RESUMEN
Formyl peptide receptor 2 (FPR2) plays an integral role in the transition of macrophages from a pro-inflammatory program to one that is pro-resolving. FPR2-mediated stimulation of resolution post myocardial infarction has demonstrated efficacy in rodent models and is hypothesized to reduce progression into heart failure. FPR2 agonists that promote long-lasting receptor internalization can lead to persistent desensitization and diminished therapeutic benefits. In vitro signaling profiles and propensities for receptor desensitization of two clinically studied FPR2 agonists, namely, BMS-986235 and ACT-389949, were evaluated. In contrast to BMS-986235, pre-stimulation with ACT-389949 led to a decrease in its potency to inhibit cAMP production. Moreover, ACT-389949 displayed greater efficacy for ß-arrestin recruitment, while efficacy of Gi activation was similar for both agonists. Following agonist-promoted FPR2 internalization, effective recycling to the plasma membrane was observed only with BMS-986235. Use of G protein-coupled receptor kinase (GRK) knock-out cells revealed a differential impact of GRK2 versus GRK5/6 on ß-arrestin recruitment and Gi activation promoted by the two FPR2 agonists. In vivo, decreases of granulocytes in circulation were greatly diminished in mice treated with ACT-389949 but not for BMS-986235. With short-term dosing, both compounds induced a pro-resolution polarization state in cardiac monocyte/macrophages post myocardial infarction. By contrast, with long-term dosing, only BMS-986235 preserved the infarct wall thickness and increased left ventricular ejection fraction in a rat model of myocardial infarction. Altogether, the study shows that differences in the desensitization profiles induced by ACT-389949 and BMS-986235 at the molecular level may explain their distinct inflammatory/pro-resolving activities in vivo.
RESUMEN
One of the most abundant flavonoids present in cacao is (-)-epicatechin (Epi) and this flavanol has been linked to the cardiovascular health promoting actions of cocoa products. We previously demonstrated that Epi reduces infarct size in rodent models of ischemia/reperfusion and permanent coronary occlusion. Reduced infarct size was associated with decreased left ventricular (LV) oxidative stress (OS) and indicators of inflammation factors, which foster myocardial fibrosis. In this study, we examine the antifibrotic actions of Epi in an aging female rat model of pre-heart failure with preserved ejection fraction (pre-HFpEF) as well as its potential to mitigate plasma levels of OS, proinflammatory/profibrotic cytokines, and improve passive and active LV function. Epi treatment [1 mg/(kg·d)] was provided daily by gavage from 21 to 22 months of age, whereas controls received water. A Millar catheter was used to assess hemodynamic function. Subsequently, hearts were arrested in diastole, a balloon inserted into the LV and passive pressure-volume curves generated. Fixed LV sections were processed for collagen area fraction quantification using Sirius Red staining. Treatment with Epi did not lead to detectable changes in LV contractile function. However, passive LV pressure volume curves were significantly right shifted with Epi. Collagen area fraction values indicated that Epi treatment significantly reduces LV fibrosis. Epi also significantly reduced plasma OS markers and levels of profibrotic and proinflammatory cytokines. In conclusion, Epi reduces cardiac fibrosis in an aged, female rat model of pre-HFpEF, which correlates with significant reductions in OS and cytokine levels in the absence of changes in LV contractile function.
Asunto(s)
Catequina , Insuficiencia Cardíaca , Animales , Colágeno , Citocinas , Femenino , Fibrosis , Insuficiencia Cardíaca/tratamiento farmacológico , Infarto , Ratas , Volumen SistólicoRESUMEN
Dysregulated inflammation following myocardial infarction (MI) leads to maladaptive healing and remodeling. The study characterized and evaluated a selective formyl peptide receptor 2 (FPR2) agonist BMS-986235 in cellular assays and in rodents undergoing MI. BMS-986235 activated G proteins and promoted ß-arrestin recruitment, enhanced phagocytosis and neutrophil apoptosis, regulated chemotaxis, and stimulated interleukin-10 and monocyte chemoattractant protein-1 gene expression. Treatment with BMS-986235 improved mouse survival, reduced left ventricular area, reduced scar area, and preserved wall thickness. Treatment increased macrophage arginase-1 messenger RNA and CD206 receptor levels indicating a proresolution phenotype. In rats following MI, BMS-986235 preserved viable myocardium, attenuated left ventricular remodeling, and increased ejection fraction relative to control animals. Therefore, FPR2 agonism improves post-MI healing, limits remodeling and preserves function, and may offer an innovative therapeutic option to improve outcomes.
