共找到 20 条结果
To our knowledge, no randomised trial with peptide receptor radionuclide therapy has been done in patients with metastatic pancreatic neuroendocrine tumours. We aimed to evaluate the antitumour activity and safety of [177Lu]Lu-dota-tate in this setting. OCLURANDOM is a randomised, open-label, non-comparative, phase 2 trial conducted in ten academic centres in France. Patients aged 18 years and older with pretreated, progressive, somatostatin receptor-positive, metastatic pancreatic neuroendocrine tumours and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1) using web-based software to receive intravenous [177Lu]Lu-dota-tate (7·4 GBq every 8 weeks up to four cycles) with concomitant amino acid infusion or oral sunitinib (37·5 mg once daily). Amino acid infusion was for at least 4 h starting 30 min before [177Lu]Lu-dota-tate infusion and included 16·8 g of arginine and 22 g of lysine in 2 L until May, 2018, and, from that date, a solution of 25 g of arginine and 25 g of lysine in 2 L. Randomisation was stratified according to Ki-67, liver involvement, and previous therapies. The primary endpoint was progression-free survival at 12 months assessed by real-time central review using Response Evaluation Criteria in Solid Tumours version 1.1 in the intention-to-treat population. Cross-over was allowed. Adverse events in the as-treated population were assessed continuously during the active phase of treatment and then every 3 months. Patients and the public were not involved in the design, conduct, reporting, or dissemination plans of this research. This trial was registered with ClinicalTrials.gov, NCT02230176, and is closed to enrolment. Between Feb 13, 2015, and July 16, 2020, 84 patients were enrolled and randomly assigned to the [177Lu]Lu-dota-tate group (n=41) or the sunitinib group (n=43). 44 (52%) patients were women and 40 (48%) were men. Median follow-up was 72·5 months (IQR 61·4-88·4). Progression-free survival rate at 12 months was 33 (80·5% [90% CI 67·5-89·9]) of 41 patients in the [177Lu]Lu-dota-tate group versus 18 (41·9% [29·1-55·5]) of 43 patients in the sunitinib group. Grade 3-4 adverse events occurred in 18 (44%) of 41 patients in the [177Lu]Lu-dota-tate group and 31 (72%) of 43 patients in the sunitinib group. The most common grade 3-4 adverse events for all treatment groups were neutropenia (two [5%] of 41 in the [177Lu]Lu-dota-tate group vs 13 [30%] of 43 in the sunitinib group) and hypertension (four [10%] in the [177Lu]Lu-dota-tate group vs eight [19%] in the sunitinib group). Drug-related serious adverse events occurred in six (15%) patients in the [177Lu]Lu-dota-tate group (transaminase increase, neutropenia, thrombosis, and fever) and ten (23%) in the sunitinib group (gastrointestinal, general disorders, and sepsis). There was a 10·3-point (95% CI 2·4-18·2) difference in the Global Health Status score between the two groups in favour of [177Lu]Lu-dota-tate. Late adverse events (grade 2 or worse) were reported in 24 (60%) patients in the [177Lu]Lu-dota-tate group and in three (43%) of seven patients in the sunitinib group. One treatment-related death (acute leukaemia) occurred in the [177Lu]Lu-dota-tate group. Using sunitinib as an internal control, our results show clinically significant antitumour efficacy of [177Lu]Lu-dota-tate in pretreated, progressive, somatostatin receptor-positive, metastatic pancreatic neuroendocrine tumours, and a better quality of life during the treatment phase. Late adverse events were reported in the [177Lu]Lu-dota-tate group that might affect the tolerance of subsequent lines of treatment. French Ministry of Health, through the National Institute for Cancer.
Oxidative stress has been implicated in aging and metabolic dysfunction, modulated by diet, lifestyle, and body composition. While structured dietary practices such as intermittent fasting and plant-based regimens have demonstrated antioxidative benefits, the biological impact of long-term religious fasting remains underexplored. Orthodox Christian fasting, characterized by periodic abstention from animal products and alignment with circadian rhythms, offers a unique naturalistic model for examining redox adaptation in humans. To identify the physiological and biological factors of oxidative stress markers in Orthodox Christian monastic women compared to age-matched controls, focusing on the roles of adiposity, insulin, vitamin D status, and age. In this cross-sectional study, 52 Orthodox nuns and 56 women from the general population were assessed. Serum levels of total antioxidant capacity (TAC), reduced glutathione (GSH), and thiobarbituric acid reactive substances were measured. Anthropometric indices (body mass index, body fat percentage, visceral fat), fasting insulin, 25-hydroxyvitamin D (25(OH)D), and age were recorded. Statistical analyses included group comparisons, Spearman correlations, and multivariable linear regression models. In the monastic group, body fat percentage (beta coefficient = 0.387, p = 0.003) and age (beta coefficient = 0.301, p = 0.014) were associated with TAC levels. Among controls, insulin positively correlated with GSH (ρ = 0.480, p < 0.001) and marginally inversely with TAC (ρ = -0.321, p = 0.060). No significant associations were found between 25(OH)D and oxidative markers in either group. Vitamin D and insulin levels were not significantly associated with oxidative stress markers in this cohort. These findings highlight the potential of long-term, culturally structured fasting to modulate redox homeostasis and suggest a complex interplay between age, adiposity, and antioxidant defenses. These findings should be interpreted within the context of a highly specific religious and cultural lifestyle and may not be generalizable to other populations. Further research is needed to elucidate underlying mechanisms and long-term clinical implications.
