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Cerebrovascular-CSF coupling measured by broadband near-infrared spectroscopy as a physiological marker of brain aging and Alzheimer's disease.

Front Aging Neurosci

Fiza Saeed, Kathy L Siepker, Soeun Jang +2 more

Alzheimer's disease (AD) is strongly associated with cerebrovascular dysfunction and impaired glymphatic clearance. These dysfunctions may precede, contribute to, and interact bidirectionally with AD pathology, highlighting the importance of identifying physiological markers for the early detection of AD. Noninvasive approaches for assessing these processes and identifying early biomarkers remain limited. Cerebrospinal fluid (CSF) plays a central role in clearing neurotoxins from the brain, but current methods for quantifying CSF dynamics are invasive, costly, and not well suited for early detection of AD.

Deep Venous Perivascular Space Dysfunction Reflects Glymphatic Aging and Predicts Cognitive Vulnerability: In Vivo Human Evidence.

Aging Dis

Kemeng Zhang, Ying Zhou, Yifei Li +4 more

Impaired glymphatic clearance has been recognized as a fundamental mechanism of cognitive decline. While models suggest cerebrospinal fluid influx along arterial perivascular spaces (aPVS) and efflux along venous PVS (vPVS), their differential roles in humans are unclear. We aimed to visualize directional glymphatic flow in vivo, classify human PVS functionally and determine their associations with cognition. This study included 91 patients undergoing intrathecal gadodiamide with serial MRI at baseline, 4.5 hours, 15 hours and 39 hours post-injection. PVS showing early (4.5h) and delayed (39h) enhancement peaks were defined as aPVS and vPVS, respectively. Among 742 basal ganglia (BG) and 1380 centrum semiovale (CSO) PVS analyzed, 10.4% and 21.6% were aPVS, while 62.7% and 52.0% were vPVS, respectively. BG-vPVS burden correlated with age (r=0.275, p<0.001) and hypertension. Among 60 patients with cognitive assessment (telephone Montreal Cognitive Assessment, T-MoCA) data, only BG-vPVS burden independently correlated with lower scores after adjusting for age and education (β=-0.16, p=0.041). This study provided direct in vivo MRI evidence of glymphatic flow within human PVS. We introduced a novel functional classification method to differentiate arterial from venous PVS, finding their different role in cognitive impairment, which may represent a potential target for therapeutic intervention.

Stagnation and Progression: How Glymphatic Failure Promotes Meningioma Malignancy in Aging.

Aging Dis

Wenfei Zhou, Naili Wei, Feng Xu +13 more

Meningiomas in the elderly present a clinical paradox: despite typically benign histology, they frequently manifest disproportionate peritumoral brain edema (PTBE) and aggressive behavior. Traditional hormonal hypotheses fail to explain this age-specific malignancy. This review articulates a "Neuro-Glymphatic-Tumor Axis" as a working hypothesis, proposing that the senescent collapse of brain clearance infrastructure, rather than tumor genetics alone, may be a key driver of this progression. Specifically, the loss of astrocytic aquaporin-4 (AQP4) polarity and the atrophy of meningeal lymphatic vessels are hypothesized to create a critical "hydrodynamic mismatch." This systemic failure may trap oncogenic toxins, specifically HMGB1 and S100A4, potentially activating RAGE signaling, while simultaneously blocking antigen drainage, which could induce a state of "immunological ignorance." Consequently, the tumor microenvironment may become physically congested and immunologically suppressed. Translating this framework into practice, we suggest that assessing "glymphatic frailty" via functional MRI and exploring microenvironment-targeted strategies, including lymphatic-sparing surgery and AQP4 modulation, represent promising future directions for dismantling the cycle of edema and recurrence in the vulnerable geriatric population.

The Copper-Gut-Brain Axis: A Triple Inflammatory Pathway Driving Neuroinflammation in Alzheimer's Disease.