RESUMEN
The identification of clinically significant genes recurrently mutated in myeloid malignancies necessitates expanding diagnostic testing with higher throughput, such as targeted next-generation sequencing. We present validation of the Thermo Fisher Oncomine Myeloid Next-Generation Sequencing Panel (OMP), targeting 40 genes and 29 fusion drivers recurrently mutated in myeloid malignancies. The study includes data from a sample exchange between two Canadian hospitals demonstrating high concordance for detection of DNA and RNA aberrations. Clinical validation demonstrates high accuracy, sensitivity, and specificity of the OMP, with a lower limit of detection of 5% for single-nucleotide variants and 10% for insertions/deletions. Prospective sequencing was performed for 187 samples from 168 unique patients presenting with suspected or confirmed myeloid malignancy and other hematological conditions to assess clinical impact of identifying variants. Of detected variants, 48% facilitated or clarified diagnoses, 29% affected prognoses, and 25% had the potential to influence clinical management. Of note, OMP was essential to identifying patients with premalignant clonal states likely contributing to cytopenias. We also found that the detection of even a single variant by the OMP assay, versus 0 variants, was predictive of overall survival, independent of age, sex, or diagnosis (P = 0.03). This study demonstrates that molecular profiling of myeloid malignancies with the OMP represents a promising strategy to advance molecular diagnostics.
Asunto(s)
ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Leucemia Mieloide Aguda/genética , Técnicas de Diagnóstico Molecular/métodos , Síndromes Mielodisplásicos/genética , Trastornos Mieloproliferativos/genética , ARN/genética , Canadá/epidemiología , ADN/aislamiento & purificación , Exactitud de los Datos , Femenino , Fusión Génica , Humanos , Mutación INDEL , Leucemia Mieloide Aguda/epidemiología , Límite de Detección , Masculino , Síndromes Mielodisplásicos/epidemiología , Trastornos Mieloproliferativos/epidemiología , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , ARN/aislamiento & purificaciónRESUMEN
Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist 13c, BMS-986235/LAR-1219. In cellular assays 13c inhibited neutrophil chemotaxis and stimulated macrophage phagocytosis, key end points to promote resolution of inflammation. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219.
Asunto(s)
Pirrolidinonas/química , Receptores de Formil Péptido/agonistas , Receptores de Lipoxina/agonistas , Animales , Quimiotaxis/efectos de los fármacos , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Células HEK293 , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/prevención & control , Humanos , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Microsomas Hepáticos/metabolismo , Neutrófilos/citología , Neutrófilos/fisiología , Fagocitosis/efectos de los fármacos , Pirrolidinonas/metabolismo , Pirrolidinonas/farmacología , Pirrolidinonas/uso terapéutico , Receptores de Formil Péptido/genética , Receptores de Formil Péptido/metabolismo , Receptores de Lipoxina/genética , Receptores de Lipoxina/metabolismo , Relación Estructura-ActividadRESUMEN
OBJECTIVES: The implementation of next-generation sequencing (NGS) in routine clinical hematology practice remains limited. We evaluate the clinical value of NGS in the screening, diagnosis, and follow-up in hematologic neoplasms. METHODS: A targeted NGS panel was used to assess a total of 178 patients for questionable or previously diagnosed myeloid neoplasms. RESULTS: Gene variants were identified in 53% of patients. Novel variants were identified in 29% of patients and variants of unknown significance in 34%. Bone marrow samples yielded a higher number of variants than in peripheral blood. NGS is a more sensitive test than conventional cytogenetics. In several cases, NGS played a key role in the screening, diagnostics, prognostic stratification, and the clinical follow-up of a wide variety of myeloid neoplasms. CONCLUSIONS: NGS is an effective tool in the evaluation of suspected and confirmed hematologic neoplasms and could become part of the routine workup of patients.
Asunto(s)
Neoplasias Hematológicas/diagnóstico , Trastornos Mieloproliferativos/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant-negative fashion. However loss-of-function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3, suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis. Here, we investigate MYBPC3 complete deletion as a disease mechanism in HCM by analyzing two unrelated patients with confirmed diagnosis of HCM that tested negative by Sanger sequencing analysis. METHODS: MYBPC3 complete deletion was investigated by Multiplex ligation-dependent probe amplification (MLPA) and microarray analyses. The mechanism of deletion was investigated by interrogating the SINEBase database. RESULTS: Patient-1 was diagnosed with nonobstructive HCM in his mid-40s while undergoing assessment for palpitations, and patient-2 with obstructive HCM in his late-20s while undergoing systolic heart murmur assessment for an unrelated illness. MLPA testing revealed a heterozygous deletion of all MYBPC3 exons in both patients. Subsequent microarray testing confirmed these deletions which extended beyond the 5' and 3' ends of MYBPC3. Genomic assessment suggested that these deletions resulted from Alu/Alu-homologous recombination. CONCLUSION: Our results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM.
