Autosomal dominant acute porphyrias are rare inherited disorders of haem biosynthesis characterised by accumulation of potentially neurotoxic porphyrin precursors and attacks of severe abdominal pain with autonomic and neuropsychiatric features. Disease severity ranges from asymptomatic individuals to those with recurrent, life-threatening attacks. The International Porphyria Network invited 34 acute porphyria specialists from 17 countries to form an expert panel. The invited group included clinicians from diverse specialities (ie, internal medicine, haematology, endocrinology, gastroenterology, hepatology, neurology, and biochemistry), together with laboratory scientists and patient representatives. The panel met online (in 2023-25) to develop 15 evidence-based recommendations with the use of the Grading of Recommendations, Assessment, Development, and Evaluations framework addressing attack prevention, management of sporadic and recurrent attacks, long-term follow-up, surveillance for primary liver cancer, and family screening. The guidelines support safe, consistent clinical care and improved outcomes, recognising global variation in resources and access to high-cost drugs, and highlighting priorities for future research.
Adiposity trends in pediatrics are increasing, escalating the risk for chronic diseases, psychological disorders, and adulthood obesity; creating more complex patients at younger ages. Organizations struggle with excess body weight (EBW) screening and follow-up compliance due to a misunderstanding of the problem, provider bias, discomfort discussing weight-related topics, and improper data collection and recording. An evidence-based quality improvement (EBQI) initiative, following the Johns Hopkins Nursing Evidence-Based Practice model and Plan-Do-Study-Act, was undertaken in a private, for-profit, pediatric primary care organization, measuring screening and quarterly follow-up scheduling rates. Processes and structures for conducting EBW screening and follow-up appointments were reviewed and amended based on the literature. A university hospital endocrinology department educated participants on the impact of EBW in pediatric patients, proper screening, diagnosis, and follow-up. Implementation of this EBQI initiative resulted in average increases of 56% for body mass index (BMI) screenings and 1,100% in BMI follow-up visits scheduled compared to baseline data. EBQI initiatives that promote BMI screening and follow-up compliance positively impact organizational outcomes and ultimately patient outcomes.
Pair bonding requires substantial neural flexibility to form and maintain complex social relationships in dynamic environments over time. Due to its involvement in synaptic plasticity, Brain-derived neurotrophic factor (BDNF) is a promising candidate for modulating this flexibility, although it has never been studied within the context of pair bonding. The present study sought analytically and biologically validate an enzyme-linked immunosorbent assay (ELISA) to measure BDNF in coppery titi monkeys (Plecturocebus cupreus), a pair bonding non-human primate model. We first validated a commercially available ELISA to detect and measure BDNF in titi monkey serum, and then subsequently characterized the natural decline of BDNF in titi monkeys throughout the day (morning to evening) and across the lifespan (into old age). Titi monkeys showed significantly lower serum levels of BDNF at the end of the day, suggesting a consistent diurnal cycle, and in older age, suggesting age-related decline. This work establishes the foundation for examining BDNF's role within the behavioral endocrinology of pair bonding.
Primary bilateral macronodular adrenal hyperplasia (PBMAH) is increasingly recognized as imaging is widely used, leading to incidental detection in asymptomatic individuals. Adrenal imaging defines radiologic features. All patients should undergo clinical and biochemical assessment for steroid excess-particularly cortisol, as many exhibit mild autonomous cortisol secretion. Genetic mutations are common, especially Armadillo Repeat Containing 5 in the more severe phenotypes and KDM1A in food-dependent cases. Aberrant hormone receptor expression and intra-adrenal adrenocorticotropin production by steroidogenic cells may also contribute to cortisol dysregulation in many patients. Management depends on cortisol status.
