Obesity is a growing global health challenge associated with major cardiometabolic complications. While bariatric surgery remains the most effective treatment for severe obesity, recent advances in incretin-based pharmacotherapy, multi-receptor agonists, and endoscopic bariatric procedures have substantially expanded therapeutic options. Beyond mechanical restriction, these interventions exert their effects through complex hormonal and neurophysiological mechanisms involving gut-brain signaling, gastric motility, and enteroendocrine adaptations. Gut-derived hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), amylin, and leptin, play a central role in the regulation of hunger, satiation, and satiety by integrating nutrient sensing, vagal afferent signaling, and central hypothalamic pathways. Surgical procedures such as laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass induce profound and durable hormonal remodeling, whereas endoscopic sleeve gastroplasty primarily modulates gastric physiology with more modest and heterogeneous endocrine effects. Intragastric balloons induce a transient delay in gastric emptying and achieve moderate short-term weight loss, although their metabolic and weight-loss effects appear limited in durability. In parallel, GLP-1 receptor agonists and emerging multi-agonist therapies reproduce several post-bariatric hormonal adaptations and achieve clinically meaningful weight loss. In this review, we summarize current knowledge on digestive hormone physiology and provide an updated overview of the hormonal mechanisms underlying pharmacologic, endoscopic, and surgical bariatric interventions, highlighting their respective roles within a continuum of obesity treatment strategies.
Abstract Human development begins with the fusion of sperm and oocyte, yet the maternal genome plays a far more active and essential role than traditionally appreciated. This review critically examines the influence of maternal genetic integrity on embryogenesis and offspring health, emphasizing that the maternal genome is not merely a passive donor of half the DNA, but a vital architect of early life. We explore the role of maternal effect genes (MEGs) in orchestrating early zygotic development, detailing their functions in epigenetic regulation, mitochondrial dynamics, DNA repair, and cell division. A curated reference of MEGs, spanning mouse models and human pathogenic variants, is presented to support future research and clinical diagnostics. Beyond early embryonic development, maternal genetic integrity has lasting implications for offspring well-being. Errors in DNA replication and repair machinery within the maternal germline can lead to de novo variants (DNVs)—spontaneous germline variants that can be passed on to the offspring and impact their health at different ages. We highlight an underappreciated contribution of maternally derived DNVs to a growing list of sporadic disorders and present the first comprehensive catalogue of associated diseases. We further examine DNVs compatible with multigenerational transmission, investigating how maternal age and mutational processes—such as recombination errors and epigenetic drift—influence both disease risk and evolutionary outcomes. By integrating insights from developmental biology, genomics, and reproductive medicine, this review reframes the maternal genome as a dynamic and fragile foundation upon which life depends—offering new directions for understanding fertility, sporadic disease, and intergenerational health.
Immune checkpoint molecules (ICMs) are a class of surface proteins predominantly expressed on immune cells that play a key role in maintaining immune homeostasis by regulating the functions of T cells and other immune cells. Beyond their established immunoregulatory roles, emerging evidence indicates that ICMs are also involved in metabolic regulation. Within the tumor microenvironment (TME), tumour-derived ICMs have been shown to modulate glucose, amino acid, and lipid metabolism in infiltrating T cells, thereby influencing their metabolic reprogramming and functional states. Certain ICMs expressed on immune cells may directly regulate systemic metabolism through cell-intrinsic, immune-independent mechanisms. Moreover, specific ICMs are constitutively expressed in key metabolic tissues, such as pancreatic islets, liver, and adipose tissue, where they are thought to contribute to the maintenance of systemic metabolic homeostasis. Clinically, host metabolic status can affect the efficacy of immune checkpoint inhibitor (ICI) therapies. Conversely, ICI treatment can lead to metabolism-related adverse effects, such as ICI-associated diabetes (ICI-DM), which may extend beyond classic autoimmune insulin-dependent diabetes. Accumulating evidence suggests that ICMs can exert direct regulatory roles in metabolism independent of their canonical immune functions. Elucidating how ICMs regulate metabolism could, on the one hand, improve ICI therapy by maintaining metabolic homeostasis and preventing T cell exhaustion, and on the other hand, facilitate the development of novel therapeutic strategies for metabolic diseases that simultaneously target metabolic and inflammatory pathways. This review synthesises current knowledge on the metabolic roles and regulatory mechanisms of ICMs.