Hypothalamic neuropeptides and neural circuits integrate peripheral signals, nutrient demand, and environmental cues to orchestrate energy homeostasis in vertebrates. Neurosecretory protein GL (NPGL) and neurosecretory protein GM (NPGM) are hypothalamic small secretory proteins encoded by paralogous genes of the FAM237 family. These genes were initially identified in birds, but database search showed evolutionary conservation across vertebrates, suggesting conserved physiological roles for NPGL and NPGM. Previous studies on NPGL have demonstrated that NPGL stimulates overeating and fat accumulation in a diet- and strain-dependent manner in both mammals and birds. Accumulating evidence suggests that NPGM may also be involved in hyperphagia and adiposity. Notably, recent progress in transcriptomics and histological analyses has revealed expression of Npgl and Npgm in specific hypothalamic neuronal subpopulations involved in energy homeostasis. Here, we summarize recent progress in understanding the metabolic actions of NPGL and NPGM. We then focus on the cellular identity of Npgl- and Npgm-expressing neurons. Finally, we discuss future directions and potential molecular mechanisms of metabolic regulation by NPGL and NPGM. Investigating the NPGL/NPGM system, which regulates energy metabolism, will contribute to understanding both conserved and species-specific mechanisms of energy homeostasis across vertebrates.
Evidence is required on the relative effectiveness of sulphonylureas, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter 2 inhibitors added to metformin for people with type 2 diabetes mellitus. To assess disparities in the initiation of second-line antidiabetic treatments prescribed among people with type 2 diabetes mellitus in England according to ethnicity and social deprivation. To compare the effectiveness of sulphonylureas, dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors added to metformin for people with type 2 diabetes mellitus who require second-line treatment in routine clinical practice. To examine heterogeneity in the comparative short-term (12 months) effectiveness of sulphonylureas versus dipeptidyl peptidase-4 inhibitors combined with metformin on levels of glycated haemoglobin across the entire target population and subpopulations of decision-making relevance. To assess the comparative effectiveness of sulphonylureas, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter 2 inhibitors added to metformin according to individual risk-factor profiles of multiple long-term conditions. To calibrate the RAPIDS microsimulation model to UK data and then use the resultant RAPIDS-UK model to predict probabilities of long-term complications for people with type 2 diabetes mellitus in England after second-line treatment with sulphonylureas, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter 2 inhibitors added to metformin. We included adults with type 2 diabetes mellitus who initiated second-line antidiabetic treatment with sulphonylureas, dipeptidyl peptidase-4 inhibitors or sodium-glucose cotransporter 2 inhibitors added to metformin monotherapy. We used data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics and the Office of National Statistics. We applied target trial emulation and instrumental variable analyses to reduce the risks of biases, including confounding. The primary outcome was change in mean glycated haemoglobin (mmol/mol) at 1-year follow-up. Secondary outcomes: change in mean body mass index, systolic blood pressure, estimated glomerular filtration rate and time to major adverse kidney event, major adverse cardiovascular event, heart failure hospitalisation, eye disease, amputation and all-cause mortality. We assessed treatment effect heterogeneity according to multiple long-term conditions. We used a microsimulation model to report the impact on long-term complications. After the instrumental variable analysis, the mean 95% confidence interval differences in glycated haemoglobin change between baseline and 1 year were: -2.5 mmol/mol (-3.7 to -1.3) for sodium-glucose cotransporter 2 inhibitors versus sulphonylureas, and -3.2 mmol/mol (-4.6 to -1.8) for sodium-glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors. Sodium-glucose cotransporter 2 inhibitors were more effective in reducing body mass index and systolic blood pressure compared to either sulphonylureas or dipeptidyl peptidase-4 inhibitors. Sodium-glucose cotransporter 2 inhibitors were also more effective at reducing mean glycated haemoglobin at 2-year follow-up, at reducing body mass index and systolic blood pressure at 1- and 2-year follow-ups and at reducing the hazards of heart failure hospitalisation (vs. dipeptidyl peptidase-4 inhibitors) and ≥ 40% decline in estimated glomerular filtration rate (vs. sulphonylureas). We did not find evidence of treatment effect heterogeneity by baseline cardiovascular disease status or multiple long-term condition profiles. The microsimulation model found that sodium-glucose cotransporter 2 inhibitors led to lower predicted incidence of end-stage kidney disease, heart failure and eye disease. Public and patient involvement translation workshop participants provided valuable insights on how best to share our findings. We could only partially evaluate the main instrumental variable assumptions. We found that sodium-glucose cotransporter 2 inhibitors were better than dipeptidyl peptidase-4 inhibitors and sulphonylureas at improving important risk factors and at reducing the risk of complications among a general population of people with type 2 diabetes mellitus. Newer antidiabetic treatments should be evaluated. This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128490. In the United Kingdom, around 4 million people have been diagnosed with type 2 diabetes, which causes high levels of sugar (glucose) in the blood. Most people start treatment with a drug called metformin, but some will later need to take additional drugs when metformin is not effective enough. We do not know drugs are best to use with metformin. We looked at the health care information routinely collected about people with type 2 diabetes when they use the National Health Service. We used the information collected between 2015 and 2021 to investigate which treatments worked best. We included 75,739 people in our study, all of whom received one of the three drug types below in addition to metformin: sulphonylureas (e.g. Diamicron) dipeptidyl peptidase-4 inhibitors (e.g. Januvia) sodium–glucose cotransporter 2 inhibitors (e.g. Forxiga). There was a lot of variation across different groups of general practices in the treatment they prescribed. We found that sodium–glucose cotransporter 2 inhibitors were more effective than sulphonylureas or dipeptidyl peptidase-4 inhibitors in reducing blood sugar levels, body mass index and blood pressure and preventing hospitalisation due to heart failure. For other outcomes (like preventing or delaying heart attack, stroke or death), there was no clear difference between drug types. Our results show that using sodium–glucose cotransporter 2 inhibitors alongside metformin may help patients manage some of the common symptoms and side effects of their diabetes. However, some of these effects are quite small. There will be people whose personal circumstances mean that the drug they are taking works especially well for them. Where we did not see a significant difference between drug types, this may be because we did not have data for enough people over a long enough period.
