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Introduction: National arthroplasty registries date back to 1975, when the Swedish Knee Arthroplasty Register was founded. This method of database collecting has since been employed for both patient follow-up and the creation of annual statistical reports. In Bulgaria, there is currently no state-approved software that offers these features. Aim: The current study aimed to report on the preliminary findings from our use of the OrthoWave software and the launch of the first Bulgarian registry for arthroplasty. Materials and methods: Using the OrthoWave program, we gathered data on 215 patients who underwent 218 surgical procedures for hip and knee replacement in the Orthopedics and Traumatology Clinic at Tsaritsa Joanna University Hospital, ISUL, between November 2022 and August 2023. Both demographic indicators (sex, age, and BMI) and characteristics of the surgical procedure (intervention execution time, approach used, type and size of prosthesis) were gathered and analyzed. Results: All subjects had a mean BMI of 29.3 kg/m², calculated using OrthoWave’s statistical analysis system. The average weight during surgery was 93 kg, with an average height of 176 cm. The mean age of patients at the time of surgery was 66.11 years. Sex distribution of patients with hip replacement was as follows: 61.38% of them were men and 32.62% were women. Women accounted for 58.9% of all patients with knee endoprostheses, while operated men accounted for 41.1%. Conclusion: In the era of evidence-based medicine, the form of register is crucial for further development of the orthopedic specialty. Our initial experience is promising, and we are looking forward to its development on a national level.

Purpose – This paper analyzes individual subjective well-being using a survey database from the Strasbourg metropolitan development council (France). The authors focus on the effects of externalities generated by public services (transport, culture and sport), environmental quality and feeling of security in the Strasbourg metropolitan area (Eurométropole de Strasbourg, EMS). Results show that EMS specificities (public facilities, environmental quality, safety and security) and individual features like opportunities to laugh or live with children significantly influence individual well-being. These findings are robust when using three subjective measures: feeling of well-being, environmental satisfaction and social life satisfaction. The authors also show that income may affect the perceived well-being of individuals belonging to a low-income group, while individuals belonging to a high-income group tend to be unsatisfied with environmental quality but satisfied with their social life. Besides, social comparison in terms of income does not matter for individual well-being in the Strasbourg metropolitan area. Design/methodology/approach – Theoretical and empirical paper —Utility theory in economics—Econometric modeling using an ordered probit model. Findings – Specificities of the Strasbourg metropolitan area-France (public services related to transport, culture and sport, environmental quality perceived as convenient for individual health, sense of security) significantly impact individual subjective well-being. Income does not substantially impact the individual subjective perception of happiness: income may matter for the feeling of well-being only for individuals belonging to a low-income group. Wealthy individuals tend to be unsatisfied with environmental quality but satisfied with their social life. Social comparison in terms of income does not matter for individual well-being in the Strasbourg metropolitan area. Research limitations/implications – Cross-sectional data, but it is the only available database from a survey conducted by EMS in 2017 to collect information on potential elements relative to individual well-being in the Strasbourg metropolitan area. Practical implications – Results shed light on the role of territorial policies in improving individual well-being and might provide some guidelines for policy-makers concerned about the population’s welfare. Policy-makers should give strong attention to public facilities (an essential element of local public action) and improve environmental quality. If they care about the population’s happiness, they have to reorient current policies in this direction. Of course, through the inquiry in 2017 giving this database, the Strasbourg agglomeration development council aimed to provide such evidence to the local administration. Nevertheless, the results were a bit upsetting for many people in the administrative and political circles, who generally prioritize economic and demographic development, while the citizens’ responses to the inquiry have revealed a strong focus on the quality of everyday life in their neighborhood. Originality/value – The present study contributes to the literature on subjective well-being, with a focus on the role of local characteristics and living environment. The authors’ starting point is related to the standard utility theory, indicating that environmental quality and public services are positive externalities. The authors investigate whether the local living environment and public facilities are crucial elements explaining individual well-being. To do this, we consider three subjective measures: feeling of well-being, environmental satisfaction and social life satisfaction, which are used as proxies of individual utility. The authors consider different explicative variables representing specificities of EMS in terms of public services (transport, culture and sport), environmental quality perceived as convenient for individual health, safety and security, etc. The authors also provide a test for relative standing by including the median monthly household income at the municipality level.

