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Responses to hormones that act through nuclear receptors are controlled by modulating hormone concentrations not only in the circulation but also within target tissues. The role of enzymes that amplify or reduce local hormone concentrations has become well-established for glucocorticoid and other lipophilic hormones; moreover, transmembrane transporters have proven critical in determining tissue responses to thyroid hormones. However, there has been less consideration of the role of transmembrane transport for steroid hormones. ATP-binding cassette (ABC) proteins were first shown to influence the accumulation of glucocorticoids in cells almost three decades ago, butobservations over the past ten years suggest that differential transport propensities of both exogenous and endogenous glucocorticoids by ABCB1 and ABCC1 transporters provides a mechanism whereby different tissues are preferentially sensitive to different steroids. This Review summarisesthis evidence and the new insights provided for the physiology and pharmacology of glucocorticoid action, including new approaches to glucocorticoid replacement.

The cellular and molecular consequences of lack of dystrophin in humans are only partially known, which is crucial for the development of new therapies aiming to slow or stop the progression Duchenne and Becker muscular dystrophies. We analyzed muscle biopsies of DMD patients and controls using single nuclei RNA sequencing (snRNAseq) and correlated the results with clinical data. DMD samples displayed an increase in regenerative fibers, satellite cells and fibro-adipogenic progenitor cells (FAPs) and a decrease in slow fibers and smooth muscle cells. Samples from patients with stable mild weakness were characterized by an increase in regenerative fibers, while those from patients with progressive weakness had fewer muscle fibers and increased FAPs. DMD muscle fibers displayed a strong regenerative signature, while DMD FAPs upregulated genes producing extracellular matrix and molecules involved in several signaling pathways. An analysis of intercellular communication profile identified FAPs as a key regulator of cell signaling in DMD samples. We show significant differences in the gene expression profiled of the different cell populations present in DMD muscle samples compared to controls.

Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure and one for which no efficacious therapies exist. Obesity and lipid mishandling greatly contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are largely unknown. Here, we report that cardiomyocyte steatosis in HFpEF is coupled with increases in the activity of the transcription factor FoxO1 (Forkhead box protein O1). FoxO1 depletion, as well as over-expression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) in cardiomyocytes each ameliorates the HFpEF phenotype in mice and reduces myocardial lipid accumulation. Mechanistically, forced expression of Xbp1s in cardiomyocytes triggers ubiquitination and proteasomal degradation of FoxO1 which occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-box-containing protein 1) a novel and direct transcriptional target of Xbp1s. Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of cardiometabolic HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes., Heart failure with preserved ejection fraction (HFpEF) is a global, major health issue for which no effective therapies are available. Here, the authors discover that the interplay between two transcription factors, Xbp1s and FoxO1, is critical for metabolic adaptation and lipid handling in HFpEF-stressed cardiomyocytes.

Objective Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states. Methods The actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding. Results 20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding. Conclusions Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice., Highlights • Carbonyl reductase 1 (Cbr1) is a novel regulator of adipose glucocorticoid metabolism and glucose homeostasis. • Cbr1 metabolises corticosterone to 20β-dihydrocorticosterone, which is both a glucocorticoid and mineralocorticoid receptor agonist. • Global knockdown of Cbr1 improves glucose tolerance in lean male mice. • Overexpression of Cbr1 in adipose tissue worsens glucose tolerance in lean male and female mice.

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice—elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using Nω-nitro-l-arginine methyl ester (l-NAME)—recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of our rodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S-nitrosylation of the endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype. We report that iNOS-driven dysregulation of the IRE1α–XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF. iNOS-driven dysregulation of the IRE1α–XBP1 pathway leads to cardiomyocyte dysfunction in mice and recapitulates the systemic and cardiovascular features of human heart failure with preserved ejection fraction.