Angiotensin receptor-neprilysin inhibitor (ARNi) therapy, combining blockade of the renin-angiotensin-aldosterone system with the inhibition of neprilysin-mediated peptide degradation, is the standard therapy for heart failure with a reduced ejection fraction. Elevated urinary C-peptide (CPR) levels were recently reported in patients receiving ARNi, suggesting changes in the renal handling of CPR. However, a statistical comparison of ARNi users and non-users has not been performed. Therefore, this study aimed to statistically evaluate the impact of ARNi therapy on serum and urinary CPR levels by comparing ARNi users and non-users in a real-world clinical cohort. We retrospectively analyzed 315 patients who underwent 24-h urinary C-peptide (U-CPR) testing at Shinshu University Hospital between January 2022 and March 2024. Demographic data, the diabetes status, and medication history, including ARNi use, were extracted from electronic medical records. Group comparisons were performed by the Mann-Whitney U test, correlations were analyzed by the Spearman's test, and multiple regression analyses identified independent predictors of serum and urinary CPR. Of 315 patients, 11 were ARNi users. U-CPR, serum CPR, the C-peptide index, and U-CPR/serum CPR ratio were significantly higher in ARNi users. Serum CPR moderately correlated with U-CPR in both groups; however, the regression slope was steeper in ARNi users, indicating a disproportionate rise in U-CPR. In multiple regression analyses, ARNi therapy was the strongest contributing factor for elevated U-CPR (β = 186.57 nmol/day) and serum CPR (β = 0.59 nmol /mL). ARNi therapy markedly increases U-CPR, likely through the neprilysin-induced inhibition of renal enzymatic degradation. Using U-CPR to assess β-cell function in patients receiving ARNi therapy is not recommended, while serum CPR remains a valid marker of insulin secretion.
Osteoporosis (OP) is a systemic metabolic bone disorder. The excessive activation of osteoclasts (OCs) leads to a decrease in bone mass and damage to the bone microstructure, which plays a crucial role in OP. β-Hydroxybutyrate (BHB), the main component of ketone bodies, not only serves as an ancillary fuel substituting for glucose but also induces anti-oxidative, anti-inflammatory, and cardioprotective features via binding to several target proteins, including histone β-hydroxybutyrylation (Kbhb). Recent research has found that BHB has a positive therapeutic effect on OP, but the underlying molecular mechanism remains unclear. In this study, we established osteoporosis (OP) animal models induced by estrogen deficiency and type 2 diabetes using ovariectomized (OVX) and db/db mice, respectively, and administered BHB to OP mice via free drinking in vivo. Our results indicated that BHB increased bone mineral density (BMD), improved bone microstructure, and inhibited the OC formation. Additionally, BHB upregulated the levels of PanKbhb, H3K9bhb, and H3K27bhb modifications in the bone tissue of OP mice. In vitro, we found that BHB or β-hydroxybutyryl-CoA (BHB-CoA) could inhibit RANKL-induced OC differentiation and bone resorption, and upregulate histone Kbhb levels in a concentration-dependent manner. Furthermore, the effects of BHB or BHB-CoA-induced histone Kbhb were reversed by inhibiting the activity of Acyl-CoA synthetase short-chain family member 2 (ACSS2) or histone acyltransferase P300. In summary, our data reveal that BHB may alleviate bone loss caused by estrogen deficiency and type 2 diabetes through ACSS2/P300-induced histone Kbhb.
PPGL are rare neuroendocrine tumors that secrete catecholamines. There are over 20 driver mutations associated with PPGL. All patients who have been diagnosed with PPGL need genetic testing. Diagnosis is made by checking either plasma or urine metanephrines. Localization studies include computed tomography, magnetic resonance imaging, and functional imaging such as positron emission tomography scans. Alpha-blockers are a central component for preparation prior to surgical removal of the tumor, which is the mainstay of therapy. For patients with metastatic disease, several different modalities can be employed from palliative surgery, chemotherapy, radionuclide therapy, HIF-2α inhibitor, and drugs in clinical trials.