Mammalian thyroid status is governed by thyroid secretion of L-thyroxine (T4) as a prohormone that is monodeiodinated in peripheral tissues to bioactive T3 (3,5,3'-triiodo-l-thyronine). T4 secretion is controlled by the hypothalamic-pituitary-thyroid (HPT) axis (central control) whereas T3 availability to target cells depends mainly on mechanisms in extrathyroidal tissues such as cellular transport and deiodination (peripheral control). Does this model apply to poikilothermic teleost fish which in contrast to homeothermic mammals may show major surges in plasma T4 due to season, feeding, reproductive state or stressors? We have evaluated the contributions of central and peripheral mechanisms to fish thyroid status in light of recent discoveries employing both traditional endocrine approaches and more modern molecular biological techniques, focusing primarily on salmonid species which may undergo a unique thyroid-implicated premigratory parr-smolt transition (PST), and which as tetraploids may express multiple paralogs of regulatory peptides. Most teleost research has focused on peripheral control by the three classic deiodinases (D1, D2 and D3). In salmonids they determine systemic (D1, D2) and tissue-specific (D2) T3 generation from T4 and the equally critical T4 and T3 degradations (D1, D3). Tetraploid salmonids may express up to four paralogs for a given deiodinase, providing the potential for species-specific or tissue-specific T3 production, curtailment of T3 action, or iodine recapture. Critical as they appear, salmonid deiodinases do not function in isolation but in concert with, and dependence on, TH plasma transport, cell-membrane translocation, hepatic conjugation, biliary excretion and gastrointestinal metabolism. Two rainbow trout properties are particularly distinct from the mammalian model: i) T3, but not T4, exchanges rapidly between plasma and erythrocytes permitting plasma T3 stability despite marked acute changes in plasma T4 and ii) in contrast to ingested T4, which is unavailable from food due to complete gastrointestinal deiodination, ingested T3 contributes to the plasma T3 pool. Thus the teleost liver, poised at the confluence of exogenous and endogenous T3 sources, may play a strategic role through its TH biliary excretion, deiodination and other pathways in regulating systemic T3 availability involved in anabolic/catabolic balance and somatic growth. A major consequence of ingested T4 degradation is the exclusive delegation of T4 availability to the HPT axis. Since mammalian TSH consistently stimulates teleost T4 secretion a mammal-like HPT central control model has been assumed. However, teleost HPT function differs from that of homeotherms in both its hypothalamic control and response to external stimuli. T4 secretion could be regulated mainly by T4 negative feedback with the HPT axis playing a subsidiary role of merely ensuring adequate T4 substrate for regulated peripheral deiodination to proceed. However, this does not account for the notable surges in salmonid plasma T4 and implies resetting of the HPT 'thyrostat'. Thus the role of central TSH control in the regulation of plasma T4 changes remains unclear, awaiting further characterization of endogenous TSH secretion. Furthermore, discoveries of TSH-subunit and TSH-receptor expression in piscine peripheral tissues such as the CNS, liver, and gonad require reassessment of TSH function with a focus not only on its traditional endocrine actions but also on its potential as a paracrine regulator of TH action in peripheral tissues. In conclusion, while there are many similarities in thyroid regulation between mammals and salmonids there are also key differences. These likely stem from the evolution of homeothermy, the constraints of terrestrial iodine availability and a plasticity in salmonid peripheral and central control resulting from tetraploidy.
