes. CONCLUSIONS: Plk2 acts as coordinator of cell proliferation and early lineage commitment in CPCs. The rapid downregulation of Plk2 on YAP inactivation marks a switch towards enhanced commitment and facilitated differentiation. These findings link early gene regulation to cell fate and provide novel insights into how CPC proliferation and differentiation are orchestrated.

The environment of professional practice and Burnout in nurses in primary healthcare.

OBJECTIVES: to assess how nurses perceive autonomy, control over the environment, the professional relationship between nurses and physicians and the organizational support and correlate them with burnout, satisfaction at work, quality of work and the intention to quit work in primary healthcare. METHOD: cross-sectional and correlation study, using a sample of 198 nurses. The tools used were the Nursing Work Index Revised, Maslach Burnout Inventory and a form to characterize the nurses. To analyze the data, descriptive statistics were applied and Spearman's correlation coefficient was used. RESULTS: the nurses assessed that the environment is partially favorable for: autonomy, professional relationship and organizational support and that the control over this environment is limited. Significant correlations were evidenced between the Nursing Work Index Revised, Maslach Burnout Inventory and the variables: satisfaction at work, quality of care and the intent to quit the job. CONCLUSION: the nurses' perceptions regarding the environment of practice are correlated with burnout, satisfaction at work, quality of care and the intent to quit the job. This study provides support for the restructuring of work processes in the primary health care environment and for communication among the health service management, human resources and occupational health areas.

The environment of professional practice and Burnout in nurses in primary healthcare / O ambiente da prática profissional e Burnout em enfermeiros na atenção básica / El ambiente de la práctica profesional y el síndrome de burnout en enfermeros en la atención básica

OBJECTIVES: to assess how nurses perceive autonomy, control over the environment, the professional relationship between nurses and physicians and the organizational support and correlate them with burnout, satisfaction at work, quality of work and the intention to quit work in primary healthcare. METHOD: cross-sectional and correlation study, using a sample of 198 nurses. The tools used were the Nursing Work Index Revised, Maslach Burnout Inventory and a form to characterize the nurses. To analyze the data, descriptive statistics were applied and Spearman's correlation coefficient was used. RESULTS: the nurses assessed that the environment is partially favorable for: autonomy, professional relationship and organizational support and that the control over this environment is limited. Significant correlations were evidenced between the Nursing Work Index Revised, Maslach Burnout Inventory and the variables: satisfaction at work, quality of care and the intent to quit the job. CONCLUSION: the nurses' perceptions regarding the environment of practice are correlated with burnout, satisfaction at work, quality of care and the intent to quit the job. This study provides support for the restructuring of work processes in the primary health care environment and for communication among the health service management, human resources and occupational health areas. .

OBJETIVOS: avaliar percepções dos enfermeiros sobre autonomia, controle sobre o ambiente, relação profissional entre enfermeiro e médico e suporte organizacional e correlacioná-las com Burnout, satisfação no trabalho, qualidade do cuidado e intenção de deixar o trabalho, na atenção básica. MÉTODO: estudo transversal e correlacional, com amostra de 198 enfermeiros. Foram utilizados o Nursing Work Index Revised, o Inventário de Burnout de Maslach e uma ficha de caracterização do enfermeiro. Para análise dos dados, foi realizada estatística descritiva e utilizado o coeficiente de correlação de Spearman. RESULTADOS: os enfermeiros avaliaram que o ambiente é parcialmente favorável para: autonomia, relação profissional e suporte organizacional e que há pouco controle sobre o mesmo. Evidenciaram-se correlações significativas entre o Nursing Work Index Revised, o Inventário de Burnout de Maslach e as variáveis: satisfação no trabalho, qualidade de cuidado e intenção de deixar o trabalho. CONCLUSÃO: percepções dos enfermeiros acerca do ambiente da prática correlacionam-se com Burnout, satisfação no trabalho, qualidade do cuidado e intenção de deixar o trabalho. Este estudo fornece subsídios para reestruturação de processos de trabalho no ambiente da atenção básica e para comunicação entre as áreas de gestão de serviços de saúde, recursos humanos e saúde do trabalhador. .

