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To investigate potential sex-related differences in patients with narcolepsy type 1, we carried out an analysis of baseline data from 93 women and 89 men with narcolepsy type 1 who participated in the TElemedicine for NARcolepsy (TENAR) trial. The following data were considered: sociodemographics; diagnostic (disease history, polysomnography, orexin, human leukocyte antigen) and clinical features, including sleepiness (Epworth Sleepiness Scale), cataplexy and other narcolepsy symptoms; disease severity (Narcolepsy Severity Scale); pharmacological treatment; depressive symptoms (Beck Depression Inventory); and self-reported relevance of eight narcolepsy-related issues. We found that, compared with men, significantly more women reported automatic behaviours (55.4% versus 40%) and had higher Epworth Sleepiness Scale (median 10 versus 9) and Beck Depression Inventory scores (median 10.5 versus 5), and there was a trend for a higher Narcolepsy Severity Scale total score in women (median 19 versus 18, p = 0.057). More women than men were officially recognized as having a disability (38% versus 22.5%) and considered 5/8 narcolepsy-related issues investigated as a relevant problem. More severe sleepiness and a greater narcolepsy-related burden in women could mirror sex differences present in the general population, or may be related to suboptimal management of narcolepsy type 1 or to more severe depressive symptoms in women. Future studies and guidelines should address these aspects.
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OBJECTIVES: Current liquid chromatography-tandem mass spectrometry (LC-MS/MS) applications for circulating androgen measurements are technically diverse. Previously, variable results have been reported for testosterone. Data are scarce for androstenedione and absent for dehydroepiandrosterone sulfate (DHEAS). We assessed the agreement of androstenedione, DHEAS and testosterone LC-MS/MS measurements among nine European centers and explored benefits of calibration system unification. METHODS: Androgens were measured twice by laboratory-specific procedures in 78 patient samples and in EQA materials. Results were obtained by in-house and external calibration. Intra- and inter-laboratory performances were valued. RESULTS: Intra-laboratory CVs ranged between 4.2-13.2â¯% for androstenedione, 1.6-10.8â¯% for DHEAS, and 4.3-8.7â¯% and 2.6-7.1â¯% for female and male testosterone, respectively. Bias and trueness in EQA materials were within ±20â¯%. Median inter-laboratory CV with in-house vs. external calibration were 12.0 vs. 9.6â¯% for androstenedione (p<0.001), 7.2 vs. 4.9â¯% for DHEAS (p<0.001), 6.4 vs. 7.6â¯% for female testosterone (p<0.001) and 6.8 and 7.4â¯% for male testosterone (p=0.111). Median bias vs. all laboratory median with in-house and external calibration were -13.3 to 20.5â¯% and -4.9 to 18.7â¯% for androstenedione, -10.9 to 4.8â¯% and -3.4 to 3.5â¯% for DHEAS, -2.7 to 6.5 % and -11.3 to 6.6â¯% for testosterone in females, and -7.0 to 8.5â¯% and -7.5 to 11.8â¯% for testosterone in males, respectively. CONCLUSIONS: Methods showed high intra-laboratory precision but variable bias and trueness. Inter-laboratory agreement was remarkably good. Calibration system unification improved agreement in androstenedione and DHEAS, but not in testosterone measurements. Multiple components, such as commutability of calibrators and EQA materials and internal standard choices, likely contribute to inter-laboratory variability.