Aging Dis

Ashwin Ambi

Serum copper increases progressively with normal aging, yet its downstream consequences for the gut microbiome and neuroinflammation remain unexplored. Gut microbiota dysbiosis and elevated lipopolysaccharide levels are established features of Alzheimer's disease, and growing evidence indicates that this dysbiosis drives neuroinflammatory disease progression. Yet the upstream trigger initiating this dysbiosis remains unknown. We propose that age-related copper dyshomeostasis serves as this missing trigger. The redox-active copper content of ceruloplasmin increases across the adult lifespan, and copper is selectively toxic to anaerobic bacteria, preferentially affecting butyrate-producing genera including Faecalibacterium, Roseburia, and Coprococcus while sparing copper-resistant species. This selective toxicity is supported by animal studies demonstrating copper-induced elimination of butyrate producers with reversible gut barrier damage and by Wilson's disease cohorts showing consistent depletion of butyrate-producing genera due to elevated copper levels. The resulting dysbiosis creates a triple inflammatory pathway: butyrate loss compromises gut barrier integrity and removes histone deacetylase-mediated suppression of neuroinflammation; the increase of Gram-negative bacteria elevates lipopolysaccharide translocation through the compromised barrier; and impaired blood-brain barrier integrity reduces amyloid-β clearance. These three insults trigger microglial activation through NF-κB signaling, creating a 'triple hit' on a single transcription factor that may explain the magnitude of neuroinflammatory effects observed in Alzheimer's disease. This mechanism explains the increased acetate/butyrate ratio recently identified as a biomarker distinguishing Alzheimer's-related from non-Alzheimer's cognitive impairment (AUC 0.951), since copper disrupts microbial metabolic cross-feeding networks that convert acetate to butyrate. We present specific, falsifiable predictions that can be tested in human cohorts and propose copper as a novel upstream therapeutic target for Alzheimer's disease prevention.

Metabolic Transition Windows in Tissue Repair: Timing, Boundary Conditions and Resolution.

Aging Dis

Fangyuan Zhu, Feixin Liang, Sijia Song

Regenerative repair is accompanied by extensive cellular remodeling, with metabolic reprogramming frequently observed across injury models. Glycolytic upregulation is commonly reported early after tissue damage, yet similar metabolic shifts have also been described in settings that progress toward functional regeneration or fibrotic remodeling. These observations indicate that pathway enrichment alone provides an incomplete explanation for divergent repair trajectories. Accumulating studies are consistent with a time-resolved perspective in which outcomes may depend on the onset, magnitude, and reversibility of metabolic remodeling, together with spatial and niche-derived boundary conditions. This review synthesizes recent work linking metabolic flux to chromatin regulation and cell-state plasticity. Metabolites such as acetyl-CoA, α-ketoglutarate, and lactate have been associated with chromatin remodeling and changes in epigenetic constraints in multiple contexts, although their necessity and directionality remain model dependent. We discuss evidence that immune microenvironments can shape metabolic boundary conditions by modulating oxygenation, inflammatory cues, and debris clearance, thereby influencing when reparative programs are engaged and whether tissues transition toward maturation and oxidative recovery. Comparative analysis across the heart, nervous system, lung, and liver supports the concept of organ-specific bottlenecks that may limit repair at distinct stages, including constrained entry into reparative states, impaired maintenance of rebuilding programs, or delayed resolution that coincides with persistent inflammation and scarring. We highlight methodological challenges that complicate causal interpretation, including reliance on transcript-level proxies and incomplete temporal sampling. We propose that advancing the field will require longitudinal and stage-resolved analyses coupled with functional repair endpoints, with explicit consideration of tissue microenvironmental context.

Association Between Serum Cortisol Levels and Variant Angina.

Korean Circ J

Jeen Hwa Lee, Sung Rok Lee, Yeon Jung Lee +5 more

Variant angina (VA) is caused by coronary vasospasm, and psychological stress has been suggested as a potential trigger. However, the clinical association between cortisol, a key stress hormone, and VA is unclear. This study aimed to evaluate the relationship between serum cortisol levels and VA.