OBJETIVOS: evaluar percepciones de los enfermeros sobre autonomía, control sobre el ambiente, relación profesional entre enfermero y médico y soporte organizacional y correlacionarlas con el síndrome de burnout, la satisfacción en el trabajo, la calidad del cuidado y la intención de dejar el trabajo, en la atención básica. MÉTODO: estudio transversal y de correlación, con muestra de 198 enfermeros. Fueron utilizados el Nursing Work Index Revised, el Inventario de Burnout de Maslach y una ficha de caracterización del enfermero. El análisis de los datos fue realizado con estadística descriptiva y se utilizó el coeficiente de correlación de Spearman. RESULTADOS: los enfermeros evaluaron que el ambiente es parcialmente favorable para: autonomía, relación profesional y soporte organizacional y que existe poco control sobre el mismo. Se evidenciaron correlaciones significativas entre el Nursing Work Index Revised, el Inventario de Burnout de Maslach y las variables: satisfacción en el trabajo, calidad del cuidado e intención de dejar el trabajo. CONCLUSIÓN: las percepciones de los enfermeros acerca del ambiente de la práctica se correlacionan con burnout, satisfacción en el trabajo, calidad del cuidado e intención de dejar el trabajo. Este estudio ofrece subsidios para la reestructuración de procesos de trabajo en el ambiente de la atención básica y para comunicación entre las áreas de administración de servicios de salud, recursos humanos y salud del trabajador. .

[Institutionalized elderly: chronological organization of daily routines and sleep quality]. / Idosos institucionalizados: organização cronológica das rotinas diárias e qualidade do sono.

This is a descriptive cross-sectional study, which aimed to identify the perception of nursing home elderly residents related to the chronological organization of their daily routines and to their sleep quality. The study was conducted with 37 elderly (14 women and 23 men, mean age of 75 years) who lived in a long term care facility located in the municipality of Campinas-SP, Brazil. The results showed that 81% of the elderlies had complaints compatible with poor sleep, but 70% of them reported that they had good sleep quality when directly questioned about it. All elderlies adequately realized the chronological organization of their routines, but this perception did not appear to contribute to the good sleep quality, as most of them had complaints compatible with poor sleep. It becomes evident that nurses should perform detailed assessment of sleep quality in order to minimize or prevent these problems and their possible consequences.

Idosos institucionalizados: organização cronológica das rotinas diárias e qualidade do sono / Institutionalized elderly: chronological organization of daily routines and sleep quality / Ancianos institucionalizados: cronológico organización de las rutinas diarias y la calidad del sueño

Estudo descritivo, transversal, cujo objetivo foi identificar a percepção de idosos institucionalizados quanto à organização cronológica das rotinas diárias e quanto à qualidade do sono. Participaram 37 indivíduos residentes em uma Instituição de Longa Permanência para Idosos pertencente ao município de Campinas-SP, sendo 14 mulheres e 23 homens, com média de idade de 75 anos. Verificou-se que 81% dos idosos apresentaram queixas compatíveis com sono de má qualidade, porém 70% deles informavam que tinham sono de boa qualidade, quando questionados diretamente a respeito. Todos os idosos perceberam adequadamente a organização cronológica de suas rotinas, porém essa percepção pareceu não contribuir para a boa qualidade do sono, visto que a maioria deles apresentou queixas compatíveis com sono de má qualidade. Torna-se evidente que os enfermeiros devem realizar avaliação detalhada da qualidade do sono a fim de minimizar ou prevenir esses problemas e suas possíveis consequências.

This is a descriptive cross-sectional study, which aimed to identify the perception of nursing home elderly residents related to the chronological organization of their daily routines and to their sleep quality. The study was conducted with 37 elderly (14 women and 23 men, mean age of 75 years) who lived in a long term care facility located in the municipality of Campinas-SP, Brazil. The results showed that 81% of the elderlies had complaints compatible with poor sleep, but 70% of them reported that they had good sleep quality when directly questioned about it. All elderlies adequately realized the chronological organization of their routines, but this perception did not appear to contribute to the good sleep quality, as most of them had complaints compatible with poor sleep. It becomes evident that nurses should perform detailed assessment of sleep quality in order to minimize or prevent these problems and their possible consequences.