Type 2 diabetes mellitus has been associated with an increased risk of cognitive decline and dementia, with patients being 1.5-2 times more likely to develop these conditions. While both sodium-glucose co-transporter 2 (SGLT2) inhibitors and thiazolidinediones (TZDs) have shown potential neuroprotective effects in previous studies, their comparative effectiveness for preventing neurodegenerative outcomes has not been established. This study aimed to compare the risk of stroke, dementia and Alzheimer's disease (AD) between patients treated with SGLT2 inhibitors and those treated with TZDs. Multicentre, retrospective, observational, new-user, active-comparator cohort study. Electronic health record-based databases from 11 secondary and tertiary institutions in South Korea from 1 January 2014 to 31 July 2025. The study period began in 2014, following the post-marketing surveillance initiation of SGLT2 inhibitors in Korea (November 2013), to ensure adequate drug availability and clinical adoption. Patients aged 40 years or older who were newly prescribed either SGLT2 inhibitors or TZDs without prior exposure. Propensity score matching (1:1) was performed using sex as the primary covariate due to data availability constraints in the Observational Medical Outcomes Partnership Common Data Model framework. The HRs with 95% CIs were measured via Cox regression analysis. The study analysed 24 172 matched pairs for stroke outcomes (40 483 person-years in the SGLT2 inhibitor group and 39 363 person-years in the TZD group), 25 111 matched pairs for dementia (41 924 person-years in the SGLT2 inhibitor group and 40 726 person-years in the TZD group) and 25 237 matched pairs for AD (42 139 person-years in the SGLT2 inhibitor group and 40 895 person-years in the TZD group) across 11 participating hospitals. After a 1:1 propensity score matching, the SGLT2 inhibitors showed no significant difference in stroke risk (HR 1.18, 95% CI 0.62 to 2.23, p=0.62), while having significant reductions in dementia risk (HR 0.66, 95% CI 0.45 to 0.98, p=0.04) and AD risk (HR 0.54, 95% CI 0.35 to 0.83, p=0.005). Moreover, these protective effects for neurodegenerative outcomes were shown to be consistent across multiple hospital sites. SGLT2 inhibitors are associated with a reduced risk of dementia and AD compared with TZDs in patients aged 40 years or older with type 2 diabetes and have neutral effects on stroke risk. These findings confirm the potential selective neuroprotective benefits of SGLT2 inhibitors for neurodegenerative outcomes, which may inform therapeutic decision-making for diabetic patients at risk of cognitive decline.
Pesticide pollution in aquatic ecosystems has been increasing, especially organophosphates such as sumithion, which pose serious risks to non-target aquatic species including Nile tilapia (Oreochromis niloticus). In our study, we systematically assessed the therapeutic effects of probiotics and Spirulina platensis on sumithion-induced oxidative stress, immunosuppression, hematological alterations, and growth inhibition in O. niloticus. A total of 240 fingerlings (12.8 ± 0.09 g) were chosen randomly to receive four treatments for experimentation: control, sumithion (0.30 mg/L), sumithion and probiotics (0.30 mg/L and 1.0 ml/L), and sumithion and Spirulina (0.30 mg/L and 50 g/kg). Each treatment had three repetitions for a duration of six weeks. The exposure of fish to sumithion caused impaired growth performance, significant (p < 0.05) increase in metabolic and oxidative stress markers, as well as a decrease in hemoglobin (Hb) concentration, induced hyperglycemia, and downregulation of immune gene expression. Conversely, treatments with probiotics and Spirulina effectively ameliorated these toxic effects. Probiotics were effective in restoring immune gene expression (interferon-gamma, IFN-γ, interleukin-1 beta, IL-1β; and tumor necrosis factor-alpha, TNF-α), reducing glucose (Glu) levels, and improving growth performance, as evidenced by the highest weight gain, specific growth rate, and increased intestine-somatic index (ISI) and lowest feed conversion ratio. Furthermore, the probiotic-supplemented group showed an upregulation in hepatic igf-1, igf-2 (insulin-like growth factors) and pituitary gh (growth hormone) expression levels. In contrast, Spirulina had a greater impact on promoting antioxidant activity and boosting hematological parameters, particularly by improving Hb, SOD (superoxide dismutase), and CAT (catalase) levels, while also contributing to a significant increase in hepatosomatic index (HSI). These results emphasize the effectiveness of probiotics and Spirulina as eco-friendly complements to alleviate sumithion-prevailed toxicity, enhancing growth, immune response, and antioxidant capacity in O. niloticus, with probiotics being an effective approach in easing physiological impairments.
Transoral endoscopic thyroidectomy via the vestibular approach (TOETVA) provides a scarless alternative to open thyroidectomy but entails specific risks, particularly mental nerve injury. How patients weigh these risks against cervical scarring and wound morbidity from open surgery remains unclear. In this prospective cross-sectional study at a high-volume endocrine surgery centre, 68 consecutive TOETVA patients completed pre- and postoperative surveys on informational priorities, risk recall, and satisfaction. To contextualize TOETVA-specific morbidity and the informational trade-offs faced by patients, we prospectively identified a contemporary open thyroidectomy cohort and applied 1:1 nearest-neighbor matching by age, sex, indication, and extent of resection, thereby supporting comparative inferences beyond simple descriptive contrasts. All patients received structured, multimodal counselling with centre-specific numerical risks, and an additional questionnaire assessed how risk information influenced procedure choice and willingness to reconsider preferences under alternative risk scenarios. TOETVA patients rated procedural details, TOETVA-specific risks-particularly mental nerve injury-and general thyroidectomy complications as highly important (≥ 4.7/5), with recall and satisfaction exceeding 90%. In the TOETVA cohort, transient recurrent laryngeal nerve palsy occurred in 7.4% and transient hypocalcaemia in 6.1%, with no permanent events; mental nerve paraesthesia affected 30.9%, persisting at 6 months in 4.4%. Matched open thyroidectomy patients showed comparable transient RLN palsy (5.9%) and hypocalcaemia (6.1%), but had 1.5% permanent RLN palsy, 1.5% permanent hypocalcaemia, no mental nerve injury, and 7.4% cervical wound complications. Overall, 94% of patients considered precise numerical risk estimates essential, and 88% reported that comparative risk information strongly influenced technique choice, with many indicating they would reconsider preferences if rates of persistent mental nerve symptoms or neck-scar morbidity changed. Patients prioritise quantified, centre-specific risk information and use it to balance the cosmetic benefits of TOETVA against mental nerve morbidity and the wound risks of open surgery, supporting routine integration of audited complication rates into shared decision-making.