Assay-Specific Diagnostic Thresholds for Adrenal Insufficiency: A Retrospective Comparison of Monoclonal Cortisol Measurements Using Roche Elecsys Cortisol II and Tosoh AIA-CL2400.

Cureus

Shunsuke Kato, Hana Akanuma, Mitsuhiko Nara +4 more

Background The diagnosis of adrenal insufficiency traditionally relies on peak cortisol values during stimulation testing, with a cut-off of 18 µg/dL established using polyclonal antibody assays. However, newer monoclonal antibody-based assays show reduced cross-reactivity with other glucocorticoids. In April 2022, our hospital changed the cortisol measurement method from Roche Elecsys Cortisol II to Tosoh AIA-CL2400, both using monoclonal antibodies but with potentially different measurement characteristics. In addition to stimulation test results, physicians initiate hydrocortisone replacement based on the patient's clinical condition. Methods We retrospectively reviewed 226 patients who underwent adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH) stimulation testing for suspected adrenal insufficiency between March 2016 and September 2023. Patients with baseline cortisol ≥18 µg/dL or receiving steroid medications other than hydrocortisone were excluded. Assessment variables included baseline cortisol, baseline ACTH, peak cortisol, and the change in cortisol during stimulation tests. Clinical diagnosis of adrenal insufficiency was defined by initiation of hydrocortisone replacement therapy. Receiver operating characteristic (ROC) curve analysis was performed to determine optimal cut-off values. Background factors included gender, age, presence of adrenal insufficiency symptoms, and structural or functional abnormalities of the hypothalamus-pituitary-adrenal (HPA) axis. Simple and multiple logistic regression analyses were conducted with the diagnosis of adrenal insufficiency as the dependent variable. Results The mean age was 54 years, and 75 (33.2%) of the participants were male. Adrenal insufficiency symptoms were present in 118 (52.2%), while 135 (59.7%) had either structural or functional abnormalities of the HPA axis. When comparing values between the two assay periods, peak cortisol was significantly different (mean: 14.6 vs. 16.8 µg/dL for Elecsys Cortisol II vs. AIA-CL2400). The proportion of patients with cortisol peaks <18 µg/dL differed (128 (68.1%) vs. 18 (47.4%)), but hydrocortisone initiation remained similar (82 (43.6%) vs. 14 (36.8%)). Multiple logistic regression analysis identified peak cortisol, presence of symptoms, and structural or functional abnormalities of the HPA axis as significant factors associated with the clinical diagnosis. ROC curve analysis revealed that the optimal cut-off value increased from 14.5 µg/dL before the assay change to 17.0 µg/dL after the change. When stratified by symptom presence, cut-off values were 14.5 µg/dL (with symptoms) and 13.1 µg/dL (without symptoms) before the change, and 17.0 µg/dL (with symptoms) and 15.1 µg/dL (without symptoms) after the change. When stratified by structural or functional abnormalities of the HPA axis, cut-off values were 13.7 µg/dL (with abnormalities) and 14.5 µg/dL (without abnormalities) before the change, and 17.5 µg/dL (with abnormalities) and 16.4 µg/dL (without abnormalities) after the change. Conclusion Our study provides two key messages: First, differences in assay methodology can significantly alter cortisol values and appropriate diagnostic cut-offs, even when transitioning between monoclonal antibody-based assays. Second, both peak cortisol and symptom presence were crucial for clinical diagnosis of adrenal insufficiency, with potentially lower cut-off values being appropriate for asymptomatic cases.

Central Adrenal Insufficiency Unmasked After Pneumonia-Associated Asthma Exacerbation Leading to the Diagnosis of Rathke's Cleft Cyst in an Elderly Woman: A Case Report.