Estudio descriptivo, transversal, cuyo objetivo fue identificar la percepción de ancianos institucionalizados acerca de la organización cronológica de las rutinas diarias y la calidad de su sueño. Participaron en este estudio 37 ancianos (14 mujeres y 23 hombres con una edad promedia de 75 años) de un establecimiento de longa estadía para ancianos, en el municipio de Campinas-SP, Brasil. Se encontró que el 81% de los ancianos tenían quejas compatibles con sueño de mala calidad, pero el 70% de ellos informaron tener sueño de buena calidad cuando se les preguntó directamente. Los ancianos reconocían adecuadamente la organización cronológica de sus rutinas, pero esta percepción no parecía contribuir a la buena calidad del sueño, pues la mayoría tenía quejas compatibles con mala calidad. Se hace evidente que las enfermeras deben realizar una evaluación detallada de la calidad del sueño buscando minimizar o evitar estos problemas y sus posibles consecuencias.

FLT3 activation improves post-myocardial infarction remodeling involving a cytoprotective effect on cardiomyocytes.

OBJECTIVES: The goal of this study was to define the role of FMS-like tyrosine kinase 3 (FLT3) in the heart. BACKGROUND: FLT3 is a prominent target of receptor tyrosine kinase inhibitors (TKIs) used for anticancer therapy. TKIs can cause cardiomyopathy but understanding of the mechanisms is incomplete, partly because the roles of specific TKI target receptors in the heart are still obscure. METHODS: Myocardial infarction was induced in mice by permanent ligation of the left anterior descending coronary artery followed by intramyocardial injection of FLT3 ligand (FL) or vehicle into the infarct border zone. Cardiac morphology and function were assessed by echocardiography and histological analysis 1 week after infarction. In addition, FLT3 expression and regulation, as well as molecular mechanisms of FLT3 action, were examined in cardiomyocytes in vitro. RESULTS: The intramyocardial injection of FL into the infarct border zone decreased infarct size and ameliorated post-myocardial infarction remodeling and function in mice. This beneficial effect was associated with reduced apoptosis, including myocytes in the infarct border zone. Cardiomyocytes expressed functional FLT3, and FLT3 messenger ribonucleic acid and protein were up-regulated under oxidative stress, identifying cardiomyocytes as FL target cells. FLT3 activation with FL protected cardiomyocytes from oxidative stress-induced apoptosis via an Akt-dependent mechanism involving Bcl-2 family protein regulation and inhibition of the mitochondrial death pathway. CONCLUSIONS: FLT3 is a cytoprotective system in the heart and a potential therapeutic target in ischemic cardiac injury. The protective mechanisms uncovered here may be further explored in view of potential cardiotoxic effects of FLT3-targeting anticancer therapy, particularly in patients with ischemic heart disease.

NOX2-derived reactive oxygen species are crucial for CD29-induced pro-survival signalling in cardiomyocytes.