Permanent hypoparathyroidism after total thyroidectomy remains a major complication, occurring in close to 10% of cases and increasing risks of cardiac, renal, and metabolic morbidity. Near-infrared autofluorescence (NIRAF) imaging has emerged as a promising adjunct to improve parathyroid gland (PG) identification and preservation. This study evaluates the efficacy of NIRAF in enhancing intraoperative PG detection compared to conventional visual inspection. This single-center retrospective cohort study included 349 patients undergoing total thyroidectomy. Outcomes were compared between a control group managed with visual PG identification alone (n = 126, 2014-2016) and a NIRAF-assisted group using Fluobeam LX® imaging (n = 223, 2021-2023). The primary outcome was the mean number of PGs identified intraoperatively. Secondary outcomes included postoperative calcium and parathyroid hormone (PTH) levels, rates of PG autotransplantation, and inadvertent PG removal. NIRAF use was associated with significantly improved intraoperative PG identification, with a higher mean number of glands visualized compared to controls (2.91 ± 0.98 vs. 2.59 ± 1.02; p = 0.004). Postoperative PTH levels were significantly higher in the NIRAF group (3.64 ± 1.72 vs. 3.03 ± 1.40 pmol/L; p < 0.001). Although postoperative calcium levels were lower in the NIRAF group (2.21 ± 0.11 vs. 2.29 ± 0.12 mmol/L; p < 0.001), the incidence of severe hypocalcemia (≤2.0 mmol/L) was low and comparable between groups (3.1% vs. 1.6%; p = 0.497). Rates of postoperative PTH <1.1 pmol/L, PG autotransplantation, and reimplantation did not differ significantly. Inadvertent PG removal was more frequent in the NIRAF group (20.6% vs. 5.6%; p < 0.001). NIRAF imaging improves intraoperative identification of PG and is associated with higher early postoperative PTH levels. Although hypoparathyroidism did not differ between the two groups, the effect of NIRAF on permanent hypoparathyroidism requires prospective evaluation, particularly when combined with perfusion assessment using indocyanine green (ICG) angiography. Standardized use and surgeon training are necessary to optimize clinical outcomes.
Grass carp (Ctenopharyngodon idella) is an important aquaculture species, yet no specific immunoassay is available for quantifying its pituitary gonadotropins-luteinizing hormone (LH) and follicle-stimulating hormone (FSH)-which are key regulators of reproduction in vertebrates. Here, we developed and validated competitive enzyme-linked immunosorbent assays (ELISAs) for grass carp LH and FSH using recombinant proteins and specific polyclonal antibodies. The recombinant proteins were expressed in E. coli based on the native hormone sequences, and polyclonal antibodies were generated in rabbits. Antibody specificity was validated by immunohistochemistry and western blotting, which confirmed that LH and FSH are produced by distinct cell populations in the grass carp pituitary, consistent with the organizational pattern observed in other teleosts. The standard curves showed excellent correlation (mean R2 = 0.994). Assay sensitivities were 1.27 ng/mL for LH and 1.18 ng/mL for FSH, with IC50 values of 9.19 ng/mL and 9.29 ng/mL, respectively. Intra-assay CVs ranged from 0.68% to 4.10% (LH) and 0.44% to 4.27% (FSH), while inter-assay CVs averaged 5.43% and 1.92%, demonstrating good reproducibility. Using this assay, we quantified LH and FSH levels in grass carp across different developmental stages, revealing distinct age- and sex-specific secretion patterns that provide insights into the differential regulation of gonadotropins during sexual maturation in cyprinids. The assay also successfully detected hormone responses to salmon gonadotropin-releasing hormone (sGnRH) stimulation both in vivo and in vitro. This ELISA system provides a reliable tool for investigating gonadotropin dynamics in grass carp and offers a methodological foundation for comparative studies on the endocrine regulation of reproduction in teleost fishes.
The search for natural alternatives to chemical additives and artificial hormones to enhance reproductive function in aquatic animals is driven by demand for eco-friendly aquaculture. This review explores how bioactive plant compounds can enhance ovarian vitellogenesis and reproductive efficiency in crustaceans and finfish. Vitellogenesis is regulated by the hypothalamic-pituitary-gonadal axis, controlling yolk protein deposition and embryogenesis. While synthetic hormones have significant effects, their environmental and health impacts have sparked interest in phytochemicals such as carotenoids, flavonoids, alkaloids, and phytoestrogens. These compounds can stimulate vitellogenin production, boost reproductive performance, and improve egg quality through immunomodulatory, hormone-mimetic, and antioxidant activities that reduce oxidative stress. Plant extracts like Moringa oleifera, Eurycoma longifolia, and Cyperus spp. boost reproductive maturity and larval survival. The review highlights their cost-effectiveness, biodegradability, and cultural acceptance aligned with sustainable aquaculture demands. Challenges include variation in bioactivity, lack of standardized protocols, and species-specific responses. Future research should explore nanotechnology, omics, and precision extraction to enhance the applications of phytochemicals. Combining traditional knowledge with modern science can improve aquaculture productivity for environmental and food security.
