Gli1 Defines a Subset of Fibro-adipogenic Progenitors that Promote Skeletal Muscle Regeneration With Less Fat Accumulation

Skeletal muscle has remarkable regenerative ability after injury. Mesenchymal fibro-adipogenic progenitors (FAPs) are necessary, active participants during this repair process, but the molecular signatures of these cells and their functional relevance remain largely unexplored. Here, using a lineage tracing mouse model (Gli1-CreER Tomato), we demonstrate that Gli1 marks a small subset of muscle-resident FAPs with elevated Hedgehog (Hh) signaling. Upon notexin muscle injury, these cells preferentially and rapidly expanded within FAPs. Ablation of Gli1+ cells using a DTA mouse model drastically reduced fibroblastic colony-forming unit (CFU-F) colonies generated by muscle cells and impaired muscle repair at 28 days. Pharmacologic manipulation revealed that Gli1+ FAPs rely on Hh signaling to increase the size of regenerating myofiber. Sorted Gli1+ FAPs displayed superior clonogenicity and reduced adipogenic differentiation ability in culture compared to sorted Gli1− FAPs. In a glycerol injury model, Gli1+ FAPs were less likely to give rise to muscle adipocytes compared to other FAPs. Further cell ablation and Hh activator/inhibitor treatments demonstrated their dual actions in enhancing myogenesis and reducing adipogenesis after injury. Examining single-cell RNA-sequencing dataset of FAPs from normal mice indicated that Gli1+ FAPs with increased Hh signaling provide trophic signals to myogenic cells while restrict their own adipogenic differentiation. Collectively, our findings identified a subpopulation of FAPs that play an essential role in skeletal muscle repair. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Association of sleep duration and quality with immunological response after vaccination against severe acute respiratory syndrome coronavirus-2 infection

Growing evidence suggests that sleep could affect the immunological response after vaccination. The aim of this prospective study was to investigate possible associations between regular sleep disruption and immunity response after vaccination against coronavirus disease 2019 (COVID-19). In total, 592 healthcare workers, with no previous history of COVID-19, from eight major Greek hospitals were enrolled in this study. All subjects underwent two Pfizer–BioNTech messenger ribonucleic acid (mRNA) COVID-19 vaccine BNT162b2 inoculations with an interval of 21 days between the doses. Furthermore, a questionnaire was completed 2 days after each vaccination and clinical characteristics, demographics, sleep duration, and habits were recorded. Blood samples were collected and anti-spike immunoglobulin G antibodies were measured at 20 ± 1 days after the first dose and 21 ± 2 days after the second dose. A total of 544 subjects (30% males), with median (interquartile range [IQR]) age of 46 (38–54) years and body mass index of 24·84 (22.6–28.51) kg/m² were eligible for the study. The median (IQR) habitual duration of sleep was 6 (6–7) h/night. In all, 283 participants (52%) had a short daytime nap. In 214 (39.3%) participants the Pittsburgh Sleep Quality Index score was >5, with a higher percentage in women (74·3%, p < 0.05). Antibody levels were associated with age (r = −0.178, p < 0.001), poor sleep quality (r = −0.094, p < 0.05), insomnia (r = −0.098, p < 0.05), and nap frequency per week (r = −0.098, p < 0.05), but after adjusting for confounders, only insomnia, gender, and age were independent determinants of antibody levels. It is important to emphasise that insomnia is associated with lower antibody levels against COVID-19 after vaccination.     

Pharmacotherapy in complicated parapneumonic pleural effusions and thoracic empyema

Parapneumonic pleural effusions (PPE) and pleural empyema (PE) present a frequently diagnostic and therapeutic challenge in clinical practice. Although pleural diseases have received increased attention during the past decade, there are still many unanswered questions concerning the diagnosis and treatment of PPE and PE. A lack of controlled studies concerning the management of PPE and PE was noted in recent guidelines. The use of fibrinolytics intrapleurally appears to enhance intercostals tube drainage, reducing the requirement for subsequent surgical mechanical debridement. Recently, there has been interest in other intrapleural agents including combination drugs consisting of streptokinase and streptodornase-alpha, Dnase. Factors to be considered in evaluating whether or not intrapleural instillation of fibrinolytics is effective include an assessment of clinical responses. This review discusses the use of fibrinolytic agents as a novel therapeutic options for treating the various stages of parapneumonic effusions and empyemas.     

Loss of dopamine D2 receptors induces atrophy in the temporal and parietal cortices and the caudal thalamus of ethanol-consuming mice

Background: The need of an animal model of alcoholism becomes apparent when we consider the genetic diversity of the human populations, an example being dopamine D2 receptor (DRD2) expression levels. Research suggests that low DRD2 availability is associated with alcohol abuse, while higher DRD2 levels may be protective against alcoholism. This study aims to establish whether (i) the ethanol‐consuming mouse is a suitable model of alcohol‐induced brain atrophy and (ii) DRD2 protect the brain against alcohol toxicity. Methods: Adult Drd2+/+ and Drd2?/? mice drank either water or 20% ethanol solution for 6 months. At the end of the treatment period, the mice underwent magnetic resonance (MR) imaging under anesthesia. MR images were registered to a common space, and regions of interest were manually segmented. Results: We found that chronic ethanol intake induced a decrease in the volume of the temporal and parietal cortices as well as the caudal thalamus in Drd2?/? mice. Conclusions: The result suggests that (i) normal DRD2 expression has a protective role against alcohol‐induced brain atrophy and (ii) in the absence of Drd2 expression, prolonged ethanol intake reproduces a distinct feature of human brain pathology in alcoholism, the atrophy of the temporal and parietal cortices.     

Mental health need: use of administrative data and record linkage to inform mental health policy and practice

Background

With mental ill-health on the rise globally, it is crucial to investigate whether the needs of individuals with mental ill-health are fully addressed. Attempts to measure negative consequences of unmet needs have been limited by the use of cross-sectional study designs or self-report measures. We aimed to investigate the interplay between perceived mental ill-health and unmet need in relation to mental health on a population level.

Physicians’ brain drain in Greece: A perspective on the reasons why and how to address it

This review study explores the “brain drain” currently evident amongst physicians in Greece, which is closely linked to the country's severe financial woes. In particular, it shows that the Greek healthcare labour market offers few opportunities and thus physicians are forsaking their homeland to seek jobs abroad. The main causes generating or greatly inflating the brain drain of Greek physicians are unemployment, job insecurity, income reduction, over-taxation, together with limited budgets for research institutes. It is argued that, to stop the evolving mass exodus of skilled medical staff, policy-makers should implement fiscal and human-centred approaches, thoroughly safeguarding both the right of skilled Greek physicians to work in their homeland with motivation and dignity, but also of Greek citizens to continue receiving high-quality healthcare by skilled physicians at times when this is mostly needed.     

Novel high energy intermediate analogues with triazasterol-related structures as inhibitors of ergosterol biosynthesis. Part I: synthesis and antifungal activity of N-alkyl-N'-(phenethyl- and cyclohexenylethyl)guanidines and N2-substituted 2-imidazolinamines

A series of N-alkyl-N'-(phenethyl- and cyclohexenylethyl) guanidines and N(2)- and N(2), 4-substituted imidazolin-2-amine hydrochlorides with triazasterol-related structures was designed and synthesized as stable analogues to mimic high energy intermediates of ergosterol biosynthesis. The in vitro antifungal susceptibility tests with a standard panel of pathogenic fungi revealed moderate to strong antimycotic effects of the sixteen prepared compounds, in some cases comparable with the activity observed for itraconazole.