Glucosylceramide synthase deficiency in the heart compromises β1-adrenergic receptor trafficking

Aims: Cardiac injury and remodelling are associated with the rearrangement of cardiac lipids. Glycosphingolipids are membrane lipids that are important for cellular structure and function, and cardiac dysfunction is a characteristic of rare monogenic diseases with defects in glycosphingolipid synthesis and turnover. However, it is not known how cardiac glycosphingolipids regulate cellular processes in the heart. The aim of this study is to determine the role of cardiac glycosphingolipids in heart function.Methods and results: Using human myocardial biopsies, we showed that the glycosphingolipids glucosylceramide and lactosylceramide are present at very low levels in non-ischaemic human heart with normal function and are elevated during remodelling. Similar results were observed in mouse models of cardiac remodelling. We also generated mice with cardiomyocyte-specific deficiency in Ugcg, the gene encoding glucosylceramide synthase (hUgcg-/- mice). In 9- to 10-week-old hUgcg-/- mice, contractile capacity in response to dobutamine stress was reduced. Older hUgcg-/- mice developed severe heart failure and left ventricular dilatation even under baseline conditions and died prematurely. Using RNA-seq and cell culture models, we showed defective endolysosomal retrograde trafficking and autophagy in Ugcg-deficient cardiomyocytes. We also showed that responsiveness to β-adrenergic stimulation was reduced in cardiomyocytes from hUgcg-/- mice and that Ugcg knockdown suppressed the internalization and trafficking of β1-adrenergic receptors.Conclusions: Our findings suggest that cardiac glycosphingolipids are required to maintain β-adrenergic signalling and contractile capacity in cardiomyocytes and to preserve normal heart function.</p

On the Role of Faith in Sustainability Management: A Conceptual Model and Research Agenda

International audienceThe objective of this article is to develop a faith development perspective on corporate sustainability. A firm’s management of sustainability is arguably determined by the way decision-makers relate to the other and the natural environment, and this relationship is fundamentally shaped by faith. This study advances theoretical understanding of the approach managers take on sustainability issues by explaining how four distinct phases of faith development—improvidence, obedience, irreverence and providence—determine a manager’s disposition towards sustainability. Combining insights from intentional and relational faith development theories, the analysis reveals that a manager’s faith disposition can be measured according to four interrelated process criteria: (1) connectivity as a measure of a manager’s actual engagement and activities aimed at relating to sustainability; (2) inclusivity as a measure of who and what is included or excluded in a manager’s moral consideration; (3) emotional affinity as a measure of a manager’s sensitivity and affection towards the well-being of others and ecological welfare; and (4) reciprocity as a measure of the degree to which a manager is rewarded for responding to the needs and concerns of ‘Others’, mainly in the form of a positive emotional (and relational) stimulus. The conceptual model consolidates earlier scholarly works on the psychological drivers of sustainability management by illuminating our search for a process of faith development that connects with an increasingly complex understanding of the role of business in society

The effect of pelvic tilt and cam on hip range of motion in young elite skiers and nonathletes

Anna Sw&auml;rd Aminoff,1 Cecilia Agnvall,2,3 Carl Todd,1 P&aacute;ll J&oacute;nasson,4 Mikael Sansone,1 Olof Thoreson,1 Leif Sw&auml;rd,1 Jon Karlsson,1 Adad Baranto1 1Department of Orthopaedics, Institute of Clinical Sciences at Sahlgrenska Academy, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden; 2Sports Medicine &Aring;re, &Aring;re, Sweden; 3&Aring;re Ski Academy, &Aring;re, Sweden; 4Orkuh&uacute;si&eth; Orthopedic Clinic, Reykjavik, Iceland Background: Current knowledge of the effect of changes in posture and the way cam morphology of the hip joint may affect hip range of motion (ROM) is limited. Purpose: To determine the effect of changes in pelvic tilt (PT) on hip ROM and with/without the presence of cam. Study design: This was a cross-sectional study. Materials and methods: The hip ROM of 87 subjects (n=61 young elite skiers, n=26 nonathletes) was examined using a goniometer, in three different seated postures (flexed, neutral, and extended). The hips of the subjects were further subgrouped into cam and no-cam morphology, based on the magnetic resonance imaging findings in the hips. Results: There was a significant correlation between the hip ROM and the seated posture in both extended and flexed postures compared with the neutral posture. There was a significant decrease in internal hip rotation when the subjects sat with an extended posture with maximum anterior PT (p&lt;0.0001). There was a significant increase in internal hip rotation when the subjects sat with a flexed posture with maximum posterior PT (p&lt;0.001). External rotation was significantly decreased in an extended posture with maximum anterior PT (p&lt;0.0001), but there was no difference in flexed posture with maximum posterior PT. The hips with cam morphology had reduced internal hip rotation in all three positions, but they responded to the changes in position in a similar manner to hips without cam morphology. Conclusion: Dynamic changes in PT significantly influence hip ROM in young people, independent of cam or no-cam morphology. Keywords: hip, cross-sectional studies, rotation, hip joint, range of motion (articular), pelvis, posture, magnetic resonance imagin

Targeting transcriptional control of soluble guanylyl cyclase via NOTCH for prevention of cardiovascular disease

Soluble guanylyl cyclase (sGC) is an effector enzyme of nitric oxide (NO). Recent work has unravelled how levels of this enzyme are controlled, and highlighted a role in vascular disease. We provide a timely summary of available knowledge on transcriptional regulation of sGC, including influences from the NOTCH signalling pathway and genetic variants. It is speculated that hypertension-induced repression of sGC starts a vicious circle that can be initiated by periods of stress, diet or genetic factors, and a key tenet is that reduction in sGC further raises blood pressure. The idea that dysregulation of sGC contributes to syndromes caused by defective NOTCH signalling is advanced, and we discuss drug repositioning for vascular disease prevention. The advantage of targeting sGC expression rather than activity is also considered. It is argued that transcriptional inputs on sGC arise from interactions with other cells, the extracellular matrix and microRNAs (miRNAs), and concluded that the promise of sGC as a target for prevention of cardiovascular disease has increased in recent time

The epidemiology of scaphoid fractures in Sweden : a nationwide registry study

The epidemiology of scaphoid fractures has been described in limited populations, and incidence reports have been inconsistent. We investigated the nationwide incidence of scaphoid fractures by evaluating data on 34,377 patients in the Swedish National Patient Register for the years 2006–2015 regarding diagnosis, age, sex and treatment. The data were validated in 300 random patients, and incidence rates were adjusted accordingly. Forty-one per cent of the initially diagnosed fractures were false positives. The adjusted true fracture incidence rate was 22 per 100,000 person-years. During the decade studied incidence rates decreased in younger men and increased in middle-aged women. The incidence of surgical treatment vs. non-operative treatment did not change over time. Men were treated surgically more often than women (6% vs. 3%) and had a greater risk for nonunion (3% vs. 1%)