Janus kinase (JAK) and interleukin-6 (IL-6) inhibitors are therapeutic options for patients with rheumatoid arthritis (RA) with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs); however, no randomized controlled trial has compared their efficacy and safety. Since both act through the JAK-signal transducer and activator of transcription pathway, a comparative evaluation is warranted. We conducted a prospective, randomized, open-label trial at 55 centers in Japan, randomizing patients with active RA despite csDMARD therapy in a 1:1 ratio to receive 200 mg/day filgotinib or subcutaneous tocilizumab as monotherapy; the primary endpoint was American College of Rheumatology (ACR) 50 at week 12, and secondary endpoints included clinical disease activity indices, musculoskeletal ultrasonography scores, patient-reported outcomes, and serum biomarkers through 52 weeks. Twenty-six patients were enrolled (13 per group) before study termination due to insufficient recruitment, and descriptive analyses were performed. At week 12, ACR50 was achieved in 38.5% (5/13) patients in the filgotinib group and 46.2% (6/13) in the tocilizumab group (risk difference: -7.69%; 95% confidence interval: -42.26 to 28.8). Both groups showed early and sustained improvements in disease activity from week 2. The improvement in patient global assessment scores was greater with filgotinib at week 2 but the difference diminished thereafter, and serum IL-6 level decreased with filgotinib but increased with tocilizumab. Four serious adverse events occurred with filgotinib, including infections and cardiac events. Because this study was underpowered and the analysis was descriptive, larger studies are needed to confirm these findings and define optimal use. (The study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) as jRCTs071200107 and in ClinicalTrials.gov as NCT05090410.).
This study assessed the efficacy and safety of a triple fixed-dose combination (FDC) of sitagliptin, metformin, and glimepiride versus co-administered metformin and glimepiride in Indian patients with uncontrolled Type 2 diabetes (T2D). In this Phase 3, randomised, double-blind, double-dummy study, adult patients with T2D and glycated haemoglobin (HbA1c) of 8%-11%, despite treatment with metformin and glimepiride, were randomised 1:1 to triple FDC of sitagliptin 50 mg, metformin 1000 mg and glimepiride 1 mg (SITA + MET + GLIM group) or metformin 1000 mg and glimepiride 2 mg (Co-administration group) for 16 weeks. Patients assigned to the SITA + MET + GLIM group could continue treatment for a 12-week open-label period. The primary endpoint was the change in HbA1c from baseline to Week 16. Overall, 190 patients were randomised to the SITA + MET + GLIM group and 202 to the Co-administration group. The least squares mean (standard error) change from baseline in HbA1c at Week 16 was -1.79 (0.07%) in the SITA + MET + GLIM group and -1.27 (0.06%) in the co-administration group (estimated treatment difference -0.51; 95% confidence interval [CI] -0.69 to -0.33; p < 0.0001). The proportion of patients with HbA1c below 7% at Week 16 was 32.1% in the SITA + MET + GLIM group and 12.6% in the Co-administration group (p < 0.0001). Adverse events occurred in 25 patients (13.2%) in the SITA + MET + GLIM group and 30 patients (14.9%) in the Co-administration group. The triple FDC was superior to co-administered metformin and high-dose glimepiride for achieving glycaemic control and was well tolerated in Indian patients with T2D. Clinical Trials Registry-India identifier: CTRI/2021/11/038169 (registered on 22 November 2021); URL: https://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=NjI1Mjk=&Enc=&userName=.
Background: Sleeve gastrectomy (SG) reliably reduces weight and triglycerides, but LDL-C responses are variable. In this retrospective observational study, we evaluated whether adjunctive monacolin K (red yeast rice; 3 mg/day) improves early lipid modulation after SG. Methods: In this single-center retrospective study of women only, 149 patients undergoing SG within the national KOS-BAR program were analyzed in four groups: controls without supplementation (CG, n = 62) and three supplementation cohorts receiving monacolin K for 6 months (G1 early (from week 1; n = 46), G2 delayed (months 3-9; n = 10), and G3 delayed (months 6-12; n = 31)). Outcomes included total cholesterol (TC), LDL-C, HDL, and triglycerides (TG). Missing data were imputed; mixed models for repeated measures assessed longitudinal changes. Results: From baseline to 6 months, LDL-C-C increased in the control group (CG; +21.9 mg/dL) and decreased in G1 (mean change: -11.1 mg/dL), with a significant group-by-time interaction (p < 0.001). HDL-C increased in both CG and G1, whereas triglyceride levels decreased more markedly in G1 than in CG (-36.2 vs. -19.6 mg/dL). Total cholesterol decreased in G1 (-13.4 mg/dL) and in G2 at 9 months (-22.5 mg/dL). Conclusions: In the early supplementation group, LDL-C-C levels decreased over the first 6 months after SG, whereas an increase was observed in the control group, which had significantly lower baseline LDL-C concentrations. In women undergoing SG, early postoperative monacolin K supplementation was associated with LDL-C stabilization and enhanced lipid optimization without impeding weight-loss benefits. Delayed initiation yields partial improvements, especially for TG and HDL-C. These observations underscore the need for prospective, sex-stratified studies with appropriate baseline adjustments to clarify the association between monacolin K use and postoperative lipid trajectories after SG.
Glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in managing type 2 diabetes mellitus (T2DM) and provide metabolic and cardiovascular benefits. Their associations with neurocognitive outcomes in clinical populations remain uncertain. We conducted a retrospective, population-based cohort study using de-identified electronic health records from the global TriNetX research network, predominantly comprising U.S.-based healthcare organizations. Adults with T2DM who initiated tirzepatide or semaglutide were included. Propensity score matching (1:1) was applied to balance baseline characteristics, including age, sex, race, and cardiometabolic and psychiatric comorbidities. Incident diagnoses of mild cognitive impairment (MCI), dementia, and Alzheimer's disease (AD) occurring at least 12 months after treatment initiation were assessed using risk ratios (RRs) and time-to-event analyses with Kaplan-Meier estimators. A total of 290,606 patients initiated semaglutide and 44,471 initiated tirzepatide. After propensity score matching, each group included 44,470 patients. Compared with semaglutide, initiation of tirzepatide was associated with a lower risk of MCI (RR 0.12; 95% CI 0.06-0.22), dementia (RR 0.15; 95% CI 0.09-0.26), and AD (RR 0.48; 95% CI 0.22-1.01). Absolute risks were low for all outcomes, and separation of survival curves was more consistent for MCI than for dementia or AD. In this real-world observational analysis of adults with T2DM, initiation of tirzepatide was associated with a lower incidence of MCI compared with semaglutide, whereas associations for dementia and AD were less consistent. These findings should be interpreted descriptively and as hypothesis-generating. Prospective randomized trials with longer follow-up and systematic neurocognitive assessment are needed to clarify whether, and under which conditions, incretin-based therapies influence neurocognitive outcomes.
Hagfishes are representatives of the phylogenetically important, early-branching vertebrate lineage Agnatha, and many endocrine signaling systems in this group remain poorly understood. In this study, we provide the first molecular and functional characterization of melanocortin receptors (Mcrs) and their accessory protein (Mrap) in hagfishes. Using genomic and transcriptomic resources from inshore hagfish (Eptatretus burgeri), Pacific hagfish (Eptatretus stoutii), and Atlantic hagfish (Myxine glutinosa), we identified genes encoding two hagfish melanocortin receptors, Mcar and Mcbr, and a single Mrap. When expressed in mammalian cells, both receptors responded to human ACTH(1-24) and α-MSH with similar affinities. Co-expression with Mrap reduced maximal activity of Mcbr but not Mcar and only modestly modulated the ligand sensitivity of either receptor. Gene expression analyses revealed that mcbr and mrap are prominently expressed in the slime gland, a tissue that also transcriptionally expressed the steroidogenic enzymes star and cyp11a1, whereas mcar is most prominently expressed in the brain. These findings suggest that hagfish Mcrs retain broad ligand responsiveness and relative Mrap-independence, consistent with a hypothesized ancestral mode of melanocortin signaling. Although no genes encoding known melanocortin prohormones have yet been identified in hagfish genomes, the presence of functional receptors and tissue-specific expression patterns suggest these genes may have physiological roles and that an as-yet-unidentified ligand may exist in hagfish. Together, these results provide new insight into the organization and evolution of the vertebrate melanocortin system and highlight hagfish as a key model for reconstructing the functional evolution of this essential endocrine signaling pathway.
Meat quality characteristics such as juiciness, tenderness, and flavor are greatly enhanced by intramuscular fat (IMF). Improving intramuscular adipose tissue accumulation while maintaining stable lipid levels in fat depots has become a critical priority in the beef sector. Understanding the molecular mechanisms driving intramuscular fat deposition is critical because it can enable the utilization of genetic selection to produce high-quality beef. Emerging research suggests that miRNAs play essential roles in regulating IMF deposition, particularly through regulating preadipocyte dynamics such as proliferation and differentiation. Our study aimed to screen and explore the function of potential miRNA in bovine intramuscular preadipocytes and to delineate the underlying molecular mechanisms governing cell proliferation and differentiation. Through time series cluster analysis following by experimental validation by qPCR and Agarose gel PCR identified that bta-miR-380-3p was potential miRNA that highly related with intramuscular preadipocyes differentiation in beef cattle. Bta-miR-380-3p enhanced the proliferation of intramuscular pre-adipocytes by increasing the cell cycle progression and show dynamic time dependent regulation during proliferation and differentiation. It also boosted the formation of lipid droplets in intramuscular pre-adipocytes. The qPCR results revealed that bta-miR-380-3p mimic boosted the expression of PPARγ, FASN, FABP4, SREBP1, and DGAT2 differentiation marker genes. These results provide new insight on the regulatory processes of intramuscular adipogenesis and identify bta-miR-380-3p as a potential target for increasing beef quality through directional selection and molecular breeding. This finding provides a theoretical framework and molecular targets for increasing IMF content.