AIMS: The highly expressed cell adhesion receptor CD29 (ß(1)-integrin) is essential for cardiomyocyte growth and survival, and its loss of function causes severe heart disease. However, CD29-induced signalling in cardiomyocytes is ill defined and may involve reactive oxygen species (ROS). A decisive source of cardiac ROS is the abundant NADPH oxidase (NOX) isoform NOX2. Because understanding of NOX-derived ROS in the heart is still poor, we sought to test the role of ROS and NOX in CD29-induced survival signalling in cardiomyocytes. METHODS AND RESULTS: In neonatal rat ventricular myocytes, CD29 activation induced intracellular ROS formation (oxidative burst) as assessed by flow cytometry using the redox-sensitive fluorescent dye dichlorodihydrofluorescein diacetate. This burst was inhibited by apocynin and diphenylene iodonium. Further, activation of CD29 enhanced NOX activity (lucigenin-enhanced chemiluminescence) and activated the MEK/ERK and PI3K/Akt survival pathways. CD29 also induced phosphorylation of the inhibitory Ser9 on the pro-apoptotic kinase glycogen synthase kinase-3ß in a PI3K/Akt- and MEK-dependent manner, and improved cardiomyocyte viability under conditions of oxidative stress. The ROS scavenger MnTMPyP or adenoviral co-overexpression of the antioxidant enzymes superoxide dismutase and catalase inhibited CD29-induced pro-survival signalling. Further, CD29-induced protective pathways were lost in mouse cardiomyocytes deficient for NOX2 or functional p47(phox), a regulatory subunit of NOX. CONCLUSION: p47(phox)-dependent, NOX2-derived ROS are mandatory for CD29-induced pro-survival signalling in cardiomyocytes. These findings go in line with a growing body of evidence suggesting that ROS can be beneficial to the cell and support a crucial role for NOX2-derived ROS in cell survival in the heart.

ß1-Integrin is up-regulated via Rac1-dependent reactive oxygen species as part of the hypertrophic cardiomyocyte response.

ß(1)-Integrin mediates cardiomyocyte growth and survival and its proper regulation is essential for the structural and functional integrity of the heart. ß(1)-Integrin expression is enhanced in hypertrophy, but the mechanism and significance of its up-regulation are unknown. Because reactive oxygen species (ROS) are important mediators of myocardial remodeling we examined their role in regulated ß(1)-integrin expression. Hypertrophy was induced in neonatal cardiomyocytes by endothelin-1 (ET-1), which activated the regulatory NADPH oxidase subunit Rac1, evoked ROS, and enhanced fetal gene expression and cardiomyocyte size. ET-1 also enhanced cell adhesion and FAK phosphorylation and inhibited oxidative stress-induced cardiomyocyte apoptosis. Further, ET-1 increased ß(1)-integrin mRNA and protein expression via Rac1-ROS-dependent MEK/ERK and EGF receptor-PI3K/Akt activation as shown by adenoviral dominant-negative Rac1 or overexpression of copper/zinc-superoxide dismutase. The relevance of regulated ß(1)-integrin expression was examined in cardiomyocytes, in which targeting siRNA impeded the ET-1-induced ß(1)-integrin up-regulation. In these cells, ET-1-induced cell adhesion, FAK phosphorylation, and hypertrophic response were significantly blunted, whereas its antiapoptotic effect was predominantly unchanged, suggesting at least partial dissociation of prohypertrophic and prosurvival signaling elicited by ET-1. In conclusion, ß(1)-integrin up-regulation in response to ET-1 is mediated via Rac1-ROS-dependent activation of prohypertrophic pathways and is mandatory for ET-1-induced FAK activation, cell adhesion, and hypertrophic response.

Burnout and Stress Among Nurses in a University Tertiary Hospital / Burnout e estresse em enfermeiros de um hospital universitário de alta complexidade / Burnout y estrés en enfermeros de un hospital universitario de alta complejidad

This cross-sectional, analytical and correlational study investigated the existence of Burnout based on a sample of 149 nurses of a university tertiary hospital from October to December 2008 and correlate Burnout with stressors in the hospital work environment. The Maslach Burnout Inventory, the Nurses’ Stress Inventory and a questionnaire to characterize the subjects were applied. The results indicated the presence of Burnout in 7.3 percent of nurses (quartile) and 10.22 percent (tercile), and also a correlation among the inventories’ domains. Vulnerability to this type of illness among nurses was increased by stress experienced in the work environment.

Estudo transversal, analítico e correlacional que objetivou investigar a existência de Burnout em amostra de 149 enfermeiros de um hospital universitário de alta complexidade, no período de outubro a dezembro de 2008, correlacionando-o com estressores do ambiente de trabalho hospitalar. Foram aplicados o inventário de Burnout de Maslach, o inventário de estresse em enfermeiros e uma ficha de caracterização dos sujeitos. Os resultados indicaram a presença das três dimensões sugestivas de Burnout em 7,3 por cento dos enfermeiros (quartil) e 10,22 por cento (tercil), bem como a correlação entre domínios dos inventários. A vulnerabilidade para esse tipo de adoecimento em enfermeiros foi potencializada pela vivência de estresse no ambiente de trabalho.