The prevalence of obesity is steadily increasing worldwide. Obesity profoundly alters the composition, structure, and function of adipose tissue (AT), the largest endocrine organ in the body. Adipose-derived mesenchymal stem cells (ASCs) are central to AT plasticity and become dysfunctional in obesity. In this review, we outline the molecular regulation of ASCs in self-renewal and differentiation, and their roles in regulating AT expansion, modulating immune and inflammatory response, and remodeling the extracellular matrix (ECM), positioning ASCs as decisive homeostatic regulators of AT. By integrating recent findings from cutting-edge studies and performing extensive bioinformatic analyses, we delineate ASC differentiation trajectories and propose a fundamentally revised view of ASCs with a heterogeneous hierarchy of functionally distinct subpopulations. Obesity impairs ASC subsets in their self-renewal and differentiation, driving fibro-inflammatory phenotypes that promote maladaptive immune response, ECM stiffening and fibrosis, and premature cellular senescence, acting as central hubs of obesity-associated tissue dysfunction. These alterations likely arise from reprogrammed ASC epigenomic landscapes and obesogenic niches characterized by an inflammatory milieu, toxic metabolites, and oxidative stress. Interestingly, substantial weight loss attenuates fibro-inflammatory stromal states and partially restores ASC pools, whereas fibrosis-associated transcriptional programs and niche memory persist, indicating incomplete reversal of obesity-induced stromal remodeling. Drawing on human, mouse, and experimental single-cell datasets, we provide mechanistic insights into the ASC-immune cell-ECM regulatory network, highlighting how obesity reshapes ASC identity, lineage trajectories, and niche signaling. Finally, we propose that therapeutic restoration of ASC plasticity may represent a promising strategy to reestablish AT homeostasis and limit the progression of metabolic disease.
Congenital pituitary hormone deficiency (CH) is a rare disorder that usually involves deficient production of growth hormone (GH) and other pituitary hormones. Many cases are syndromic, affecting other aspects of craniofacial development and sometimes other organs. There are many genes implicated in congenital pituitary hormone deficiency, and some of them also cause more severe disorders like septo-optic dysplasia (SOD) and holoprosencephaly (HPE). It is not clear why mutations in the same gene can cause such variable clinical features. In addition, the molecular etiology of many cases is not identified with current genetic testing approaches. To realize the promise of the human genome project, more genetic causes need to be identified, and the basis for variable clinical presentations needs to be better understood. In this review we provide information about the overlapping genetic causes of this spectrum of disorders in humans, discuss the influence of genetic background and environment on presentations, and highlight animal models that expand our understanding of how genetic and environmental factors can synergize to generate diverse phenotypes. Evidence for genetic and environmental contributions to this spectrum of disorders is strong.
Obesity is an alarmingly growing global epidemic strongly associated with type 2 diabetes, cardiovascular disease, metabolic syndrome, and chronic kidney disease. Metabolic dysfunction-associated steatotic liver disease (MASLD) is considered an important contributor within this interconnected spectrum, representing a new component of the broader cardio-kidney-metabolic (CKM) syndrome, now more aptly labelled as the cardio-kidney-liver-metabolic (CKLM) syndrome. This narrative review synthesizes evidence from epidemiological studies, clinical trials, and ongoing scientific research to explore the multifaceted associations, complex interplay and shared pathophysiological mechanisms among these disorders. The clinical implications of this interplay are substantial, underscoring the need for a holistic approach encompassing early detection, comprehensive risk assessment, and multi-targeted interventions. Therapeutic strategies discussed include lifestyle modification, anti-diabetic, anti-obesity, lipid-lowering agents, and bariatric surgery. Given MASLD's potential role in the CKLM spectrum, future research should deepen the understanding of shared mechanisms and develop integrated clinical management strategies to improve outcomes and reduce their global burden.