Le mouvement de décolonisation au sein des institutions universitaires du continent africain s’est traduit au Sénégal par le recrutement d’un personnel africain et par un effort constant dans la confection des curricula. Qu’en est-il ailleurs, au sein d’institutions qui sont ancrées dans le passé colonial des États qui les abritent ? Le cas canadien, du fait de son histoire avec les peuples autochtones, permet aussi de mettre en perspective les dimensions oppressives du point de vue épistémologique et hiérarchique au sein des univers académiques. Cette contribution propose une réflexion sur ces enjeux à partir d’une collaboration pédagogique entre deux collègues appartenant respectivement à une institution sénégalaise et canadienne. Nous arguons que les rapports de pouvoir ancrés dans l’histoire coloniale au sein de l’université peuvent être renégociés grâce à l’ouverture d’espaces d’enseignement alternatifs. Ces derniers, en initiant des programmes et cours innovants reposant sur une collaboration décomplexée et mobilisant une pédagogie sensible peuvent permettre une réelle décolonisation pédagogique et des méthodologies de recherche.

IntroductionGrowth hormone secretagogues (GHSs) exert multiple actions, being able to activate GHS-receptor 1a, control inflammation and metabolism, to enhance GH/insulin-like growth factor-1 (IGF-1)-mediated myogenesis, and to inhibit angiotensin-converting enzyme. These mechanisms are of interest for potentially targeting multiple steps of pathogenic cascade in Duchenne muscular dystrophy (DMD).MethodsHere, we aimed to provide preclinical evidence for potential benefits of GHSs in DMD, via a multidisciplinary in vivo and ex vivo comparison in mdx mice, of two ad hoc synthesized compounds (EP80317 and JMV2894), with a wide but different profile. 4-week-old mdx mice were treated for 8 weeks with EP80317 or JMV2894 (320 µg/kg/d, s.c.).ResultsIn vivo, both GHSs increased mice forelimb force (recovery score, RS towards WT: 20% for EP80317 and 32% for JMV2894 at week 8). In parallel, GHSs also reduced diaphragm (DIA) and gastrocnemius (GC) ultrasound echodensity, a fibrosis-related parameter (RS: ranging between 26% and 75%). Ex vivo, both drugs ameliorated DIA isometric force and calcium-related indices (e.g., RS: 40% for tetanic force). Histological analysis highlighted a relevant reduction of fibrosis in GC and DIA muscles of treated mice, paralleled by a decrease in gene expression of TGF-β1 and Col1a1. Also, decreased levels of pro-inflammatory genes (IL-6, CD68), accompanied by an increment in Sirt-1, PGC-1α and MEF2c expression, were observed in response to treatments, suggesting an overall improvement of myofiber metabolism. No detectable transcript levels of GHS receptor-1a, nor an increase of circulating IGF-1 were found, suggesting the presence of a novel receptor-independent mechanism in skeletal muscle. Preliminary docking studies revealed a potential binding capability of JMV2894 on metalloproteases involved in extracellular matrix remodeling and cytokine production, such as ADAMTS-5 and MMP-9, overactivated in DMD.DiscussionOur results support the interest of GHSs as modulators of pathology progression in mdx mice, disclosing a direct anti-fibrotic action that may prove beneficial to contrast pathological remodeling.