A Sí­ndrome do Intestino Curto consiste em uma falência do intestino por perda parcial ou total do intestino caracterizada pela incompetência do organismo em manter o controle hidroeletrolí­tico e calórico-proteico com dieta ingerida por via oral. Objetiva-se identificar na literatura a ação do enfermeiro, assim como a importância do trabalho multiprofissional para a obtenção de bons resultados no plano terapêutico. Trata-se de estudo descritivo do tipo observacional, as informações foram obtidas por meio de revisão do prontuário e entrevista com o acompanhante da criança. Resultados: Foram realizadas as etapas do Processo de Enfermagem, detalhando a ação da equipe de enfermagem. Devido ao tratamento complexo e delicado, conclui-se que o enfermeiro deve agir de forma holí­stica e estabelecer ví­nculo com pacientes e familiares, além da sua relação com a equipe multidisciplinar, a fim de que o plano terapêutico estabeleça uma assistência eficaz, visando a melhor qualidade de vida do paciente e famí­lia.Palavras-chave: sí­ndrome do intestino curto, nutrição parenteral, processo de enfermagem.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is now the dominant form of heart failure (HF). Limited insight into underlying mechanisms has culminated in the longstanding absence of evidence-based therapies capable of mitigating the substantial morbidity and mortality associated with the syndrome. Existing clinical and epidemiological evidence suggests that excessive body fat and lipid mishandling contribute to HFpEF. However, molecular mechanism(s) governing metabolic alterations and perturbations in lipid homeostasis in HFpEF are unknown. We recently developed a novel, clinically relevant, murine model of HFpEF, uncovering suppression of the Xbp1s (spliced form of the X-box-binding protein 1) arm of the UPR (unfolded protein response) signaling pathway as a critical driver of HFpEF pathogenesis. Objectives: To define and manipulate mechanisms downstream of Xbp1s in HFpEF and decipher its cardioprotective actions. Methods and Results: In the myocardium of experimental HFpEF, we detected cardiomyocyte steatosis coupled with increases in the abundance and activity of FoxO1 (Forkhead box protein O1), a conserved transcription factor involved in cell metabolism. FoxO1 depletion, as well as Xbp1s over-expression, in cardiomyocytes each ameliorated the HFpEF phenotype and reduced myocardial lipid accumulation. Strikingly, forced expression of Xbp1s in cardiomyocytes triggered proteasomal degradation of FoxO1. Furthermore, we discovered that FoxO1 is ubiquitinated upon Xbp1s over-expression, and Xbp1s-induced proteasomal degradation of FoxO1 occurs, in large part, through activation of the E3 ubiquitin ligase STUB1 (STIP1 homology and U-Box-containing protein 1), a protein we identified as a novel and direct transcriptional target of Xbp1s. Conclusions: Our findings uncover the Xbp1s-FoxO1 axis as a pivotal mechanism in the pathogenesis of HFpEF and unveil previously unrecognized mechanisms whereby the UPR governs metabolic alterations in cardiomyocytes.

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. Our group recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes1,2. We recently also showed that Meis1, a TALE family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a Meis1 cofactor in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can both extend the postnatal window of cardiomyocyte proliferation and reactivate cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1/Hoxb13 double knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and an improvement in left ventricular systolic function following myocardial infarction both by echocardiography and MRI. ChIP-seq analysis demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204 (S204), resulting in its nuclear localization and cell cycle arrest. Collectively, these results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.

A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1-Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.

Background: Myocardium irreversibly injured by ischemic stress must be efficiently repaired to maintain tissue integrity and contractile performance. Macrophages play critical roles in this process. These cells transform across a spectrum of phenotypes to accomplish diverse functions ranging from mediating the initial inflammatory responses that clear damaged tissue to subsequent reparative functions that help rebuild replacement tissue. Although macrophage transformation is crucial to myocardial repair, events governing this transformation are poorly understood. Methods: Here, we set out to determine whether innate immune responses triggered by cytoplasmic DNA play a role. Results: We report that ischemic myocardial injury, along with the resulting release of nucleic acids, activates the recently described cyclic GMP-AMP synthase–stimulator of interferon genes pathway. Animals lacking cyclic GMP-AMP synthase display significantly improved early survival after myocardial infarction and diminished pathological remodeling, including ventricular rupture, enhanced angiogenesis, and preserved ventricular contractile function. Furthermore, cyclic GMP-AMP synthase loss of function abolishes the induction of key inflammatory programs such as inducible nitric oxide synthase and promotes the transformation of macrophages to a reparative phenotype, which results in enhanced repair and improved hemodynamic performance. Conclusions: These results reveal, for the first time, that the cytosolic DNA receptor cyclic GMP-AMP synthase functions during cardiac ischemia as a pattern recognition receptor in the sterile immune response. Furthermore, we report that this pathway governs macrophage transformation, thereby regulating postinjury cardiac repair. Because modulators of this pathway are currently in clinical use, our findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.