暂无摘要（点击查看详情）
Down syndrome (DS) is associated with immune dysregulation and a broad spectrum of autoimmune diseases; however, autoimmune involvement of the pituitary gland remains poorly characterized. Isolated adrenocorticotropic hormone deficiency (IAD) is a rare cause of secondary adrenal insufficiency, and its relationship to DS-related autoimmunity has not yet been elucidated. We encountered a single case of DS that was complicated by IAD. We describe the clinical course in detail and present immunological findings suggestive of an autoimmune basis for IAD in the context of DS. To experimentally evaluate pituitary-directed autoimmunity, circulating antibodies were analyzed using immunofluorescence staining of mouse pituitary tissue. Immunoglobulin G derived from an individual with DS and IAD specifically showed reactivity toward corticotrophs, as demonstrated by colocalization with ACTH immunostaining. HLA genotyping did not identify alleles previously associated with idiopathic IAD, suggesting a disease mechanism distinct from established genetic susceptibility. The identification of anti-corticotroph antibodies in DS provides the first immunological evidence linking IAD to DS-related autoimmunity. These findings suggest that autoimmune IAD may represent a previously unrecognized component of endocrine polyautoimmunity in DS and underscore the importance of considering pituitary autoimmunity in the endocrine assessment of this population. However, considering that the present findings are derived from a single case, further studies are warranted to confirm their broader applicability.
Progesterone production by the corpus luteum is essential for embryo implantation and early pregnancy maintenance and is acutely stimulated by luteinizing hormone (LH). While LH signaling through protein kinase A (PKA) is well established, downstream regulatory networks that constrain or shape luteal steroidogenesis remain incompletely defined. Here, we identify a previously unrecognized role for the Hippo signaling pathway in regulating luteal progesterone production. Using primary bovine luteal cells isolated from corpora lutea, we examined the relationship between LH/PKA signaling and Hippo signaling pathway activity. Expression, phosphorylation, and subcellular localization of Hippo pathway components were assessed by immunoblotting and nuclear fractionation. Progesterone production was quantified by ELISA. LH-induced transcriptional responses were analyzed using upstream regulator prediction from RNA sequencing. Functional roles of YAP1 and TAZ were evaluated using adenoviral overexpression of constitutively active mutants and siRNA-mediated knockdown. Hippo pathway components were enriched in luteal cells relative to follicular precursors. LH rapidly increased phosphorylation and cytoplasmic sequestration of YAP1 and TAZ in small luteal cells through PKA. Pharmacologic inhibition of LATS1/2 did not alter LH-stimulated progesterone production, suggesting that LH-induced steroidogenesis is not limited by LATS-dependent regulation of YAP1/TAZ. Sustained activation of YAP1 or TAZ suppressed LH-induced progesterone synthesis, whereas depletion of either factor enhanced progesterone output. Consistently, RNA-seq analysis identified YAP1/TAZ, and TEAD transcription factors as inhibited upstream regulators following LH stimulation in small luteal cells. Our findings support a model in which LH, via PKA and activation of Hippo signaling promotes progesterone synthesis by restraining YAP1/TAZ transcriptional activity in small luteal cells. This work identifies Hippo signaling as an unrecognized regulatory layer in luteal steroidogenesis and highlights YAP1/TAZ as potential therapeutic target for luteal insufficiency and infertility.
High-altitude hypobaric hypoxia induces inflammation and oxidative stress, yet the role of myeloperoxidase (MPO) in this pathology remains incompletely understood. This study aimed to investigate whether MPO mediates injury to the liverspleen axis under hypoxic conditions. Using a 3day murine hypoxia model, we unexpectedly found that MPO deficiency exacerbated, rather than mitigated, damage to the liverspleen axis. Compared with hypoxic wildtype mice, MPO-/- mice displayed aggravated histopathological injury, accompanied by excessive phagocyte recruitment and elevated expression of key chemokines (KC, MCP1, MIP2) and proinflammatory mediators (TNFα, IL1β, IL17A). At the molecular level, MPO absence increased splenic protein expression of NFκB, NLRP3, and iNOS, while dysregulating the antioxidant response via the NRF2/HO1 pathway. These results reveal a novel protective role for MPO during hypoxic stress, where it functions to moderate the innate immune response and limit collateral tissue damage in the liverspleen axis. The study provides new insights into the complex immunomodulatory functions of MPO and suggests its activity is essential for maintaining immune homeostasis during acute hypoxia.