Birds rely on a specialized set of photoreceptive neurons called deep brain photoreceptors (DBPs) for the detection of light signals which are then integrated to modulate the expression of gonadotropin hormones. Therefore, we want to investigate DBPs expression, melanopsin (OPN 4), neuropsin (OPN5), and vertebrate ancient opsin (VAOpn), and their regulation of gonadotropin releasing hormone (GnRH) and gonadotropin inhibitory hormone (GnIH) genes in regards to sex and age in Pekin ducks. 460 hatchlings were randomly allocated to 4 rooms and exposed to 24 h light (LL) or photostimulation (PS; n = 30 hens and 7 drakes/pen; 4 pens/treatment) for 19 weeks. Ducks were euthanized via an intravenous injection of sodium pentobarbital (Fatal Plus; 396 mg/mL/kg body weight) at weeks 0, 5, 10, and 19 (n = 6/sex/treatment/timepoint) for brain sample collection which was further hemisected into diencephalon. Gene expressions of OPN 4, OPN5, and VAOpn, GnRH, and GnIH were quantified using qRT-PCR. In the hens, OPN4 expression was higher (p < 0.05) in LL compared to PS at week 0, suggesting a rapid transcriptional response to continuous light but no difference in OPN5 expression. VAOpn expression was reduced (P < 0.05) in PS compared to LL at week 10 in the hens. In parallel, GnRH expression was higher (p < 0.05) under LL compared to PS at week 19, peaked at week 0 in both treatments and declined (p < 0.05) thereafter in the hens. In contrast, GnIH expression increased (p < 0.01) with age in both sexes, and was lower in the PS hens compared to LL hens at week 10. These findings demonstrate photoperiod-dependent variation in DBPs alongside GnRH and GnIH transcription which is consistent with a possible involvement in sex-specific reproductive development in ducks.
A core set of patient-reported outcomes (PROs) for systemic lupus erythematosus (SLE) has not been established, and no studies have compared predictive validity of disease-specific and generic quality of life (QOL) instruments. We aimed to compare the predictive validity of the Lupus PRO and Medical Outcomes Study Short-Form-12 (SF-12) for damage accrual in patients with SLE. The Lupus PRO questionnaire contains both health-related (HR) and non-HR-QOL measures, whereas the SF-12 indices are the physical component summary (PCS), mental component summary (MCS), and role-social component summary (RCS). Damage accrual was evaluated using an increase of one unit in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We examined the association and predictive accuracy of the Lupus PRO and SF-12 scores at baseline for damage accrual using survival models for recurrent events. Among 1326 patients, those with a higher HR-QOL on Lupus PRO at baseline showed significantly lower damage accrual (hazard ratio: 0.94, 95% confidence interval [CI]: 0.89-0.99), whereas higher PCS and RCS of SF-12 were associated with lower damage accrual (0.92, 95% CI: 0.86-0.98; 0.92, 95% CI: 0.86-0.99). The Akaike Information Criterion, Bayesian Information Criterion, C-index, and area under the curve were comparable between the Lupus PRO and SF-12. Only higher PCS of the SF-12 was associated with glucocorticoid-independent SDI. Predictive metrics and discriminatory performance were comparable between the Lupus PRO and SF-12. Our findings highlight both disease-specific and generic QOL measurements can be valuable options for core set outcomes.
Psychiatric comorbidities are highly prevalent among general hospital inpatients but often remain undetected when mental health referrals rely solely on clinical judgment. Systematic screening may improve identification, yet comparative evidence using structured diagnostic interviews remains limited. The study evaluates diagnostic confirmation rate of systematic PHQ-4 screening versus clinician-initiated referral in identifying psychiatric comorbidities among medical inpatients. In this quasi-experimental pilot study, systematic screening using the Patient Health Questionnaire-4 (PHQ-4) was implemented on one medical ward (n = 127 admissions), while two comparable wards followed treatment as usual (TAU; n = 267 admissions), with psychosomatic consultations initiated by medical staff based on clinical judgment. Patients screening positive (PHQ-4 ≥ 6 or subscale ≥ 4) were referred for consultation. All referred patients underwent structured diagnostic assessment using the Mini-DIPS interview. Primary outcomes were the proportion of referred patients with a confirmed psychiatric diagnosis (diagnostic confirmation rate) and overall identification rates. Secondary outcomes included time from admission to referral and consultation, as well as treatment recommendations and their uptake. Among interviewed patients, screening was associated with a numerically higher rate of diagnostic confirmation than TAU (11/13, 84.6% vs. 8/14, 57.1%), although this difference did not reach statistical significance. A higher proportion of admissions with confirmed psychiatric disorders was observed in the screening group (11/127, 8.7%) compared with TAU (8/267, 3.0%). Referral rates were higher in the screening group (21/127, 16.5% vs. 22/267, 8.2%), and time to consultation was shorter (median 1 vs. 3.5 days). Depressive and anxiety disorders predominated. Follow-up consultation showed high adherence, whereas uptake of inpatient treatment was low. Systematic PHQ-4 screening was associated with higher detection of psychiatric comorbidities and earlier consultation-liaison involvement, suggesting that clinician-initiated referral alone may miss substantial psychiatric morbidity. However, given the quasi-experimental design and limited sample size, the findings should be interpreted cautiously. Larger randomized studies are needed to evaluate implementation and patient outcomes.