The growth hormone secretagogue receptor (GHSR), primarily known as the receptor for the hunger hormone ghrelin, potently controls food intake, yet the specific Ghsr-expressing cells mediating the orexigenic effects of this receptor remain incompletely characterized. Since Ghsr is expressed in gamma-aminobutyric acid (GABA)–producing neurons, we sought to investigate whether the selective expression of Ghsr in a subset of GABA neurons is sufficient to mediate GHSR's effects on feeding. First, we crossed mice that express a tamoxifen-dependent Cre recombinase in the subset of GABA neurons that express glutamic acid decarboxylase 2 (Gad2) enzyme (Gad2-CreER mice) with reporter mice, and found that ghrelin mainly targets a subset of Gad2 -expressing neurons located in the hypothalamic arcuate nucleus (ARH) and that is predominantly segregated from Agouti-related protein (AgRP)–expressing neurons. Analysis of various single-cell RNA-sequencing datasets further corroborated that the primary subset of cells coexpressing Gad2 and Ghsr in the mouse brain are non-AgRP ARH neurons. Next, we crossed Gad2-CreER mice with reactivable GHSR-deficient mice to generate mice expressing Ghsr only in Gad2 -expressing neurons (Gad2-GHSR mice). We found that ghrelin treatment induced the expression of the marker of transcriptional activation c-Fos in the ARH of Gad2-GHSR mice, yet failed to induce food intake. In contrast, food deprivation–induced refeeding was higher in Gad2-GHSR mice than in GHSR-deficient mice and similar to wild-type mice, suggesting that ghrelin-independent roles of GHSR in a subset of GABA neurons is sufficient for eliciting full compensatory hyperphagia in mice. [ABSTRACT FROM AUTHOR]

Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.

The membrane is an integral component of the G protein-coupled receptor signaling machinery. Here authors demonstrate that lipids regulate the signaling efficacy and selectivity of the ghrelin receptor GHSR through specific interactions and bulk effects and observe PIP2 and GM3 induced shifts of the conformational equilibrium of GHSR away from its inactive state.

Feeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical because of the ubiquitous source of energy-dense foods and the consequent obesity epidemic. Hypothalamic agouti-related peptide-secreting neurons (AgRP neurons) provide the primary orexigenic drive of homeostatic feeding. Using models of neuronal inhibition or ablation, we demonstrate that the feeding response to a fast ghrelin or serotonin receptor agonist relies on AgRP neurons. However, when palatable food is provided, AgRP neurons are dispensable for an appropriate feeding response. In addition, AgRP-ablated mice present exacerbated stress-induced anorexia and palatable food intake--a hallmark of comfort feeding. These results suggest that, when AgRP neuron activity is impaired, neural circuits sensitive to emotion and stress are engaged and modulated by food palatability and dopamine signaling.

There is increasing support for water molecules playing a role in signal propagation through G protein-coupled receptors (GPCRs). However, exploration of the hydration features of GPCRs is still in its infancy. Here, we combined site-specific labeling with unnatural amino acids to molecular dynamics to delineate how local hydration of the ghrelin receptor growth hormone secretagogue receptor (GHSR) is rearranged upon activation. We found that GHSR is characterized by a specific hydration pattern that is selectively remodeled by pharmacologically distinct ligands and by the lipid environment. This process is directly related to the concerted movements of the transmembrane domains of the receptor. These results demonstrate that the conformational dynamics of GHSR are tightly coupled to the movements of internal water molecules, further enhancing our understanding of the molecular bases of GPCR-mediated signaling.

The growth hormone secretagogue receptor (GHSR) signals in response to ghrelin, but also acts via ligand-independent mechanisms that include either constitutive activation or interaction with other G protein-coupled receptors, such as the dopamine 2 receptor (D2R). A key target of GHSR in neurons is voltage-gated calcium channels type 2.2 (CaV2.2). Recently, the liver-expressed antimicrobial peptide 2 (LEAP2) was recognized as a novel GHSR ligand, but the mechanism of action of LEAP2 on GHSR is not well understood. Here, we investigated the role of LEAP2 on the canonical and non-canonical modes of action of GHSR on CaV2.2 function. Using a heterologous expression system and patch-clamp recordings, we found that LEAP2 impairs the reduction of CaV2.2 currents induced by ghrelin-evoked and constitutive GHSR activities, acting as a GHSR antagonist and inverse agonist, respectively. We also found that LEAP2 prevents GHSR from modulating the effects of D2R signaling on CaV2.2 currents, and that the GHSR-binding N-terminal region LEAP2 underlies these effects. Using purified labeled receptors assembled into lipid nanodiscs and Forster Resonance Energy Transfer (FRET) assessments, we found that the N-terminal region of LEAP2 stabilizes an inactive conformation of GHSR that is dissociated from Gq protein and, consequently, reverses the effect of GHSR on D2R-dependent Gi activation. Thus, our results provide critical molecular insights into the mechanism mediating LEAP2 modulation of GHSR.