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Androstenodiona , Sulfato de Deshidroepiandrosterona , Testosterona , Femenino , Humanos , Masculino , Persona de Mediana Edad , Androstenodiona/sangre , Androstenodiona/análisis , Calibración , Sulfato de Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona/análisis , Sulfato de Deshidroepiandrosterona/normas , Cromatografía Líquida con Espectrometría de Masas/métodos , Cromatografía Líquida con Espectrometría de Masas/normas , Espectrometría de Masas en Tándem/normas , Espectrometría de Masas en Tándem/métodos , Testosterona/sangre , Testosterona/análisis , Testosterona/normasRESUMEN
OBJECTIVES: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) panels that include glucocorticoid-related steroids are increasingly used to characterize and diagnose adrenal cortical diseases. Limited information is currently available about reproducibility of these measurements among laboratories. The aim of the study was to compare LC-MS/MS measurements of corticosterone, 11-deoxycortisol and cortisone at eight European centers and assess the performance after unification of calibration. METHODS: Seventy-eight patient samples and commercial calibrators were measured twice by laboratory-specific procedures. Results were obtained according to in-house and external calibration. We evaluated intra-laboratory and inter-laboratory imprecision, regression and agreement against performance specifications derived from 11-deoxycortisol biological variation. RESULTS: Intra-laboratory CVs ranged between 3.3 and 7.7%, 3.3 and 11.8% and 2.7 and 12.8% for corticosterone, 11-deoxycortisol and cortisone, with 1, 4 and 3 laboratories often exceeding the maximum allowable imprecision (MAI), respectively. Median inter-laboratory CVs were 10.0, 10.7 and 6.2%, with 38.5, 50.7 and 2.6% cases exceeding the MAI for corticosterone, 11-deoxycortisol and cortisone, respectively. Median laboratory bias vs. all laboratory-medians ranged from -5.6 to 12.3% for corticosterone, -14.6 to 12.4% for 11-deoxycortisol and -4.0 to 6.5% for cortisone, with few cases exceeding the total allowable error. Modest deviations were found in regression equations among most laboratories. External calibration did not improve 11-deoxycortisol and worsened corticosterone and cortisone inter-laboratory comparability. CONCLUSIONS: Method imprecision was variable. Inter-laboratory performance was reasonably good. However, cases with imprecision and total error above the acceptable limits were apparent for corticosterone and 11-deoxycortisol. Variability did not depend on calibration but apparently on imprecision, accuracy and specificity of individual methods. Tools for improving selectivity and accuracy are required to improve harmonization.
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Cortisona , Humanos , Cromatografía Liquida/métodos , Cortodoxona , Corticosterona , Espectrometría de Masas en Tándem/métodos , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVES: Preoperative localization of pathological parathyroid glands with imaging is essential for focused unilateral neck exploration and minimally invasive techniques. Recently published studies suggested that contrast-enhanced ultrasonography (CEUS) had high accuracy in the localization of hyperfunctioning parathyroid glands, with a general increase in the sensitivity as compared to conventional sonography. The purpose of this study was to determine the usefulness of CEUS in the localization of parathyroid lesions relating to surgical and histopathological data, in comparison to color Doppler ultrasound (CDUS), in the same series of patients. METHODS: Records of 142 patients who underwent parathyroidectomy were retrospectively examined comparing imaging and intraoperative/histopathologic findings. RESULTS: The overall sensitivity of CEUS was 77.6% compared with 74.6% for CDUS, although no significative differences were found (P = .516). Conversely, CDUS has shown higher sensitivity than CEUS in the group of patients with associated thyroid pathology but there was no statistical difference (P = .529). The sensitivity for detection of multiple adenomas was the same for both procedures. CONCLUSIONS: We found no significative superior sensitivity of CEUS also in case of concomitant thyroid pathology and multiple glands disease.
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Hiperparatiroidismo Primario , Neoplasias de las Paratiroides , Humanos , Glándulas Paratiroides/diagnóstico por imagen , Estudios Retrospectivos , Neoplasias de las Paratiroides/cirugía , Ultrasonografía/métodos , Ultrasonografía Doppler en Color/métodos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Obesity and related co-morbidities represent a major health challenge nowadays, with a rapidly increasing incidence worldwide. The gut microbiome has recently emerged as a key modifier of human health that can affect the development and progression of obesity, largely due to its involvement in the regulation of food intake and metabolism. However, there are still few studies that have in-depth explored the functionality of the human gut microbiome in obesity and even fewer that have examined its relationship to eating behaviors. METHODS: In an attempt to advance our knowledge of the gut-microbiome-brain axis in the obese phenotype, we thoroughly characterized the gut microbiome signatures of obesity in a well-phenotyped Italian female cohort from the NeuroFAST and MyNewGut EU FP7 projects. Fecal samples were collected from 63 overweight/obese and 37 normal-weight women and analyzed via a multi-omics approach combining 16S rRNA amplicon sequencing, metagenomics, metatranscriptomics, and lipidomics. Associations with anthropometric, clinical, biochemical, and nutritional data were then sought, with particular attention to cognitive and behavioral domains of eating. RESULTS: We identified four compositional clusters of the gut microbiome in our cohort that, although not distinctly associated with weight status, correlated differently with eating habits and behaviors. These clusters also differed in functional features, i.e., transcriptional activity and fecal metabolites. In particular, obese women with uncontrolled eating behavior were mostly characterized by low-diversity microbial steady states, with few and poorly interconnected species (e.g., Ruminococcus torques and Bifidobacterium spp.), which exhibited low transcriptional activity, especially of genes involved in secondary bile acid biosynthesis and neuroendocrine signaling (i.e., production of neurotransmitters, indoles and ligands for cannabinoid receptors). Consistently, high amounts of primary bile acids as well as sterols were found in their feces. CONCLUSIONS: By finding peculiar gut microbiome profiles associated with eating patterns, we laid the foundation for elucidating gut-brain axis communication in the obese phenotype. Subject to confirmation of the hypotheses herein generated, our work could help guide the design of microbiome-based precision interventions, aimed at rewiring microbial networks to support a healthy diet-microbiome-gut-brain axis, thus counteracting obesity and related complications.