Asunto(s)
Elementos Alu , Cardiomiopatía Hipertrófica/genética , Proteínas Portadoras/genética , Cardiomiopatía Hipertrófica/patología , Eliminación de Gen , Recombinación Homóloga , Humanos , Masculino , Persona de Mediana EdadRESUMEN
KEY POINTS: Heart failure with preserved ejection fraction (HFpEF) is seen more frequently in older women; risk factors include age, hypertension and excess weight. No female animal models of early stage remodelling (pre-HFpEF) have examined the effects that the convergence of such factors have on cardiac structure and function. In this study, we demonstrate that ageing can lead to the development of mild chamber remodelling, diffuse fibrosis and loss of diastolic function. The loss of oestrogens further aggravates such changes by leading to a notable drop in cardiac output (while preserving normal ejection fraction) in the presence of diffuse fibrosis that is more predominant in endocardium and is accompanied by papillary fibrosis. Excess weight did not markedly aggravate such findings. This animal model recapitulates many of the features recognized in older, female HFpEF patients and thus, may serve to examine the effects of candidate therapeutic agents. ABSTRACT: Two-thirds of patients with heart failure with preserved ejection fraction (HFpEF) are older women, and risk factors include hypertension and excess weight/obesity. Pathophysiological factors that drive early disease development (before heart failure ensues) remain obscure and female animal models are lacking. The study evaluated the intersecting roles of ageing, oestrogen depletion and excess weight on altering cardiac structure/function. Female, 18-month-old, Fischer F344 rats were divided into an aged group, aged + ovariectomy (OVX) and aged + ovariectomy + 10% fructose (OVF) in drinking water (n = 8-16/group) to induce weight gain. Left ventricular (LV) structure/function was monitored by echocardiography. At 22 months of age, animals were anaesthetized and catheter-based haemodynamics evaluated, followed by histological measures of chamber morphometry and collagen density. All aged animals developed hypertension. OVF animals increased body weight. Echocardiography only detected mild chamber remodelling with ageing while intraventricular pressure-volume loop analysis showed significant (P < 0.05) decreases vs. ageing in stroke volume (13% OVX and 15% for OVF), stroke work (34% and 52%) and cardiac output (29% and 27%), and increases in relaxation time (10% OVX) with preserved ejection fraction. Histology indicated papillary and interstitial fibrosis with ageing, which was higher in the endocardium of OVX and OVF groups. With ageing, ovariectomy leads to the loss of diastolic and global LV function while preserving ejection fraction. This model recapitulates many cardiovascular features present in HFpEF patients and may help understand the roles that ageing and oestrogen depletion play in early (pre-HFpEF) disease development.
Asunto(s)
Estrógenos/metabolismo , Fibrosis/patología , Ventrículos Cardíacos/anatomía & histología , Función Ventricular/fisiología , Remodelación Ventricular/fisiología , Envejecimiento , Animales , Colágeno/metabolismo , Ecocardiografía , Femenino , Cardiopatías , Ventrículos Cardíacos/patología , Hemodinámica , Ovariectomía , Ratas , Ratas Endogámicas F344RESUMEN
Dysregulated inflammation following myocardial infarction (MI) promotes left ventricular (LV) remodeling and loss of function. Targeting inflammation resolution by activating formyl peptide receptors (FPRs) may limit adverse remodeling and progression towards heart failure. This study characterized the cellular and signaling properties of Compound 43 (Cmpd43), a dual FPR1/FPR2 agonist, and examined whether Cmpd43 treatment improves LV and infarct remodeling in rodent MI models. Cmpd43 stimulated FPR1/2-mediated signaling, enhanced proresolution cellular function, and modulated cytokines. Cmpd43 increased LV function and reduced chamber remodeling while increasing proresolution macrophage markers. The findings demonstrate that FPR agonism improves cardiac structure and function post-MI.
