Orphan nuclear receptor Nur77 affects cardiomyocyte calcium homeostasis and adverse cardiac remodelling

Distinct stressors may induce heart failure. As compensation, β-adrenergic stimulation enhances myocardial contractility by elevating cardiomyocyte intracellular Ca2+ ([Ca2+]i). However, chronic β-adrenergic stimulation promotes adverse cardiac remodelling. Cardiac expression of nuclear receptor Nur77 is enhanced by β-adrenergic stimulation, but its role in cardiac remodelling is still unclear. We show high and rapid Nur77 upregulation in cardiomyocytes stimulated with β-adrenergic agonist isoproterenol. Nur77 knockdown in culture resulted in hypertrophic cardiomyocytes. Ventricular cardiomyocytes from Nur77-deficient (Nur77-KO) mice exhibited elevated diastolic and systolic [Ca2+]i and prolonged action potentials compared to wild type (WT). In vivo, these differences resulted in larger cardiomyocytes, increased expression of hypertrophic genes

Satisfaction in Older Persons and General Practitioners during the Implementation of Integrated Care.

Integrated care for older persons with complex care needs is widely advocated. Particularly professionals and policy makers have positive expectations. Care outcome results are ambiguous. Receiver and provider satisfaction is relevant but still poorly understood.During implementation of integrated care in residential homes (The MOVIT project), we compared general satisfaction and satisfaction with specific aspects of General Practitioner (GP) care in older persons and GPs before (cohort I) and after at least 12 months of implementation (cohort II).The general satisfaction score for GP care given by older persons does not change (Cohort I (n = 762) mean score 8.0 (IQR:7.0-9.0) vs. Cohort II (n = 505) mean score 8.0 (IQR:7.0-8.0);P = 0.01). Expressions of general satisfaction in GPs do not show consistent change (Cohort I (n = 87) vs Cohort II (n = 66), percentage satisfied about; role as GP, 56% vs 67%;P = 0.194, ability to provide personal care, 60% vs 67%;P = 0.038, quality of care, 54% vs 62%;P = 0.316). Satisfaction in older persons about some specific aspects of care do show change; GP-patient relationship, points 61.6 vs 63.3;P = 0.001, willingness to talk about mistakes, score 3.47 vs 3.73;P = 0.001, information received about drugs, score 2.79 vs 2.46;P = 0.002. GPs also report changes in specific aspects: percentage satisfied about multidisciplinary meetings; occurrence, 21% vs 53%;P = <0.001, GP presence, 12% vs 41%;P = <0.001, and participation, 29% vs.51%;P = 0.046.General satisfaction about care received and provided shows no consistent change in older persons and GPs during the implementation of integrated care. Specific changes in satisfaction are found. These show an emphasis on inter-personal aspects in older persons and organizational aspects in GPs

Perceived doctor-patient relationship and satisfaction with general practitioner care in older persons in residential homes

Objective: Understanding patient satisfaction from the perspective of older adults is important to improve quality of their care. Since patient and care variables which can be influenced are of specific interest, this study examines the relation between patient satisfaction and the perceived doctor-patient relationship in older persons and their general practitioners (GPs). Design: Cross-sectional survey. Subjects and setting: Older persons (n = 653, median age 87 years; 69.4% female) living in 41 residential homes. Main outcome measures: Patient satisfaction (report mark) and perceived doctor-patient relationship (Leiden Perioperative care Patient Satisfaction questionnaire); relationships were examined by comparing medians and use of regression models. Results: The median satisfaction score was 8 (interquartile range 7.5–9; range 0–10) and doctor-patient relationship 65 (interquartile range 63–65; range 13–65). Higher satisfaction scores were related to higher scores on doctor-patient relationship (Jonckheere Terpstra test, p for trend <.001) independent of gender, age, duration of stay in the residential home, functional and clinical characteristics. Adjusted for these characteristics, per additional point for doctor-patient relationship, satisfaction increased with 0.103 points (β = 0.103, 95% CI 0.092–0.114; p < .001). In those with a ‘low’ doctor-patient relationship rating, the percentage awarding ‘sufficient or good’ to their GP for ‘understanding about the personal situation’ was 12%, ‘receiving attention as an individual’ 22%, treating the patient kindly 78%, and being polite 94%. Conclusion: In older persons, perceived doctor-patient relationship and patient satisfaction are related, irrespective of patient characteristics. GPs may improve patient satisfaction by focusing more on the affective aspects of the doctor-patient relationship.Key Points Examination of the perceived doctor-patient relationship as a variable might better accommodate patients’ expectations and improve satisfaction with the provided primary care

General satisfaction about General Practitioner care reported by older persons and General Practitioners.

<p>General satisfaction about General Practitioner care reported by older persons and General Practitioners.</p

Satisfaction about specific aspects of integrated care of GP care in General Practitioners.

<p>Satisfaction about specific aspects of integrated care of GP care in General Practitioners.</p

Satisfaction about specific aspects of integrated care in GP care in older persons.

<p>Satisfaction about specific aspects of integrated care in GP care in older persons.</p

Characteristics of participating older persons having had at least one contact with a General Practitioner in the preceding 12 months and participating General Practitioners.