Skeletal muscle plays a central role in insulin-controlled glucose homeostasis. The molecular mechanisms related to insulin resistance in this tissue are incompletely understood. Herpud1 is an endoplasmic reticulum membrane protein that maintains intracellular Ca2+ homeostasis under stress conditions. It has recently been reported that Herpud1-knockout mice display intolerance to a glucose load without showing altered insulin secretion. The functions of Herpud1 in skeletal muscle also remain unknown. Based on these findings, we propose that Herpud1 is necessary for insulin-dependent glucose disposal in skeletal muscle. Here we show that Herpud1 silencing decreased insulin-dependent glucose uptake, GLUT4 translocation to the plasma membrane, and Akt Ser473 phosphorylation in cultured L6 myotubes. A decrease in insulin-induced Akt Ser473 phosphorylation was observed in soleus but not in extensor digitorum longus muscle samples from Herpud1-knockout mice. Herpud1 knockdown increased the IP3R-dependent cytosolic Ca2+ response and the activity of Ca2+-dependent serine/threonine phosphatase calcineurin in L6 cells. Calcineurin decreased insulin-dependent Akt phosphorylation and glucose uptake. Moreover, calcineurin inhibition restored the insulin response in Herpud1-depleted L6 cells. Based on these findings, we conclude that Herpud1 is necessary for adequate insulin-induced glucose uptake due to its role in Ca2+/calcineurin regulation in L6 myotubes.

Cardiac hypertrophy is an adaptive response triggered by pathological stimuli. Regulation of the synthesis and the degradation of the Ca2+ channel inositol 1,4,5-trisphosphate receptor (IP3R) affects progression to cardiac hypertrophy. Herpud1, a component of the endoplasmic reticulum-associated degradation (ERAD) complex, participates in IP3R1 degradation and Ca2+ signaling, but the cardiac function of Herpud1 remains unknown. We hypothesize that Herpud1 acts as a negative regulator of cardiac hypertrophy by regulating IP3R protein levels. Our results show that Herpud1-knockout mice exhibit cardiac hypertrophy and dysfunction and that decreased Herpud1 protein levels lead to elevated levels of hypertrophic markers in cultured rat cardiomyocytes. In addition, IP3R levels were elevated both in Herpud1-knockout mice and Herpud1 siRNA-treated rat cardiomyocytes. The latter treatment also led to elevated cytosolic and nuclear Ca2+ levels. In summary, the absence of Herpud1 generates a pathological hypertrophic phenotype by regulating IP3R protein levels. Herpud1 is a novel negative regulator of pathological cardiac hypertrophy.

Glucocorticoids play a critical role in metabolic homeostasis. Chronic or excessive activation of the glucocorticoid receptor (GR) in adipose tissue contributes to metabolic disorders such as glucose intolerance and insulin resistance. Steroid-metabolising enzymes in adipose, such as 11β-HSD1 or 5α-reductase, modulate the activation of GR by converting primary glucocorticoids into more or less potent ligands. Carbonyl reductase 1 (CBR1) is a novel regulator of glucocorticoid metabolism, converting corticosterone/cortisol to 20β-dihydrocorticosterone/cortisol (20β-DHB/F); a metabolite which retains GR activity. CBR1 is abundant in adipose tissue and increased in obese adipose of mice and humans1 and increased Cbr1 expression is associated with increased fasting glucose1. We hypothesised that increased Cbr1/20β-DHB in obese adipose contributes to excessive GR activation and worsens glucose tolerance. We generated a novel murine model of adipose-specific Cbr1 over-expression (R26-Cbr1Adpq) by crossing conditional knock-in mice with Adiponectin-Cre mice. CBR1 protein and activity were doubled in subcutaneous adipose tissue of male and female R26-Cbr1Adpq mice compared with floxed controls; corresponding to a two-fold increase 20β-DHB (1.6 vs. 4.2ng/g adipose; P=0.0003; n=5-7/group). There were no differences in plasma 20β-DHB or corticosterone. Bodyweight, lean or fat mass, did not differ between male or female R26-Cbr1Adpq mice and floxed controls. Lean male R26-Cbr1Adpq mice had higher fasting glucose (9.5±0.3 vs. 8.4±0.3mmol/L; P=0.04) and worsened glucose tolerance (AUC 1819±66 vs. 1392±14; P=0.03). Female R26-Cbr1Adpq mice also had a worsened glucose tolerance but fasting glucose was not altered with genotype. There were no differences in fasting insulin or non-esterified fatty acid between genotypes in either sex. Expression of GR-induced genes Pnpla2, Gilz and Per1, were increased in adipose of R26-Cbr1Adpq mice. Following high-fat diet induced obesity, no differences in bodyweight, lean or fat mass, with genotype were observed in male and female mice, and genotype differences in fasting glucose and glucose tolerance were abolished. In conclusion, adipose-specific over-expression of Cbr1 in lean male and female mice led to increased levels of 20β-DHB in adipose but not plasma, and both sexes having worsened glucose tolerance. The influence of adipose CBR1/20β-DHB on glucose tolerance was not associated with altered fat mass or bodyweight and was attenuated by high-fat diet-induced obesity. These metabolic consequences of Cbr1 manipulation require careful consideration given the wide variation in CBR1 expression in the human population, the presence of inhibitors and enhancers in many foodstuffs and the proposed use of inhibitors as an adjunct for cancer treatment regimens. Reference: Morgan et al., Scientific Reports. 2017; 7.