Cureus

Natsumi Yamamoto, Ryuichi Ohta, Akira Yamasaki +1 more

Rathke's cleft cyst (RCC) is a benign pituitary lesion that is often asymptomatic but can cause hypopituitarism, including central adrenal insufficiency, which may become clinically apparent under physiological stress. However, RCC presenting with adrenal insufficiency unmasked by acute respiratory illness is rare, particularly in elderly patients. We report a case of RCC diagnosed after adrenal insufficiency became evident following pneumonia-associated asthma exacerbation. An 89-year-old woman presented with fever, productive cough, and generalized fatigue and was diagnosed with pneumonia-triggered asthma exacerbation. Initial laboratory evaluation revealed hyponatremia (serum sodium 126 mEq/L). She was treated with bronchodilators, systemic corticosteroids, and antibiotics, resulting in prompt improvement of respiratory symptoms and normalization of serum sodium levels. After discontinuation of corticosteroids and discharge, she developed persistent fatigue, anorexia, and right eyelid ptosis. Brain magnetic resonance imaging revealed a 22-mm cystic lesion in the pituitary gland consistent with RCC. Endocrine evaluation demonstrated markedly reduced adrenocorticotropic hormone and cortisol levels, along with central hypothyroidism, hypogonadism, and growth hormone deficiency, confirming panhypopituitarism with central adrenal insufficiency. Hydrocortisone replacement therapy was initiated, leading to clinical stabilization. Surgical intervention was deferred due to advanced age and absence of visual field defects, and the patient was managed conservatively with hormone replacement and follow-up imaging. This case highlights that acute respiratory illness may precipitate overt adrenal insufficiency in patients with previously unrecognized RCC. Transient improvement with corticosteroids during acute treatment may mask the underlying endocrine disorder, delaying diagnosis. Persistent fatigue, hyponatremia, or neurological findings after resolution of respiratory illness should prompt evaluation for central adrenal insufficiency and pituitary pathology, as early recognition and hormone replacement are essential to prevent life-threatening complications.

Innovations in Obesity Treatment: Beyond Adipose Tissue Dysfunction.

Obes Rev

Jesica Martínez-Godfrey, Irene Pomares-Bri, Paula de Juan-Maciá +5 more

Obesity, a chronic disease characterized by excessive adipose tissue accumulation, represents a critical global health challenge with profound metabolic, inflammatory, and oncogenic implications. To provide a multidisciplinary perspective, this narrative review integrates current literature examining metabolic, immunological, and oncological evidence to outline obesity as a multisystem disorder. Chronic inflammation is examined as a central mediator linking excessive adiposity to insulin resistance, type 2 diabetes, and cancer development, specifically detailing how adipose tissue dysfunction, altered adipokine profiles, and immune cell infiltration drive systemic pathogenesis. Emerging insights into the molecular mechanisms of tumor progression in a metabolically altered environment are highlighted, emphasizing the roles of hyperinsulinemia and dysregulated adipokines like leptin and adiponectin. In addition, the review explores innovative therapeutic strategies for obesity-related cancer, including the use of metformin and therapies targeting insulin-like growth factor 1 receptor and colony-stimulating factor 1 receptor pathways. It also discusses the therapeutic promise of white adipose tissue browning through inductors such as menthol and capsinoids to enhance metabolic homeostasis. Furthermore, hormonal and neural dysregulation of appetite control are addressed. Novel pharmacological treatments targeting appetite, such as glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonists, as well as neuromodulation techniques are discussed as promising avenues for personalized and effective interventions. This comprehensive understanding of obesity's complex nature is crucial for developing novel, integrated approaches to complement traditional diet and exercise strategies.

Oxytocin and Autism - A precision medicine framework to unpack mechanisms and evidence.

Neurosci Biobehav Rev

Kelsie A Boulton, Adam J Guastella

One of the great scientific questions in social neuroscience is how our knowledge of oxytocin, a neuropeptide and hormone with a crucial role in social behaviour, can be translated into meaningful advances to support social development. There is a compelling case for investigating oxytocin as a therapeutic target, from animal studies to converging human evidence from biomarker studies, genetic and epigenetic research, and neuroimaging findings implicating the oxytocinergic system in the social phenotype of Autism Spectrum Disorder (ASD). Despite decades of investigation, intranasal oxytocin has not shown consistent clinical benefits for autistic populations. This review synthesises evidence for oxytocinergic system involvement in ASD, with a focus on clinical trial findings. We argue for progress toward a precision medicine framework integrating biomarker-informed participant stratification, novel trial designs to control for placebo responses, objective outcome measures, and novel approaches to administration, drug development and endogenous stimulation. Together, these innovations offer opportunities to deliver on the potential to bridge existing knowledge of oxytocin's role in development with its therapeutic potential for ASD.