Endocrine disorders in pediatric patients often involve a variety of imaging modalities as part of a diagnostic workup or disease surveillance. This pictorial essay and review of the literature highlights adrenal and reproductive system imaging findings related to endocrine-related diseases. This review includes descriptions of normal adrenal gland anatomy and imaging characteristics, as well as the clinical presentations and diagnostic imaging of congenital adrenal hyperplasia and of benign and malignant adrenal masses. Additionally, normal reproductive tract development and puberty will be covered, followed by an overview of Müllerian anomalies, 46,XY gonadal dysgenesis, and polycystic ovarian syndrome. Differential diagnostic considerations, appropriate imaging protocols, and clinical management strategies will be discussed.
The Lancet Diabetes & Endocrinology Commission recognizes clinical obesity as an independent disease, although its link to heart failure (HF) remains underexplored. The goal of this study was to evaluate the impact of clinical obesity on new-onset HF risk and subsequent all-cause mortality after the development of HF. Clinical obesity was defined based on body mass index, waist circumference, waist-to-hip ratio, waist-to-height ratio, and 10 clinical criteria. A total of 99,131 participants from the Kailuan Study cohort were classified into nonobese, preclinical obesity, and clinical obesity groups. A Cox proportional hazards model was applied to assess the association between clinical obesity and the risk of new-onset HF, and all-cause mortality was examined among those with HF. Over a median follow-up of 16.0 years, 3,280 participants developed HF, and there were 19,170 deaths from any cause. Compared with the nonobese group, clinical obesity was associated with a 63% higher risk of new-onset HF (adjusted [aHR]: 1.63; 95% CI: 1.49-1.77), with varying risks across HF subtypes. Within the clinical obesity group, HF risk increased with the number of clinical criteria: one (aHR: 1.50; 95% CI: 1.37-1.64), two (aHR: 1.91; 95% CI: 1.70-2.14), and three or more (aHR: 2.20; 95% CI: 1.80-2.68). However, clinical obesity was not associated with increased all-cause mortality after HF (aHR: 1.01; 95% CI: 0.90-1.15). These findings highlight clinical obesity as a risk factor for new-onset HF and all-cause mortality, driven both by excess weight and associated clinical conditions. Recognizing clinical obesity as an independent disease may support more effective HF prevention strategies.
Diabetic ketoacidosis (DKA) is a life-threatening complication of type 1 diabetes (T1DM) and a leading cause of pediatric mortality. Prevention depends on caregivers' ability to recognize early signs and initiate proper sick-day management. However, data on DKA awareness among Iranian parents remains limited. This study aimed to evaluate both subjective self-ratings and objective calculated knowledge regarding DKA among parents of children with T1DM. This cross-sectional study was conducted among 217 parents at a pediatric diabetes clinic in Shiraz, Iran. A validated questionnaire (Cronbach's alpha = 0.8), adapted through forward-backward translation, assessed demographics, disease duration, HbA1c, and DKA knowledge. Data were analyzed using descriptive statistics, Kruskal-Wallis tests, and Spearman's correlations (rs) to identify predictors of awareness. Most participants were mothers (80.6%), and 38.7% reported DKA as the initial presentation at diagnosis. Subjective knowledge scores (0-10) were 1.86 ± 3.07 for mothers and 0.89 ± 2.16 for fathers (P = 0.06). Mothers demonstrated significantly higher calculated objective awareness than fathers (P = 0.007). Higher objective knowledge significantly correlated with higher education levels (rs=0.280, P = 0.01), longer disease duration (P = 0.01), and prior DKA admission (P = 0.02). Awareness showed no significant relationship with the child's most recent HbA1c levels (P = 0.98). Parental DKA knowledge is critically inadequate. As DKA mortality is preventable through early detection, targeted educational interventions and accessible resources are urgently needed to empower parents and improve clinical outcomes for children with T1DM.