Mutations in the gene encoding polycystin-1 (PC1) underlie autosomal dominant polycystic kidney disease (ADPKD). ADPKD patients present with multiple cardiovascular co-morbidities believed to be caused by renal dysfunction. LV hypertrophy and diastolic dysfunction can manifest during childhood or in young adults prior to a formal diagnosis of hypertension, and evidence suggests that LV function is impaired in ADPKD patients with normal or moderately reduced kidney function. These facts suggest that cardiomyocyte-autonomous effects may contribute to the cardiovascular abnormalities seen in ADPKD. Contractile function (systolic and diastolic) measured by echo was significantly reduced in PC1 cKO ( Pkd1 F/F ;αMHC-Cre) mice compared with controls ( Pkd1 F/F ). PC1 cKO cardiomyocytes manifest impaired contractility and smaller and slower Ca 2+ transients. Using a multidimensional approach, we discovered that cardiomyocytes lacking PC1 have shorter action potentials (APD50/90) and decreased SERCA activity. These alterations impair EC-coupling and decrease SR Ca 2+ loading during pacing. Remarkably, square pulses under voltage clamp (-80 to +10 mV) produced Ca 2+ transients with similar amplitude between genotypes, which highlights that alterations in action potential (AP) duration drive most of the EC-coupling changes. PC1-deficient cardiomyocytes manifested an increase in outward K + currents (I to , I Kslow1/2 and I ss ) but not in inward currents (I K1 ). PC1 over-expression in HEK293T cells reduced the currents of heterologously expressed Kv4.3/2.1/1.5 channels. The inhibitory effects of PC1 on Kv4.3 currents were mediated by PC1-CT (C-terminus) through its coiled-coil domain (CCD). Interestingly, a naturally occurring human mutant PC1 R4228X , located in the CCD, manifested no suppressive effects on Kv4.3 channel. Finally, to begin to test for relevance to human pathology, we found that PC1 ablation reduces AP duration, and PC1-CT over-expression had the opposite effect in human stem cell-derived cardiomyocytes. Our findings uncover a novel role for PC1 controlling action potential duration and SERCA. PC1-deficient cardiomyocytes manifest impaired contractility, likely contributing to contractile dysfunction in ADPKD patients.