The textbook view of the regulation of calcium homeostasis centers on parathyroid hormone, calcitriol, and calcitonin. While this paradigm has long dominated the field, it represents only part of a broader evolutionary and physiological landscape. This article focuses on Stanniocalcin 1 (STC1), a calciotropic hormone originally discovered in bony fish. Since its discovery in the 1970s, our understanding of STC1 has evolved from a "fish-specific" hormone to a member of a multifunctional glycoprotein family with deep roots in metazoan evolution. Recent studies in zebrafish show that STC1 inhibits calcium uptake through two mechanisms: it reduces TRPV6-dependent calcium influx and limits the proliferation of calcium-transporting ionocytes. Mechanistically, STC1 suppresses local insulin-like growth factor (IGF) signaling by binding pappalysin-family IGF-binding protein (IGFBP) proteases, thereby modulating IGFBP processing and downstream IGF activity. This STC1-Pappalysin-IGFBP-IGF axis has recently been positioned as a central node in an organ-brain communication pathway that links calcium uptake to brain function and animal behavior. In humans and other mammals, STC1 is expressed in many tissues locally and exerts local actions in a paracrine fashion. Dysregulation of STC1 expression has been associated with chronic kidney diseases and multiple cancer types. Recent studies have uncovered a novel role for STC1 in tumor immune evasion as a phagocytosis checkpoint and a "don't eat me" signal. This review integrates recent findings on the multifunctional roles of STC1 in regulating calcium homeostasis, IGF signaling, and cancer immunity, and to highlight the therapeutic potential of targeting STC1 in kidney diseases and cancer immunotherapy.
Sex steroid hormones, such as estrogen, progesterone, and testosterone, are primarily known as critical regulators of reproductive function in both males and females. However, increasing evidence indicates that fluctuating levels of sex hormones also affect non-reproductive organs, including tissues in the musculoskeletal system. Observations from muscle and bone literature support a model in which hormonal state modulates exercise-induced mechanotransduction and downstream extracellular matrix (ECM) remodeling. However, soft connective tissues - cartilage, meniscus, tendon, ligament, intervertebral disc - are often overlooked, despite being the primary sites of career-ending sports injuries and chronic degeneration. This review focuses on these tissues, aiming to examine how sex hormones and other sex-specific molecules critically regulate the process of exercise adaptation at the tissue level. We first outline sex steroid biosynthesis, bioavailability, and receptor mechanisms and then examine how steroids intersect with mechanosensing and mechanotransduction. Looking further downstream, we then assess how hormonal state regulates ECM turnover and functional adaptations. We propose novel connections and mechanisms by which sex hormones and other sex-specific molecules determine load-induced responses via specific mechanotransduction pathways and through ECM remodeling. We conclude by outlining open questions and experimental needs that would aid in establishing causal relationships between sex hormones and exercise responses in soft musculoskeletal tissues.
This consensus paper, jointly developed by the Austrian Society of Laboratory Medicine and Clinical Chemistry (OGLMKC), the Austrian Society for Quality Assurance and Standardization of Medicinal Diagnostics (OQUASTA), and the Austrian Society of Nephrology (OGN), outlines standardized approaches to the laboratory diagnosis of chronic kidney disease (CKD) within the framework of cardiovascular-renal-metabolic health. CKD represents a major public health burden, with low awareness among affected individuals and significant implications for morbidity, mortality, and healthcare costs.The document emphasizes the central role of two key laboratory parameters-the estimated glomerular filtration rate (eGFR) and the urinary albumin-to-creatinine ratio (uACR)-for early detection, diagnosis, and monitoring of CKD. It highlights current gaps in implementation, particularly the underuse of uACR in routine screening as well as challenges arising from methodological heterogeneity and lack of standardization.The consensus provides detailed recommendations for analytical and preanalytical standardization, uniform calculation methods recommending the EKFC equation to evaluate eGFR, structured reporting, and the integration of risk prediction tools such as the kidney failure risk equation (KFRE). It further addresses quality assurance measures, including external proficiency testing, and stresses the importance of harmonized reporting formats to improve clinical interpretation.Finally, the paper calls for systematic integration of CKD screening into primary care, improved reimbursement structures, and enhanced digital integration of laboratory data. The overarching goal is to improve early detection, ensure comparability of results, and strengthen patient care across healthcare settings.