暂无摘要（点击查看详情）
Approved in 2015 for radioiodine-refractory differentiated thyroid carcinoma (RR-DTC), the multikinase inhibitor lenvatinib has demonstrated substantial efficacy; nevertheless, severe adverse effects, intrinsic resistance or development of acquired resistance often limit its use. A novel approach to sensitize tumor cells to therapy is the administration of antibiotics that target mitochondrial metabolism. We analyzed the effects of a combination of lenvatinib with the tetracycline-class antibiotics tigecycline and eravacycline in DTC cells with reduced response to lenvatinib and explored the underlying mechanism of action. Cell viability was quantified after treatment with either single agents or combination therapies consisting of lenvatinib with tigecycline or eravacycline. Baseline oxidative metabolism and drug-induced changes in oxygen consumption rate were measured. Three-dimensional spheroid cultures were used to better mimic the in vivo tumor milieu. Apoptosis was assessed by caspase-3/7 activity, and expression of apoptosis-related proteins was elucidated by immunoblotting. We found that combining lenvatinib with tigecycline or eravacycline resulted in stronger reductions in 2D and 3D cell viability compared to single-agent treatments in K1 DTC cells, which show limited lenvatinib responsiveness. Both combination therapies markedly impaired mitochondrial respiration, accompanied by down-regulation of anti-apoptotic Bcl-2 family members, activation of caspase-3/7, and cleavage of Poly (ADP-ribose) polymerase (PARP), which are hallmarks of apoptosis. Although limited to in vitro models and subject to pharmacological limitations, our findings provide a mechanistic proof-of-concept that mitochondria-targeting antibiotics may enhance lenvatinib responsiveness in a DTC cell line.
Evidence regarding sources of heterogeneity in the efficacy of statins for primary prevention of cardiovascular disease (CVD) remains limited. This study aimed to identify trial-level factors contributing to such heterogeneity. Relevant studies were systematically identified from a previous systematic review and through searches in PubMed, Embase, and Cochrane up to 20 January 2026. The protocol was registered in PROSPERO (CRD42024579932). Randomized controlled trials (RCTs) in adults without prior CVD that investigated statin treatment were included. Risk of bias was assessed using the Cochrane Risk of Bias tool. Meta-analyses were conducted to pool risk ratios (RRs) and 95% confidence intervals (CIs) for major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, and cardiovascular death. Univariate meta-regression analyses were conducted to assess the impact of trial-level covariates on the effect sizes, expressed as the ratio of risk ratios (RRR). Within-study subgroup differences were meta-analyzed by pooling ratio of effect sizes. Meta-regression analyses were conducted using complete-case trial-level data. 25 RCTs (102,667 participants) were included. Compared to no statin treatment, statin treatment was associated with a reduced risk of MACE (RR, 0.73[95% CI, 0.67 to 0.80], P < 0.001), MI (RR, 0.68[95% CI, 0.60 to 0.77], P < 0.001), stroke (RR, 0.76[95% CI, 0.65 to 0.89], P = 0.001) and cardiovascular death (RR, 0.81[95% CI, 0.71 to 0.95], P = 0.008). Univariate meta-regression indicated that higher baseline total cholesterol (RRR, 1.29 [95% CI, 1.07 to 1.57], P = 0.008), higher low-density lipoprotein cholesterol (LDL-C) (RRR, 1.31 [95% CI, 1.07 to 1.62], P = 0.010), higher triglycerides (RRR, 1.81 [95% CI, 1.17 to 2.81], P = 0.008) and lower statin intensity (RRR, 0.74 [95% CI, 0.59 to 0.94], P = 0.015) were significantly associated with reduced efficacy of statins for stroke prevention at the trial level. Statin therapy demonstrated consistent efficacy in CVD prevention across diverse populations, except that baseline lipid profiles and statin intensity may represent exploratory, hypothesis-generating signals of potential effect modification for stroke prevention, warranting further investigation.
Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally. Ferroptosis, a regulated form of cell death, has emerged as a promising frontier in CRC treatment. The transcriptional regulator ETV4 (ETS variant transcription factor 4) is implicated in CRC pathogenesis. However, its functional role has not been fully elucidated, and its potential to modulate ferroptosis in CRC is entirely unknown. This study aimed to investigate whether ETV4 modulates ferroptosis in CRC by regulating SLC7A11 and to explore the underlying mechanism involved. Bioinformatic analysis was conducted to detect ETV4 expression and to identify pathways regulated by ETV4. Real‑time quantitative PCR (RT‑qPCR) and Western blot assays were used to measure gene expression at the mRNA and protein levels. The biological functions of ETV4 were assessed via CCK‑8, colony formation, wound‑healing, apoptosis analysis, transmission electron microscopy (TEM) and Transwell assays. Key ferroptosis markers-reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential (JC‑1), and ferrous iron (FerroOrange) were examined to determine whether ETV4 knockdown promotes ferroptosis. ETV4 is highly expressed in CRC tissues and cell lines, and its expression level is positively correlated with advanced TNM stages. Silencing ETV4 suppressed CRC cell proliferation, clonogenicity, and migration. Bioinformatic analysis confirmed that ETV4 may suppress the ferroptosis pathway. Functional assays revealed that ETV4 knockdown enhanced ferroptosis in CRC cells. Mechanistically, ETV4 depletion downregulated SLC7A11, whereas SLC7A11 overexpression reversed the ferroptosis phenotype induced by ETV4 knockdown. ETV4 promotes CRC progression by inhibiting ferroptosis through the upregulation of SLC7A11. Therefore, the ETV4/SLC7A11 axis represents a potential therapeutic target for CRC treatment.
To evaluate finerenone-associated adverse events (AEs) and to investigate the association between finerenone use and renal injury via data mining of the Food and Drug Administration Adverse Event Reporting System (FAERS). To minimize statistical bias, the data extraction period was set from database inception (2004) to provide a stable background for disproportionality analysis. Four disproportionality algorithms (ROR, PRR, BCPNN, and MGPS) and stricter case-screening methods were employed to improve analytical precision. Additionally, a clinical priority evaluation was conducted to rank clinical risks and surveillance levels for these AEs. Supplementary analysis was performed to assess the relationship between finerenone and renal injury, as well as associated risk factors. A total of 1316 finerenone-related reports were identified. 30 AEs were detected as significantly positive signals, with most being related to renal function (15 PTs, 50%), blood pressure (5 PTs, 16.67%), and blood potassium (4 PTs, 13.33%). Among them, blood glucose increased, blood creatine increased, and flank pain were new potential AEs. Acute kidney injury, hyperkalemia, renal impairment, glomerular filtration rate decreased, blood creatinineincreased, blood potassium increased, and hyponatremia exhibited moderate clinical priority levels and warrant further study. Signals reflecting renal injury were detected in patients regardless of baseline nephropathy. Male sex, taking more than 3 drugs, and using amlodipine may be risk factors for finerenone-related nephrotoxicity. These results highlight new finerenone-related AEs, provide ranked guidance for pharmacovigilance through clinical priority evaluation, and clarify factors that influence renal injury, providing guidance for individualized treatment and improved drug safety.
暂无摘要（点击查看详情）