<p>Characteristics of participating older persons having had at least one contact with a General Practitioner in the preceding 12 months and participating General Practitioners.</p

Malic Acid Production by Saccharomyces cerevisiae: Engineering of Pyruvate Carboxylation, Oxaloacetate Reduction, and Malate Export▿ †

Malic acid is a potential biomass-derivable “building block” for chemical synthesis. Since wild-type Saccharomyces cerevisiae strains produce only low levels of malate, metabolic engineering is required to achieve efficient malate production with this yeast. A promising pathway for malate production from glucose proceeds via carboxylation of pyruvate, followed by reduction of oxaloacetate to malate. This redox- and ATP-neutral, CO2-fixing pathway has a theoretical maximum yield of 2 mol malate (mol glucose)−1. A previously engineered glucose-tolerant, C2-independent pyruvate decarboxylase-negative S. cerevisiae strain was used as the platform to evaluate the impact of individual and combined introduction of three genetic modifications: (i) overexpression of the native pyruvate carboxylase encoded by PYC2, (ii) high-level expression of an allele of the MDH3 gene, of which the encoded malate dehydrogenase was retargeted to the cytosol by deletion of the C-terminal peroxisomal targeting sequence, and (iii) functional expression of the Schizosaccharomyces pombe malate transporter gene SpMAE1. While single or double modifications improved malate production, the highest malate yields and titers were obtained with the simultaneous introduction of all three modifications. In glucose-grown batch cultures, the resulting engineered strain produced malate at titers of up to 59 g liter−1 at a malate yield of 0.42 mol (mol glucose)−1. Metabolic flux analysis showed that metabolite labeling patterns observed upon nuclear magnetic resonance analyses of cultures grown on 13C-labeled glucose were consistent with the envisaged nonoxidative, fermentative pathway for malate production. The engineered strains still produced substantial amounts of pyruvate, indicating that the pathway efficiency can be further improved

Glycosphingolipid-Glycan Signatures of Acute Myeloid Leukemia Cell Lines Reflect Hematopoietic Differentiation

Aberrant expression of certain glycosphingolipids (GSLs) is associated with the differentiation of acute myeloid leukemia (AML) cells. However, the expression patterns of GSLs in AML are still poorly explored because of their complexity, the presence of multiple isomeric structures, and tedious analytical procedures. In this study, we performed an in-depth GSL glycan analysis of 19 AML cell lines using porous graphitized carbon liquid chromatography-mass spectrometry revealing strikingly different GSL glycan profiles between the various AML cell lines. The cell lines of the M6 subtype showed a high expression of gangliosides with α2,3-sialylation and Neu5Gc, while the M2 and M5 subtypes were characterized by high expression of (neo)lacto-series glycans and Lewis A/X antigens. Integrated analysis of glycomics and available transcriptomics data revealed the association of GSL glycan abundances with the transcriptomics expression of certain glycosyltransferases (GTs) and transcription factors (TFs). In addition, correlations were found between specific GTs and TFs. Our data reveal TFs GATA2, GATA1, and RUNX1 as candidate inducers of the expression of gangliosides and sialylation via regulation of the GTs ST3GAL2 and ST8SIA1. In conclusion, we show that GSL glycan expression levels are associated with hematopoietic AML classifications and TF and GT gene expression. Further research is needed to dissect the regulation of GSL expression and its role in hematopoiesis and associated malignancies

The metabolic hormone adiponectin affects the correlation between nutritional status and pneumococcal vaccine response in vulnerable indigenous children.

BackgroundAlmost 200 million children worldwide are either undernourished or overweight. Only a few studies have addressed the effect of variation in nutritional status on vaccine response. We previously demonstrated an association between stunting and an increased post-vaccination 13-valent pneumococcal conjugate vaccine (PCV13) response. In this prospective study, we assessed to what extent metabolic hormones may be a modifier in the association between nutritional status and PCV13 response.MethodsVenezuelan children aged 6 weeks to 59 months were vaccinated with a primary series of PCV13. Nutritional status and serum levels of leptin, adiponectin and ghrelin were measured upon vaccination and their combined effect on serum post-vaccination antibody concentrations was assessed by generalized estimating equations multivariable regression analysis.ResultsA total of 210 children were included, of whom 80 were stunted, 81 had a normal weight and 49 were overweight. Overweight children had lower post-vaccination antibody concentrations than normal weight children (regression coefficient -1.15, 95% CI -2.22 --0.072). Additionally, there was a significant adiponectin-nutritional status interaction. In stunted children, higher adiponectin serum concentrations were associated with lower post-PCV13 antibody concentrations (regression coefficient -0.19, 95% CI -0.24 --0.14) while the opposite was seen in overweight children (regression coefficient 0.14, 95% CI 0.049-0.22).ConclusionMetabolic hormones, in particular adiponectin, may modify the effect of nutritional status on pneumococcal vaccine response. These findings emphasize the importance of further research to better understand the immunometabolic pathways underlying vaccine response and enable a future of optimal personalized vaccination schedules