Hydrogen reshapes the senescent microenvironment of callus to enhance the healing of anti-osteoporotic-drug-induced atypical femoral fracture.

Biomaterials

Yuanming An, Haozhi Zhang, Yuantao Zhang +10 more

Long-term bisphosphonates (BPs) are widely used to treat osteoporosis, however, they are paradoxically associated with the development of atypical femoral fractures (AFFs), which often characterized by impaired healing. In this study, we induced an AFF model using zoledronate (ZOL) administration in ovariectomized (OVX) osteoporotic rats, following a unilateral femoral fracture. Here we identified that a local pro-senescent microenvironment causes persistent inflammation and impairs effective regeneration in rat AFFs. Molecular hydrogen has demonstrated anti-senescence and anti-inflammatory properties, yet its effects on AFF healing remain unexplored. Therefore, we treated the AFF rats with hydrogen rich water (HRW). The outcomes were assessed by radiographs, histology, micro-CT, and biomechanical tests. The fracture microenvironment was analyzed based on the indicators of senescence, fibrosis, macrophage polarization, cytokine expression, and angiogenesis. We found that HRW significantly promoted callus bridging and resolved the non-union gap in ZOL-induced AFFs, whereas the ZOL group exhibited persistent fibrous tissue. Micro-CT and biomechanical tests confirmed that HRW did not compromise the mechanical strength of the bone mass elevated by BPs. Instead, HRW specifically attenuated the local senescent microenvironment, with a reduction in both SA-β-gal activity and the expression of p16, p21 within the fracture gap. This was accompanied by clearance of pathological fibroblasts, a shift from pro-inflammatory M1 to anti-inflammatory M2 macrophages, a rebalanced cytokine profile, and restored formation of osteogenesis-coupled type-H vessels. Our findings confirm that molecular hydrogen facilitates AFFs healing by locally reversing the senescent microenvironment, rather than boosting systemic bone formation. This creates a favorable niche for callus bridging, representing a novel therapeutic strategy for fracture delayed union or non-union.

The cellular ecosystem of skeletal muscle regeneration: molecular mechanisms, pathological disorders, and potential therapeutic strategies.

Stem Cell Res Ther

Jiahuan Gong, Hongyi Xu, Xinlei Yao +5 more

Skeletal muscle regeneration is a highly coordinated physiological process. It relies on the intricate collaboration of a complex cellular ecosystem. This ecosystem includes muscle stem cells, immune cells, stromal cells, vascular cells, neural cells, and the extracellular matrix. Research has recently expanded beyond focusing solely on satellite cells. It now delves into the multi-level regulatory networks within this ecosystem. These networks encompass key signaling pathways, such as Wnt/β-catenin, TGF-β, Hippo/YAP, and AMPK. They also include epigenetic regulation, cellular metabolic reprogramming, and extracellular vesicle-mediated intercellular communication. However, under pathological conditions, this regenerative program is severely impaired. This leads to failed repair, fibrosis, and fatty infiltration, ultimately resulting in loss of muscle function. This review aims to systematically outline recent advances in the field of skeletal muscle regeneration. First, from the perspective of the "cellular ecosystem," we will elaborate on the dynamic behaviors and regulatory mechanisms of various cell types during regeneration. Second, we will dissect the core mechanisms underlying regenerative failures in various pathological states. Third, we will comprehensively evaluate the most promising current intervention strategies. Finally, considering the limitations of current research, we will provide future perspectives. This review aims to systematically integrate existing knowledge and provide a clear roadmap for future research, ultimately offering a robust theoretical foundation and innovative insights for the development of clinical treatments targeting skeletal muscle regenerative disorders.