BACKGROUND: Polycystin-1 (PC1) is a transmembrane protein originally identified in autosomal dominant polycystic kidney disease where it regulates the calcium-permeant cation channel polycystin-2. Autosomal dominant polycystic kidney disease patients develop renal failure, hypertension, left ventricular hypertrophy, and diastolic dysfunction, among other cardiovascular disorders. These individuals harbor PC1 loss-of-function mutations in their cardiomyocytes, but the functional consequences are unknown. PC1 is ubiquitously expressed, and its experimental ablation in cardiomyocyte-specific knockout mice reduces contractile function. Here, we set out to determine the pathophysiological role of PC1 in cardiomyocytes. METHODS: Wild-type and cardiomyocyte-specific PC1 knockout mice were analyzed by echocardiography. Excitation-contraction coupling was assessed in isolated cardiomyocytes and human embryonic stem cell-derived cardiomyocytes, and functional consequences were explored in heterologous expression systems. Protein-protein interactions were analyzed biochemically and by means of ab initio calculations. RESULTS: PC1 ablation reduced action potential duration in cardiomyocytes, decreased Ca2+ transients, and myocyte contractility. PC1-deficient cardiomyocytes manifested a reduction in sarcoendoplasmic reticulum Ca2+ stores attributable to a reduced action potential duration and sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) activity. An increase in outward K+ currents decreased action potential duration in cardiomyocytes lacking PC1. Overexpression of full-length PC1 in HEK293 cells significantly reduced the current density of heterologously expressed Kv4.3, Kv1.5 and Kv2.1 potassium channels. PC1 C terminus inhibited Kv4.3 currents to the same degree as full-length PC1. Additionally, PC1 coimmunoprecipitated with Kv4.3, and a modeled PC1 C-terminal structure suggested the existence of 2 docking sites for PC1 within the N terminus of Kv4.3, supporting a physical interaction. Finally, a naturally occurring human mutant PC1R4228X manifested no suppressive effects on Kv4.3 channel activity. CONCLUSIONS: Our findings uncover a role for PC1 in regulating multiple Kv channels, governing membrane repolarization and alterations in SERCA activity that reduce cardiomyocyte contractility.

Background: The primary cilium is a singular cellular structure that extends from the surface of many cell types and plays crucial roles in vertebrate development, including that of the heart. Whereas ciliated cells have been described in developing heart, a role for primary cilia in adult heart has not been reported. This, coupled with the fact that mutations in genes coding for multiple ciliary proteins underlie polycystic kidney disease, a disorder with numerous cardiovascular manifestations, prompted us to identify cells in adult heart harboring a primary cilium and to determine whether primary cilia play a role in disease-related remodeling. Methods: Histological analysis of cardiac tissues from C57BL/6 mouse embryos, neonatal mice, and adult mice was performed to evaluate for primary cilia. Three injury models (apical resection, ischemia/reperfusion, and myocardial infarction) were used to identify the location and cell type of ciliated cells with the use of antibodies specific for cilia (acetylated tubulin, γ-tubulin, polycystin [PC] 1, PC2, and KIF3A), fibroblasts (vimentin, α-smooth muscle actin, and fibroblast-specific protein-1), and cardiomyocytes (α-actinin and troponin I). A similar approach was used to assess for primary cilia in infarcted human myocardial tissue. We studied mice silenced exclusively in myofibroblasts for PC1 and evaluated the role of PC1 in fibrogenesis in adult rat fibroblasts and myofibroblasts. Results: We identified primary cilia in mouse, rat, and human heart, specifically and exclusively in cardiac fibroblasts. Ciliated fibroblasts are enriched in areas of myocardial injury. Transforming growth factor β-1 signaling and SMAD3 activation were impaired in fibroblasts depleted of the primary cilium. Extracellular matrix protein levels and contractile function were also impaired. In vivo, depletion of PC1 in activated fibroblasts after myocardial infarction impaired the remodeling response. Conclusions: Fibroblasts in the neonatal and adult heart harbor a primary cilium. This organelle and its requisite signaling protein, PC1, are required for critical elements of fibrogenesis, including transforming growth factor β-1–SMAD3 activation, production of extracellular matrix proteins, and cell contractility. Together, these findings point to a pivotal role of this organelle, and PC1, in disease-related pathological cardiac remodeling and suggest that some of the cardiovascular manifestations of autosomal dominant polycystic kidney disease derive directly from myocardium-autonomous abnormalities.

National Institutes of Health HL-120732 HL-128215 HL-126012 American Heart Association 14SFRN20510023 14SFRN20670003 16POST30680016 13POST16520009 Fondation Leducq 11CVD04 Cancer Prevention and Research Institute of Texas RP110486P3 PEW Latin American Fellows Program in the Biomedical Science 00002991 Yale O'Brien Kidney Center P30 DK079310 Fondo Nacional de Desarrollo Cientifico y Tecnologico, FONDECYT 1171075 11150282 1161156 FONDAP 15130011 PAI Insertion Program from the Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT), Santiago, Chile 79150007

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice-elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using N

Skeletal muscle plays a central role in insulin-controlled glucose homeostasis. The molecular mechanisms related to insulin resistance in this tissue are incompletely understood. Herpud1 is an endoplasmic reticulum membrane protein that maintains intracellular Ca