RESUMEN
BACKGROUND: The incidence of cardiovascular disease is higher in HIV-positive (HIV+) patients than it is in the average population, and combination antiretroviral therapy (cART) is a recognized risk factor for cardiovascular disease. However, the molecular mechanisms that link cART and cardiovascular disease are currently unknown. Our study explores the role of the activation of p90RSK, a reactive oxygen species-sensitive kinase, in engendering senescent phenotype in macrophages and accelerating atherogenesis in patients undergoing cART. METHODS: Peripheral whole blood from cART-treated HIV+ individuals and nontreated HIV-negative individuals was treated with H2O2 (200 µmol/L) for 4 minutes, and p90RSK activity in CD14+ monocytes was measured. Plaque formation in the carotids was also analyzed in these individuals. Macrophage senescence was determined by evaluating their efferocytotic ability, antioxidation-related molecule expression, telomere length, and inflammatory gene expression. The involvement of p90RSK-NRF2 signaling in cART-induced senescence was assessed by p90RSK-specific inhibitor (FMK-MEA) or dominant-negative p90RSK (DN-p90RSK) and NRF2 activator (NRF2A). Further, the severity of atherosclerosis was determined in myeloid cell-specific wild-type and DN-p90RSK transgenic mice. RESULTS: Monocytes from HIV+ patients exhibited higher levels of p90RSK activity and were also more sensitive to reactive oxygen species than monocytes from HIV-negative individuals. A multiple linear regression analysis involving cART, Reynolds cardiovascular risk score, and basal p90RSK activity revealed that cART and basal p90RSK activity were the 2 significant determinants of plaque formation. Many of the antiretroviral drugs individually activated p90RSK, which simultaneously triggered all components of the macrophage senescent phenotype. cART inhibited antioxidant response element reporter activity via ERK5 S496 phosphorylation. NRF2A reversed the H2O2-induced overactivation of p90RSK in cART-treated macrophages by countering the induction of senescent phenotype. Last, the data obtained from our gain- or loss-of-function mice conclusively showed the crucial role of p90RSK in inducing senescent phenotype in macrophages and atherogenesis. CONCLUSIONS: cART increased monocyte/macrophage sensitivity to reactive oxygen species- in HIV+ individuals by suppressing NRF2-ARE activity via p90RSK-mediated ERK5 S496 phosphorylation, which coordinately elicited senescent phenotypes and proinflammatory responses. As such, our report underscores the importance of p90RSK regulation in monocytes/macrophages as a viable biomarker and therapeutic target for preventing cardiovascular disease, especially in HIV+ patients treated with cART.
Asunto(s)
Senescencia Celular , Seropositividad para VIH/metabolismo , VIH-1 , Macrófagos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Animales , Antirretrovirales/administración & dosificación , Femenino , Seropositividad para VIH/tratamiento farmacológico , Seropositividad para VIH/genética , Seropositividad para VIH/patología , Humanos , Macrófagos/patología , Masculino , Ratones , Factor 2 Relacionado con NF-E2/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas 90-kDa/antagonistas & inhibidores , Proteínas Quinasas S6 Ribosómicas 90-kDa/genéticaRESUMEN
BACKGROUND: Compassionate care is recognized as an intrinsic element of patient-centered care. Although the evidence seems to indicate that compassionate care can be developed in health professions students, few methodologies reported have been interprofessional in nature. This paper describes Caregivers Are Heroes, an interprofessional educational strategy designed to imbue compassion/caring. METHODS: The sample population consisted of 51 caregivers and 170 students enrolled in three graduate programs during the 2014 summer semester. Students conducted caregiver interviews (CGI) in interprofessional groups of 3 to 4 students. Pre- and post-CGI surveys were designed to measure change in student attitudes and perceptions from the CGI experience. Questions were taken from the Attitude Towards Helping Others (AHO) scale and the Zarit Burden Interview Screen (ZBIS). RESULTS: Analysis indicated a significant change in responses for one of the four AHO statements and significant correlation between caregiver ZBIS score and student post-CGI ZBIS score. CONCLUSION: Quantitative outcomes support the use of this strategy to promote changes in student attitudes that might lead to caring and compassion when interacting with caregivers and the recipients of their care. The variability of caregiver ZBIS scores is consistent with the literature on caregiver burden and emphasizes the need for students to appreciate the individuality of the caregiver experience.