DAX-1 (NR0B1) is a pivotal regulator of mammalian reproductive and endocrine development. Discovered as a gene whose dosage imbalance can reverse sex in XY individuals, DAX-1 is now recognized as a key component of the network controlling gonadal formation and function. Despite decades of research, the molecular mechanisms of its function in gonad development and function remain only partially understood. We combine genetic, developmental, molecular and biochemical perspectives to present how DAX-1 regulates gene expression from early sex determination and gonadal differentiation to the maintenance of steroidogenic homeostasis in adrenal and gonadal tissues. Recent advances have reshaped our view of DAX-1 beyond its classical role as a transcriptional repressor. Evidence shows that it functions within dynamic transcriptional networks, interacting with regulators such as SF-1 (NR5A1), SOX9 and other nuclear receptors to fine-tune gene expression in a context-dependent manner. Genomic, structural, and proteomic studies reveal that DAX-1 participates in complexes integrating developmental and hormonal cues, coordinating differentiation and steroidogenesis. Moreover, its emerging roles in RNA-associated gene regulation broaden its functions beyond canonical nuclear receptor signaling. We revisit DAX-1 contribution to sex determination and differentiation from an evolutionary and mechanistic viewpoint, emphasizing its interactions with the SRY-SOX9 axis and its dosage-sensitive influence on gonadal fate. The developmental and clinical consequences of DAX-1 mutations and copy number variations manifest as a spectrum of human phenotypes, from adrenal hypoplasia congenita to differences/disorders of sex development (DSD), highlighting its essential role in maintaining endocrine balance.
Neurological involvement in Q fever is rare, often presenting with non-specific symptoms and posing significant diagnostic challenges. We report a case of Q fever meningoencephalitis characterized by a relapse of neurological symptoms and atypical cerebrospinal fluid findings. In addition, we conducted a review of published English language cases of acute Q fever with neurological manifestations reported over the past 35 years. A 49-year-old previously healthy woman presented with acute aphasia and somnolence. Cerebrospinal fluid analysis revealed lymphocytic pleocytosis with elevated protein. Brain imaging was unremarkable, while the electroencephalogram demonstrated bilateral frontotemporal slowing. After initial improvement, she experienced a relapse with transient aphasia, confusion and fever. A repeat lumbar puncture revealed neutrophilic pleocytosis with elevated protein. Extensive investigations excluded viral, bacterial, autoimmune and neoplastic etiologies. Serology identified infection with Coxiella burnetii. She was treated with doxycycline for 14 days and made a complete recovery. This case highlights the diagnostic complexity of Q fever meningoencephalitis, presenting with a relapse of neurological symptoms and unusual cerebrospinal fluid findings. These features may reflect infection-related inflammation, although postinfectious vasculitis or seizure-related phenomena cannot be excluded. The case underscores the importance of considering Q fever in atypical or fluctuating meningoencephalitis, even in regions with low incidence, and illustrates the diagnostic value of serology. We also provide a review of previously reported neurological manifestations of acute Q fever to provide broader clinical context. While the overall clinical and serological findings strongly support Q fever-associated central nervous system involvement, some degree of diagnostic uncertainty remains given the multifactorial mechanisms that may contribute to neurological manifestations.