Las Guías Alimentarias Basadas en Alimentos (GABA), son instrumentos educativos que ayudan a la población a seleccionar alimentos apropiados para una buena nutrición y salud. La mayoría de los países tienen GABA, pero su difusión e implementación presentan grandes debilidades. Se presenta el proceso para la formulación y validación de las GABA 2012 para la población chilena. Se revisó la evidencia científica reciente y se validaron los mensajes con el Metaplán, método para el análisis de problemas, con 48 grupos focales en Arica, Santiago y Chillán-Concepción. Los mensajes promueven el consumo de alimentos saludables, un menor consumo de energía y de nutrientes críticos. En los mensajes definitivos se incorporó los comentarios y sugerencias de los participantes y de 2 paneles de expertos. Su implementación debería incorporar estrategias de promoción de los Ministerios de Salud, Educación, Agricultura, universidades, la industria y los medios masivos, para lograr cambios en el comportamiento alimentario de los segmentos más vulnerables de la población chilena.

Obesity is a major worldwide problem, despite considerable efforts against it. While excess body fat defines obesity, adipose tissue quality and functionality are key to whether cardiovascular and metabolic comorbidities develop. Adipose tissue cellular composition can vary considerably, and excess adipocyte progenitors (preadipocytes) is associated with obesity. We have proposed that calcium sensing receptor (CaSR) activation in adipose tissue leads to dysfunction. This study evaluated whether CaSR activation elevates preadipocyte proliferation. Human LS14 preadipocytes were exposed to CaSR activators cinacalcet (2 µM), GdCl 3 (5 µM) and spermine (1 µM), and cell viability was evaluated after 72h. CaSR activators elevated proliferation by 19–24%, and CaSR silencing (siRNA) abolished the effect. Cinacalcet elevated phospho-ERK1/2 content, and upstream inhibition of ERK1/2 phosphorylation reverted cinacalcet-induced proliferation. Cinacalcet also elevated expression of the proinflammatory factors IL1β, IL6 and CCL2. The results suggest that CaSR induces preadipocyte proliferation, partly through ERK1/2 activation. Considering reported proinflammatory and adipogenic CaSR effects, excess preadipocyte proliferation further supports the dysfunctional effect of CaSR in obesity.

Background: The less affluent and educated members of the society tend to be less prone to healthy lifestyles. Aim: To describe feeding habits, nutrition, quality of life and working conditions of construction workers comparing two recent surveys, namely the 2009 Chilean National Health Survey (NHS) and the 2010 Work, Employment and Health Survey (WEH). Material and methods: One hundred ninety male workers aged 43 ± 13 years were surveyed about feeding habits during working days and weekends, smoking and usual physical activity. Weight, height and blood pressure were also measured. Results: In 2010, 82% of workers were overweight or obese compared with 67% rates in the NHS of 2009. The rate of sedentariness was 86% compared with 84% in the NHS of 2009 and 93% in the WEH 2010. Forty one percent smoked and those aged less than 25 years consumed more calories than the other age groups. There was a high intake of carbonated beverages, bread, salted and red meats and a low consumption of fruits, vegetables, legumes and fish. Seventy seven percent had a meal at midafternoon and only 25% ate supper. Lunch had a fixed schedule, was considered good and usually was prepared by a family member. The level of satisfaction with work, family life and life in general was high. The satisfaction with health and physical condition was lower. Conclusions: The unhealthy lifestyles of these construction workers should alert health authorities.

The elevated prevalence of obesity worldwide is a challenging public health problem. Dietary calcium intake is frequently below recommendations, and evidence gathered for more than a decade suggests that inadequate calcium intake may be related to increased body weight and/or body fat, although a consensus has yet to be reached. Whole-body energy balance and the cellular mechanisms involved have been proposed to explain this relationship, and increasing evidence from epidemiological, clinical, and basic research lends support to the hypothesis that calcium is linked to the regulation of body weight. This review provides a critical appraisal of evidence from studies that examined several different aspects of this issue. Different mechanisms are highlighted and, based on recent work, new perspectives are offered, which incorporate the concept of obesity-associated inflammation and the possible role of the extracellular calcium-sensing receptor.