Se trata de un estudio transversal, analítico y de correlación que tuvo por objetivo investigar la existencia de Burnout en una muestra de 149 enfermeros de un hospital universitario de alta complejidad, en el período de octubre a diciembre de 2008, correlacionándolo con factores de estrés del ambiente de trabajo hospitalario. Fueron aplicados el Inventario de Burnout de Maslach, el Inventario de Estrés en Enfermeros y una ficha de caracterización de los sujetos. Los resultados indicaron la presencia de las tres dimensiones indicativas de Burnout en 7,3 por ciento de los enfermeros (cuartil) y 10,22 por ciento (tercil), así como la correlación entre dominios de los inventarios. La vulnerabilidad para ese tipo de enfermedad, en enfermeros, fue potencializada por la existencia de factores de estrés en el ambiente de trabajo.

Reactive oxygen/nitrogen species and the myocardial cell homeostasis: an ambiguous relationship.

The totality of functional cardiomyocytes and an intact cardiac progenitor cell pool are key players in the myocardial cell homeostasis. Perturbation of either one may compromise the structural and functional integrity of the heart and lead to heart failure. Reactive oxygen/nitrogen species (ROS/RNS) are important regulators of cardiomyocyte viability; more recently, the interrelation between ROS and progenitor cell behavior and fate has moved into the spotlight. Increasing evidence suggests not only that ROS participate in the regulation of cardiac progenitor cell survival but also that they likewise affect their functional properties in terms of self-proliferation and differentiation. The apparent dichotomy of ROS/RNS effects with their adaptive and regulatory character on the one hand and their maladaptive and damaging features on the other pose a great challenge in view of the therapeutic exploitation of their role in the regulation of the myocardial cell homeostasis. In this article, mechanisms and potential significance of ROS/RNS action in the regulation of the myocardial cell homeostasis, in particular with respect to the preservation of viable cardiomyocytes and the maintenance of a functional cardiac progenitor cell pool, will be discussed.

Burnout and stress among nurses in a university tertiary hospital.

This cross-sectional, analytical and correlational study investigated the existence of Burnout based on a sample of 149 nurses of a university tertiary hospital from October to December 2008 and correlate Burnout with stressors in the hospital work environment. The Maslach Burnout Inventory, the Nurses' Stress Inventory and a questionnaire to characterize the subjects were applied. The results indicated the presence of Burnout in 7.3% of nurses (quartile) and 10.22% (tercile), and also a correlation among the inventories' domains. Vulnerability to this type of illness among nurses was increased by stress experienced in the work environment.

egc-Encoded superantigens from Staphylococcus aureus are neutralized by human sera much less efficiently than are classical staphylococcal enterotoxins or toxic shock syndrome toxin.

PCR was employed to determine the presence of all known superantigen genes (sea, seq, and tst) and of the exotoxin-like gene cluster (set) in 40 Staphylococcus aureus isolates from blood cultures and throat swabs; 28 isolates harbored superantigen genes, five on average, and this strictly correlated with their ability to stimulate T-cell proliferation. In contrast, the set gene cluster was detected in every S. aureus strain, suggesting a nonredundant function for these genes which is different from T-cell activation. No more than 10% of normal human serum samples inhibited the T-cell stimulation elicited by egc-encoded enterotoxins (staphylococcal enterotoxins G, I, M, N, and O), whereas between 32 and 86% neutralized the classical superantigens. Similarly, intravenous human immunoglobulin G preparations inhibited egc-encoded superantigens with 10- to 100-fold-reduced potency compared with the classical enterotoxins. Thus, there are surprisingly large gaps in the capacity of human serum samples to neutralize S. aureus superantigens.