Asunto(s)
Cuidadores/psicología , Empatía , Empleos en Salud/educación , Relaciones Interprofesionales , Estudiantes del Área de la Salud/psicología , Actitud del Personal de Salud , Educación de Postgrado , HumanosRESUMEN
It is difficult to produce reliable polar strain elastograms (radial and circumferential) because the center of the carotid artery is typically unknown. Principal strain imaging can overcome this limitation, but suboptimal lateral displacement estimates make this an impractical approach for visualizing mechanical properties within the carotid artery. We hypothesized that compounded plane wave imaging can minimize this problem. To test this hypothesis, we performed (i) simulations with vessels of varying morphology and mechanical behavior (i.e., isotropic and transversely isotropic), and (ii) a pilot study with 10 healthy volunteers. The accuracy of principal and polar strain (computed using knowledge of the precise vessel center) elastograms varied between 7% and 17%. In both types of elastograms, strain concentrated at the junction between the fibrous cap and the vessel wall, and the strain magnitude decreased with increasing fibrous cap thickness. Elastograms of healthy volunteers were consistent with those of transversely isotropic homogeneous vessels; they were spatially asymmetric, a trend that was common to both principal and polar strains. No significant differences were observed in the mean strain recovered from principal and polar strains (p > 0.05). This investigation indicates that principal strain elastograms measured with compounding plane wave imaging overcome the problems incurred when polar strain elastograms are computed with imprecise estimates of the vessel center.
Asunto(s)
Arterias Carótidas/fisiología , Simulación por Computador , Diagnóstico por Imagen de Elasticidad/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Anciano , Arterias Carótidas/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU. METHODS: We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children's Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype-phenotype correlations. RESULTS: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys-Drash syndrome. INTERPRETATION: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU.
Asunto(s)
Estudios de Asociación Genética/métodos , Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Unidades de Cuidado Intensivo Neonatal , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Femenino , Humanos , Recién Nacido , Masculino , Mutación , Ontario , Proyectos Piloto , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: A homozygous loss-of-function mutation p.(Arg316Gln) in the fat mass and obesity-associated (FTO) gene, which encodes for an iron and 2-oxoglutarate-dependent oxygenase, was previously identified in a large family in which nine affected individuals present with a lethal syndrome characterised by growth retardation and multiple malformations. To date, no other pathogenic mutation in FTO has been identified as a cause of multiple congenital malformations. METHODS: We investigated a 21-month-old girl who presented distinctive facial features, failure to thrive, global developmental delay, left ventricular cardiac hypertrophy, reduced vision and bilateral hearing loss. We performed targeted next-generation sequencing of 4813 clinically relevant genes in the patient and her parents. RESULTS: We identified a novel FTO homozygous missense mutation (c.956C>T; p.(Ser319Phe)) in the affected individual. This mutation affects a highly conserved residue located in the same functional domain as the previously characterised mutation p.(Arg316Gln). Biochemical studies reveal that p.(Ser319Phe) FTO has reduced 2-oxoglutarate turnover and N-methyl-nucleoside demethylase activity. CONCLUSION: Our findings are consistent with previous reports that homozygous mutations in FTO can lead to rare growth retardation and developmental delay syndrome, and further support the proposal that FTO plays an important role in early development of human central nervous and cardiovascular systems.
Asunto(s)
Discapacidades del Desarrollo/genética , Mutación Missense , Proteínas/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Femenino , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , LactanteRESUMEN
We present the investigation and management of a premature, hypotensive neonate born after a pregnancy complicated by anhydramnios to highlight the impact of early and informed management for rare kidney disease. Vasopressin was used to successfully treat refractory hypotension and anuria in the neonate born at 27 weeks of gestation. Next generation sequencing of a targeted panel of genes was then performed in the neonate and parents. Subsequently, two compound heterozygous deletions leading to frameshift mutations were identified in the angiotensin 1-converting enzyme gene ACE; exon 5:c.820_821delAG (p.Arg274Glyfs*117) and exon24: c.3521delG (p.Gly1174Alafs*12), consistent with a diagnosis of renal tubular dysgenesis. In light of the molecular diagnosis, identification, and treatment of associated low aldosterone level resulted in further improvement in renal function and only mild residual chronic renal failure is present at 14 months of age. Truncating alterations in ACE most often result in fetal demise during gestation or in the first days of life and typically as a result of the Potter sequence. The premature delivery, and serendipitous early treatment with vasopressin, and then later fludrocortisone, resulted in an optimal outcome in an otherwise lethal condition.