The less affluent and educated members of the society tend to be less prone to healthy lifestyles.To describe feeding habits, nutrition, quality of life and working conditions of construction workers comparing two recent surveys, namely the 2009 Chilean National Health Survey (NHS) and the 2010 Work, Employment and Health Survey (WEH).One hundred ninety male workers aged 43±13 years were surveyed about feeding habits during working days and weekends, smoking and usual physical activity. Weight, height and blood pressure were also measured.In 2010, 82% of workers were overweight or obese compared with 67% rates in the NHS of 2009. The rate of sedentariness was 86% compared with 84% in the NHS of 2009 and 93% in the WEH 2010. Forty one percent smoked and those aged less than 25 years consumed more calories than the other age groups. There was a high intake of carbonated beverages, bread, salted and red meats and a low consumption of fruits, vegetables, legumes and fish. Seventy seven percent had a meal at midafternoon and only 25% ate supper. Lunch had a fixed schedule, was considered good and usually was prepared by a family member. The level of satisfaction with work, family life and life in general was high. The satisfaction with health and physical condition was lower.The unhealthy lifestyles of these construction workers should alert health authorities.

We established that human adipose cells and the human adipose cell line LS14 express the calcium-sensing receptor (CaSR) and that its activation induces inflammatory cytokine production. Also, its expression is enhanced upon exposure to obesity-associated proinflammatory cytokines. We have thus proposed that CaSR activation may be associated with adipose dysfunction. Here, we evaluated a possible effect on adipogenesis. We induced adipose differentiation of primary and LS14 human preadipocytes with or without the simultaneous activation of CaSR, by the exposure to the calcimimetic cinacalcet. Activation of the receptor for 24 h decreased by 40 % the early differentiation marker CCAAT/enhancer-binding protein β. However, upon longer-term (10 day) exposure to the adipogenic cocktail, cinacalcet exerted the opposite effect, causing a dose-response increase in the expression of the mature adipose markers adipocyte protein 2, adiponectin, peroxisome proliferator-activated receptor γ, fatty acid synthase, and glycerol-3-phosphate dehydrogenase. To assess whether there was a time-sensitive effect of CaSR activation on adipogenesis, we evaluated the 10 day effect of cinacalcet exposure for the first 6, 24, 48 h, 6, and 10 days. Our observations suggest that regardless of the period of exposure, 10 day adipogenesis is elevated by cinacalcet. CaSR activation may interfere with the initial stages of adipocyte differentiation; however, these events do not seem to preclude adipogenesis from continuing. Even though adipogenesis (particularly in subcutaneous depots) is associated with insulin sensitivity and adequate adipose function, the implications of our findings in visceral adipocytes, especially in the context of inflamed AT and overnutrition, remain to be established.

Among the diseases that produce a great amount of garbage of health, the individuals bearers of diabetes insulino-dependent mellittus are important producers of solid garbage of health. The main objective of this study is to identify how the insulino-dependent diabetics do the discard of the syringes and needles used in their residences. The method of the research was the descriptive study. The researched population was constituted of 70 insulino-dependent individuals. The collection of data was accomplished through questionnaire, in the period of October of 2006 to March of 2007. Inside of the relevant results, in which 100% do not know what biological garbage is and 51.43% discard in the common garbage the needles and syringes and ignore the course of the garbage to the embankment, the importance is demonstrated by becoming aware and educating the population of the risks of this practice being fundamental for the environment.

Entre as doenças que produzem uma grande quantidade de lixo de saúde, os indivíduos portadores de diabetes mellittus insulino-dependentes são importantes produtores de lixo sólido de saúde. O principal objetivo deste estudo é identificar como os diabéticos insulino-dependentes fazem o descarte das seringas e agulhas utilizadas nas suas residências. O método da pesquisa foi o estudo descritivo. A população pesquisada foi constituída de 70 indivíduos insulino-dependentes. A coleta de dados foi realizada por meio de questionário, no período de outubro de 2006 a março de 2007. Dentro dos resultados relevantes, nos quais 100% não sabem o que é lixo biológico e 51,43% descartam no lixo comum as agulhas e seringas e desconhecem o percurso do lixo até o aterro, demonstrase a importância de conscientizar e educar a população dos riscos desta prática como fundamental para o meio ambiente.