GLP-1 RA semaglutide for alcohol use disorder: a potential multi-target therapy.

Acta Diabetol

Sergio Maimone, Antonio Galante, Carlotta Castoro +2 more

Switching patterns of GLP-1 receptor agonists from 2018 to 2025 in the largest private healthcare network in Poland.

Acta Diabetol

Krzysztof Łupina, Artur Dziewierz, Jakub Janczura +1 more

To characterize switching among GLP-1 receptor agonists (GLP-1 RAs) in a large private-sector cohort in Poland and to quantify therapy- and patient-level associations with switching while accounting for switching opportunity and calendar-time dynamics.

A retrospective audit of weight loss and health outcomes following bariatric surgery at a tertiary public hospital.

Obes Res Clin Pract

Joanna Perin Lee, Ahmed Bahamdan, Janet Franklin +6 more

To assess longterm weight and comorbidity outcomes following bariatric surgery at a publicly funded obesity service.

Treatment of Modifiable Risks in Metabolic Dysfunction-Associated Steatotic Liver Disease: Drugs Targeting Obesity and Type 2 Diabetes.

Clin Liver Dis

Sonal Kumar, Maria Paula Macedo, Michael Roden +1 more

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly nonalcoholic fatty liver disease, is increasingly prevalent and closely linked to obesity and type 2 diabetes (T2D). These metabolic conditions not only represent drivers of disease progression, but also as therapeutic targets for modifying the disease course. This study reviews the pathophysiological contributions of obesity and T2D to MASLD and evaluates pharmacologic strategies aimed at these drivers. Incretin-based therapies, especially GLP-1 receptor agonists and co-agonists have emerged as leading agents in promoting weight loss, reducing cardiovascular and renal outcomes in T2D and obesity.

Currently Approved and Future Regimens for Metabolic Dysfunction-Associated Steatohepatitis.

Clin Liver Dis

Eliabe S Abreu, Mazen Noureddin, Hirokazu Takahashi +2 more

Metabolic dysfunction-associated steatohepatitis (MASH), the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), has historically been treated with lifestyle modification (dietary changes, exercise and weight loss). While lifestyle modification remains foundational in the treatment of MASLD/MASH, resmetirom (a thyroid hormone β-receptor agonist) and semaglutide (a glucagon-like-peptide-1 receptor agonist) are now Food and Drug Administration-approved for patients with MASH and clinically significant hepatic fibrosis (ie, F2-F3 fibrosis). Emerging therapies will allow for future opportunities at a personalized approach to treatment of MASH. This article reviews currently approved and future regimens for the treatment of MASH and MASH-related cirrhosis.

Prognostic value of pretest probability of heart failure with preserved ejection fraction in patients with coronary artery disease: an insight from the CLIDAS-PCI database.

Cardiovasc Interv Ther

Tomoaki Nishikawa, Shunsuke Tamaki, Kazuhisa Nishimura +17 more

Coronary artery disease (CAD) is a major risk factor for the development of heart failure (HF) with preserved ejection fraction (HFpEF) and is associated with increased mortality. However, an optimal strategy to screen for HFpEF among patients with CAD has not yet been established. The HFpEF-ABA score was introduced to estimate the pretest probability of HFpEF and was shown to predict adverse HF events. This retrospective multicenter cohort study included patients registered in the Clinical Deep Data Accumulation System database who underwent percutaneous coronary intervention from April 2013 to March 2019. Patients with a left ventricular (LV) ejection fraction ≥ 50% and no known history of HF were included. Age, body mass index, and a history of atrial fibrillation were used to calculate the HFpEF-ABA score, and patients were dichotomized at a 50% threshold for descriptive risk stratification. The primary endpoint was a composite of all-cause death and unplanned HF hospitalization. Among 3307 patients, those with high HFpEF-ABA scores were more likely to have hypertension, renal dysfunction, anemia, larger left atrial size, higher LV mass index, and elevated brain natriuretic peptide levels, consistent with an HFpEF phenotype. Over a median follow-up of 721 days, 275 patients experienced the primary endpoint. The HFpEF-ABA score was independently associated with the primary endpoint as both a continuous and a categorical variable (hazard ratio: 1.07 [95% confidence interval: 1.00-1.14], P = 0.043, and 1.37 [1.07-1.76], P = 0.015, respectively). The HFpEF-ABA score identifies CAD patients with an HFpEF phenotype and predicts adverse outcomes.