Resuscitative thoracotomy (RT) is recommended for selected patients with traumatic cardiac arrest, particularly after penetrating trauma; however, most evidence is derived from high-volume centers, creating uncertainty about its implementation in settings with a low prevalence of penetrating injuries. This study aimed to develop evidence-informed, consensus-based recommendations for the systematic implementation of RT in such contexts. A modified Delphi process was conducted with 24 specialists representing 10 Austrian medical societies and two emergency medical services. A systematic literature review was carried out to enable the development of 22 open-ended questions. Responses from the first round were synthesized into 28 statements. Consensus was achieved on all 28 statements after 4 rounds, with participation rates of 100
Fitness tracking, facilitated by wearable devices, has emerged as a popular method for monitoring physical activity levels in the general population; however, its usage, acceptance and utility in patients with multiple sclerosis (pwMS) remain understudied. To investigate the prevalence of fitness tracking device usage in pwMS and to explore acceptance and willingness to share data for use in healthcare. We surveyed a cohort of consecutively and prospectively included pwMS diagnosed according to revised McDonald criteria 2017 in MS outpatient departments from two centers in Bern, Switzerland and Vienna, Austria. Out of a total of 200 pwMS (70
Follicular thyroid carcinoma (FTC) is known to occasionally show distant recurrence (DR); however, no prognostic scoring system has been established. Furthermore, although prognostic factors have been identified, their weights as predictors of poor prognosis remain unclear. In this study, we aimed to establish a weighted scoring system for predicting DR in FTC using conventional prognostic factors and Ki-67 labeling index (LI). We analyzed data of 597 patients with FTC without distant metastasis at initial surgery. Tumor size >4 cm, male sex, age ≥60 years, Ki-67 LI >5%, and vascular invasion (VI) ≥4 (V2) significantly and VI 0-4 (V1) marginally affected DR. Wide capsular invasion was not significantly associated with DR. Stepwise model selection using the Akaike Information Criterion identified age ≥60 years, Ki-67 LI >5%, V1, V2, and tumor size >4 cm as suitable components of the score. According to the beta coefficient value, we assigned a score of 2 to age ≥60 years, Ki-67 LI >5%, and V2, and a score of 1 to tumor size >4 cm and V1, with the sum representing the final score. We categorized patients into three categories according to the DR rates: low-risk (score 0-2; n = 388, 65.0%), intermediate-risk (score 3-4; n = 156, 26.1%), and high-risk (score 5-7; n = 53, 8.9%). The 10-year DR-free survival rates declined from the low- to the high-risk categories (96.0% vs. 90.3% vs. 54.9%). These findings indicate that high-risk patients identified using this prognostic scoring model should be carefully monitored for DR following completion thyroidectomy.
Treatment options for chronic hepatitis D (CHD) are limited in patients who do not respond to recommended treatment with bulevirtide ± pegylated interferon. The use of REP 2139-Mg is a novel treatment option that has recently demonstrated efficacy and safety in phase 2 trials and a compassionate access program that included three patients treated at the Vienna General Hospital with compensated advanced chronic liver disease and clinically significant portal hypertension (CSPH). Long-term outcome of CSPH patients treated with REP 2139-Mg is unknown; thus, surrogate endpoints are of interest in this population. In the 3 patients receiving REP 2139-Mg for 12 months at our center, we monitored the hepatic venous pressure gradient (HVPG) as the strongest prognostic surrogate biomarker in compensated cirrhosis at baseline, and after 3 and 12 months of treatment. The HVPG dynamics alongside additional liver function tests observed are summarized in this report and two out of three patients achieved undetectable hepatitis-D-virus(HDV)-RNA and low hepatitis B surface Antigen (HBsAg) following pronounced alanine aminotransferase (ALT) flares during REP 2139-Mg treatment. The first patient showed virologic non-response and no HVPG dynamics during treatment. The second patient developed jaundice upon treatment initiation, resulting in a transient increase in HVPG despite virologic response. The third patient achieved virologic response that was paralleled by sustained reductions in HVPG.