Asunto(s)
Anuria/tratamiento farmacológico , Hipotensión/tratamiento farmacológico , Recien Nacido Prematuro/fisiología , Peptidil-Dipeptidasa A/genética , Vasopresinas/uso terapéutico , Adulto , Anuria/genética , Anuria/patología , Secuencia de Bases , Femenino , Fludrocortisona/uso terapéutico , Mutación del Sistema de Lectura/genética , Eliminación de Gen , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hipotensión/genética , Hipotensión/patología , Recién Nacido , Túbulos Renales Proximales/anomalías , Túbulos Renales Proximales/patología , Datos de Secuencia Molecular , Embarazo , Resultado del Tratamiento , Anomalías Urogenitales/genética , Anomalías Urogenitales/patologíaRESUMEN
The aim of this exploratory study was to examine how community-dwelling adults with severe mental illness describe themselves as eaters and how these eating identities relate to dietary intake. Twenty participants completed one in-depth qualitative interview and three 24-h dietary recalls. Two distinct groups were identified; self-described healthy eaters (n = 10) and self-described unhealthy eaters (n = 10). Healthy eaters emphasized fruits and vegetables, limiting sweets, three meals a day, overcoming cost concerns, and benefits of healthy eating. Unhealthy eaters emphasized junk foods, fried foods, few fruits and vegetables, cost and household barriers to healthy eating, and concerns about consequences of unhealthy eating. Self-described healthy eaters consumed significantly more vegetables and less kilocalories, carbohydrates, fat, and saturated fat than self-described unhealthy eaters. Understanding how eating identities relate to dietary intake provides important insights for development of more effective approaches to promote healthy eating in this high risk population.
Asunto(s)
Dieta/métodos , Conducta Alimentaria/psicología , Conductas Relacionadas con la Salud , Trastornos Mentales/rehabilitación , Anciano , Anciano de 80 o más Años , Femenino , Frutas , Promoción de la Salud , Humanos , Entrevista Psicológica , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Investigación Cualitativa , South Carolina , VerdurasRESUMEN
BACKGROUND: P2Y(6), a purinergic receptor for UDP, is enriched in atherosclerotic lesions and is implicated in pro-inflammatory responses of key vascular cell types and macrophages. Evidence for its involvement in atherogenesis, however, has been lacking. Here we use cell-based studies and three murine models of atherogenesis to evaluate the impact of P2Y(6) deficiency on atherosclerosis. METHODOLOGY/PRINCIPAL FINDINGS: Cell-based studies in 1321N1 astrocytoma cells, which lack functional P2Y(6) receptors, showed that exogenous expression of P2Y(6) induces a robust, receptor- and agonist-dependent secretion of inflammatory mediators IL-8, IL-6, MCP-1 and GRO1. P2Y(6)-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y(6) and in acute peritonitis models of inflammation. To evaluate the role of P2Y(6) in atherosclerotic lesion development, we used P2Y(6)-deficient mice in three mouse models of atherosclerosis. A 43% reduction in aortic arch plaque was observed in high fat-fed LDLR knockout mice lacking P2Y(6) receptors in bone marrow-derived cells. In contrast, no effect on lesion development was observed in fat-fed whole body P2Y(6)xLDLR double knockout mice. Interestingly, in a model of enhanced vascular inflammation using angiotensin II, P2Y(6) deficiency enhanced formation of aneurysms and exhibited a trend towards increased atherosclerosis in the aorta of LDLR knockout mice. CONCLUSIONS: P2Y(6) receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells. However, the overall impact of whole body P2Y(6) deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y(6) in vascular disease pathophysiologies, such as aneurysm formation.
Asunto(s)
Aterosclerosis/metabolismo , Macrófagos/metabolismo , Receptores Purinérgicos P2/metabolismo , Animales , Aterosclerosis/inmunología , Línea Celular Tumoral , Citocinas/metabolismo , Femenino , Técnicas de Inactivación de Genes , Humanos , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fenotipo , Receptores de LDL/deficiencia , Receptores de LDL/genética , Receptores Purinérgicos P2/deficiencia , Receptores Purinérgicos P2/genéticaRESUMEN
Educators must determine whether occupational therapy students are adequately prepared for Level II fieldwork once they have successfully completed the didactic portion of their coursework. Although studies have shown that students regard the use of video cameras and simulated patient encounters as useful tools for assessing professional and clinical behaviors, little has been published in the occupational therapy literature regarding the practical application of simulated patients or reflective video analysis. We describe a model for a final Comprehensive Practical Exam that uses both simulated patients and reflective video analysis to assess student preparedness for Level II fieldwork, and we report on student perceptions of these instructional modalities. We provide recommendations for designing, implementing, and evaluating simulated patient experiences in light of existing educational theory.