Phenotypic and genotypic analysis of pediatric patients with congenital isolated growth hormone deficiency resulting from biallelic variants in the GHRHR gene: a Belgian registry study.

Eur J Pediatr

Simone Van de Velde, Emese Boros, Chloë Brunelle +6 more

Pathogenic variants in the growth hormone releasing hormone receptor (GHRHR) gene cause severe isolated growth hormone deficiency (IGHD). Over 82 distinct variants have been described, mostly in South and East Asia and Northern Brazil. This study characterizes the phenotypic and genotypic variability of children harboring (likely) pathogenic GHRHR variants, included in the Belgian and Luxembourg Registry for Growth Hormone Treated Children. We retrospectively reviewed clinical, biochemical, genetic and neuroimaging data from seven children with severe IGHD carrying biallelic GHRHR variants. Peak growth hormone (GH) concentrations were measured following insulin and glucagon-induced hypoglycemia. Auxological parameters at diagnosis and pituitary magnetic resonance imaging (MRI) findings were obtained from medical records. Three children of Syrian origin from two consanguineous families carried a novel likely pathogenic c.367G > T, p.(Glu123*) variant in a homozygous state. Among the four Belgian-origin patients, one was homozygous for a pathogenic c.674_677delinsGCTGTTGGCAGAAG, p.(Val225Gly*fs165) variant, while two siblings were compound heterozygous including this particular variant and an additional pathogenic c.271dupG, p.(Ala91Glyfs*13) frameshift variant. The other Belgian patient was compound heterozygous for the well described likely pathogenic c.431 T > A, p.(Leu144His) variant and a previously undescribed c.150C > A, p.(Asn50Lys) variant. IGHD was diagnosed between 7 months and 7 years. Height SDS at presentation ranged from - 4.6 to - 3.4. Peak GH levels after stimulation were markedly reduced (0.35-3.4 ng/ml), confirming severe growth hormone deficiency (GHD). No dysmorphic features were observed. Anterior pituitary hypoplasia at MRI was seen in six patients.

Optimization and verification of high-fat diet formulation for establishing a rat model of obesity-related precocious puberty.

Animal Model Exp Med

Jiayi Gong, Wei Qian, Deji Song +3 more

Childhood obesity is closely linked to the rising incidence of precocious puberty (PP), yet valid preclinical models of obesity-related PP remain lacking. High-fat diets (HFD) are widely used for obesity models, but the suitability of different HFD formulations for inducing PP is unknown. Female Sprague-Dawley (SD) rats were randomized to control, 45% HFD, or 60% HFD groups at postnatal day (PND) 21. Body weight and daily caloric intake were monitored; vaginal opening (VO) was recorded from PND 35. At study termination, serum levels of estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), leptin, and adiponectin were measured. Ovarian histology and vaginal cytology were assessed. In vitro, GT1-7 cells were treated with recombinant mouse leptin for 24 h, and GnRH secretion was quantified. Compared to controls and the 60% HFD group, rats fed 45% HFD exhibited significantly increased body weight, earlier VO onset, and elevated weights of organs. The 45% HFD group also had higher serum E2, LH, FSH, GnRH, and leptin levels, alongside reduced adiponectin; ovarian histology showed advanced follicular development, and vaginal smears displayed estrus-stage cytology. In contrast, the 60% HFD group had no significant changes in body weight or hormonal parameters, and limited ovarian development. In vitro, leptin treatment significantly upregulated GnRH secretion in GT1-7 cells. The 45% HFD formulation is optimal for constructing a juvenile rat model of obesity-related PP, as it recapitulates key phenotypic, histological, and endocrine features of the disease.