Appetite regulation is a complex yet vital concept, with several pathways conserved throughout evolution that are still to be fully understood. Appetite, or the drive to search for and consume food, is driven by the integration of different food and environmental cues, as well as internal state. It is dynamically managed by intricate systems that can be broadly categorized into homeostatic (driven by physiological energy needs) and hedonic feeding (driven by pleasure and reward). This review compiles and analyzes recently described and unconventional mechanisms of appetite control in mammals, detailing their underlying molecular pathways and neural circuit integration, and implications for drug discovery. The hypothalamus plays a vital role in this, serving as the main hub for appetite control, integrating peripheral hormonal and neural signals to maintain energy balance and where several pathways converge. Beyond the established hypothalamic Arcuate Nucleus (ARC) circuit, key regulators examined include neuropeptides like Orexin A, Oxyntomodulin, PACAP, and Galanin, alongside key receptor systems such as the Melanocortin-3 receptor (MC3R), the Endocannabinoid (ECS) and the Endorphin Systems. We also explore the roles of the NUCB2/nesfatin-1 pathway and amino acid transporters (SLCs). These examinations resulted in a blurred vision of the distinction between homeostatic and hedonic regulation, with pathways converging on the hypothalamus as well as the mesolimbic reward system. Understanding this interconnected regulatory network is vital for improving therapies for disorders such as obesity, anorexia nervosa, and binge-eating disorder. This comprehensive knowledge paves the way for the development of targeted, precision medicine, or the implementation of multi-target compounds.
Endometriosis affects approximately 10% of reproductive-aged women worldwide and is a leading cause of chronic pelvic pain. Despite its high prevalence and substantial socioeconomic burden, the mechanisms underlying endometriosis-associated pain remain incompletely understood, resulting in delayed diagnosis and limited therapeutic durability. Notably, pain severity frequently shows poor correlation with lesion burden, indicating that endometriosis-associated pain extends beyond the presence of endometriotic lesions alone. Accumulating evidence supports a model in which endometriosis-associated pain arises from the convergence of endocrine dysregulation, immune activation, aberrant neuroangiogenesis, and maladaptive neural plasticity, with estrogen dominance and progesterone resistance serving as central upstream drivers of pain biology. Estrogen-dependent inflammation and progesterone resistance establish a permissive microenvironment that promotes immune dysfunction, neurotrophic signaling, and nociceptor sensitization. These peripheral processes drive sustained afferent input to the central nervous system, leading to peripheral, central, and cross-organ sensitization that can perpetuate pain independently of lesion activity. In this review, we synthesize current evidence across the clinical spectrum of pain, mechanistic pathways, and therapeutic approaches in endometriosis. We integrate insights from inflammatory and immune pathways, neuroimmune crosstalk, hormonal regulation, and sensitization processes, emphasizing progesterone resistance and estrogen-mediated signaling as central modulators. Advances from preclinical models and emerging multi-omics technologies are highlighted to define pain signatures that transcend lesion-based classification. Finally, we discuss emerging therapeutic strategies targeting neuroimmune and endocrine pathways and propose a precision medicine framework that incorporates mechanistic biomarkers, translational models, and pain-specific clinical endpoints to improve stratification, reduce ineffective interventions, and achieve individualized pain relief for women with endometriosis.
OBJECTIVES:Glucocorticoid (GC)- and MTX-sparing strategies are clinically important in RA, yet comparative real-world evidence for sarilumab (SAR) vs Janus kinase inhibitors (JAKi) is limited. Whether treatment effects differ by age at onset-late-onset RA (LORA) vs young-onset RA (YORA)-also remains unclear. This study aimed to compare the effectiveness and safety of SAR and JAKi in patients with LORA and YORA. METHODS:We conducted a multicentre real-world cohort study of adults with RA initiating SAR or a JAKi. Outcomes over 12 months included change from baseline in MTX dose (ΔMTX, mg/week) and GC dose (ΔGC, mg/day), cumulative treatment discontinuation and change in Clinical Disease Activity Index (CDAI). Analyses were performed within LORA and YORA strata, and propensity score matching (PSM) was applied separately in each stratum to balance baseline characteristics. Sensitivity analyses were conducted in the matched cohorts. RESULTS:Both SAR and JAKi were associated with progressive tapering of concomitant MTX and GC during follow-up. SAR was associated with a higher frequency of MTX discontinuation compared with JAKi. In contrast, GC discontinuation and CDAI improvement were broadly similar between treatments across age strata and MTX subgroups. Findings were consistent after PSM and in sensitivity analyses within both LORA and YORA. CONCLUSION:In routine clinical practice, SAR and JAKi support de-escalation of concomitant therapy. SAR may permit earlier MTX withdrawal without loss of disease control, with comparable GC tapering and disease activity improvement in both LORA and YORA.