RESUMOA prematuridade expressa relevância a saude neonatal, demonstrando comprometimento ascendente com relacao a morbimortalidadedesta clientela, cuja maior incidencia pode ser atribuida as praticas inadequadas com a pele do prematuro. Revisao da literatur a sobre ainteracao benefica entre a pele do Recem-Nascido Pre-Termo e o manuseio adequado, norteado pelo enfermeiro, que por meio dapadronizacao dos cuidados de interferencia direta e avaliacao continua da integridade cutânea e o assistir o prematuro. Divulga aimportância do cuidado com a pele do Recem Nascido Prematuro, possibilitando nao apenas a sobrevivencia, mas a oportunidade de seintegrar e desfrutar da vida com qualidade.Descritores:: Recem-nascido; Enfermagem; Assistencia de enfermagem.ABSTRACTThe prematurity expressed relevance to the health neonatal, demonstrating ascending compromising regarding morbi-mortality of thispatients, whose larger incidence can be attributed to the inadequate practices with the skin of the premature. Revision of the literatureabout the beneficial interaction among the skin of premature infant newborn and the appropriate handling, orientated by the nur se, thatthrough the standardization of the cares of direct interference and continuous evaluation of the cutaneous integrity and attending thepremature. It publishes the importance of the care with the skin of the premature newbor, not just making possible the survival, but theopportunity to integrate and to enjoy of the life with quality.Descriptores: : Infant, newborn; Nursing; Nursing care.RESUMENLa prematuridad expresa una relevancia para la salud neonatal, demonstando un comprometimiento ascendiente la relacion de lamorbimortalidade de esta clientela, cuya mayor incidencia puede ser atribuida a las practicas inadecuadas con la piel del prematuro.Revision de la literatura sobre la interaccion beneficiosa entre la piel del recien nacido pre-termino y el manejo adecuado direccionadopor el enfermero, que por medio de la padronizacion de los cuidados de interferencia directa y evaluacion continua de la integridadcutanea y la asistencia al prematuro. Divulga la importancia del cuidado con la piel del recien nacido prematuro, posibilitando no apenasla sobreviviencia, como la oportunidad de integrar y disfrutar de la vida con cualidadDescriptores:: Recien nacido; Enfermeria; Atencion de enfermeria.Submissao: Submissao: 12/12/2008 Aprovacao:ovacao: 31/08/2009REVISAORevistaBrasileirade Enfermagem

Objective : to a ccomplish the literature review with the main phases of the woman's development. Methods : bibliographical study, from retrospective approach, in books and national and international newspapers in the sites of the Latin American and Caribbean Sciences of the Health Center - BIREME - and database Latin American and Caribbean Sciences of the Health Literature - LILACS. Results : they were found twenty one bibliographies. Conclusion : the woman goes by several transformations in her life and that the nurse has capacity to attend her in the best possible way, but, is important to be update and to elaborate tools to optimize the work process and to favor the woman a quality service. Descriptors : obstetric nursing; postpartum; sexual maturation. RESUMO Objetivo : realizar revisao da literatura com as principais fases de desenvolvimento da mulher. Metodos : estudo bibliografico, de carater retrospectivo, em livros e periodicos nacionais e internacionais, em sites do Centro Latino Americano e do Caribe em Ciencias da Saude - BIREME - e base de dados Literatura Latino-Americana e do Caribe em Ciencias da Saude - LILACS. Resultados : foram encontradas 21 referencias. Conclusao : a mulher passa por varias transformacoes em sua vida e o enfermeiro tem capacidade para assisti-la da melhor forma possivel, mas para isso, e importante estar atualizado, e elaborar ferramentas para otimizar o processo de trabalho e favorecer a mulher um atendimento de qualidade. Descritores : enfermagem obstetrica; puerperio; maturacao sexual. RESUMEN Objetivo : realizar una revision bibliografica con las principales fases del desarrollo de la mujer. Metodos : estudio bibliografico, de carater retrospectivo, logrado a partir de libros y periodicos nacionales e internacionales, en la Centro Latino Americano y del Caribe en Ciencias de la Salud - BIREME - y en la base de datos Literatura Latino-Americana y del Caribe en Ciencias de la Salud - LILACS. Resultados : f ueron encontradas veinte y una bibliografias. Conclusion : l a mujer pasa por varias transformaciones en su vida y que el enfermero tiene la capacidad para asistir de la mejor manera posible, pero para esto, es importante la constante actualizacion y elaboracion de herramientas para optimizar el proceso de trabajo y favorecer un atendimiento de calidad. Descriptores : obstetricia enfermeria; puerperio; maduracion sexual.