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Microbioma Gastrointestinal , Humanos , Femenino , Microbioma Gastrointestinal/genética , ARN Ribosómico 16S/genética , Multiómica , Obesidad/genética , Dieta , Conducta Alimentaria/fisiología , Heces/microbiologíaRESUMEN
BACKGROUND: Data about classification of hypogonadism and estrogen deficiency in male people living with HIV (PLWH) are scanty. AIM: To investigate the prevalence and characterization of biochemical hypogonadism and relative estrogen deficiency in male PLWH aged < 50 comparing liquid chromatography-tandem mass spectrometry (LC-MS/MS) with chemiluminescent immunoassay (CI), and combining gonadotropin, sex hormone-binding globulin (SHBG) and serum estradiol (E2) measurements. METHODS: Prospective, cross-sectional, observational study. Serum total testosterone (TT), E2, gonadotropins, SHBG were measured by CI. TT and E2 were also assessed by LC-MS/MS. Free testosterone (cFT) was calculated by Vermeulen equation. RESULTS: A total of 316 PLWH (45.3 ± 5.3 years) were enrolled. TT and cFT by LC-MS/MS were lower compared to CI (p < 0.0001). The prevalence of biochemical hypogonadism was higher with LC-MS/MS than CI, both for TT (5.1% vs 3.2%, p < 0.0001) or cFT (9.5% vs 7%, p < 0.0001). The prevalence of hypogonadism (overt + compensated) was 17.1% for cFT using LC-MS/MS. Secondary form of hypogonadism was more prevalent than primary. The prevalence of relative estrogen deficiency was of 30.0% among hypogonadal patients and 15.5% among eugonadal. CONCLUSIONS: The prevalence of male hypogonadism results underestimated by CI compared to LC-MS/MS in PLWH, both for TT and cFT. SHBG and gonadotropins are essential for detecting T deficiency.
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Infecciones por VIH , Hipogonadismo , Globulina de Unión a Hormona Sexual/análisis , Cromatografía Liquida , Estudios Transversales , Infecciones por VIH/complicaciones , Humanos , Hipogonadismo/complicaciones , Inmunoensayo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Espectrometría de Masas en Tándem , TestosteronaRESUMEN
OBJECTIVES: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is recommended for measuring circulating steroids. However, assays display technical heterogeneity. So far, reproducibility of corticosteroid LC-MS/MS measurements has received scant attention. The aim of the study was to compare LC-MS/MS measurements of cortisol, 17OH-progesterone and aldosterone from nine European centers and assess performance according to external quality assessment (EQA) materials and calibration. METHODS: Seventy-eight patient samples, EQA materials and two commercial calibration sets were measured twice by laboratory-specific procedures. Results were obtained by in-house (CAL1) and external calibrations (CAL2 and CAL3). We evaluated intra and inter-laboratory imprecision, correlation and agreement in patient samples, and trueness, bias and commutability in EQA materials. RESULTS: Using CAL1, intra-laboratory CVs ranged between 2.8-7.4%, 4.4-18.0% and 5.2-22.2%, for cortisol, 17OH-progesterone and aldosterone, respectively. Trueness and bias in EQA materials were mostly acceptable, however, inappropriate commutability and target value assignment were highlighted in some cases. CAL2 showed suboptimal accuracy. Median inter-laboratory CVs for cortisol, 17OH-progesterone and aldosterone were 4.9, 11.8 and 13.8% with CAL1 and 3.6, 10.3 and 8.6% with CAL3 (all p<0.001), respectively. Using CAL1, median bias vs. all laboratory-medians ranged from -6.6 to 6.9%, -17.2 to 7.8% and -12.0 to 16.8% for cortisol, 17OH-progesterone and aldosterone, respectively. Regression lines significantly deviated from the best fit for most laboratories. Using CAL3 improved cortisol and 17OH-progesterone between-method bias and correlation. CONCLUSIONS: Intra-laboratory imprecision and performance with EQA materials were variable. Inter-laboratory performance was mostly within specifications. Although residual variability persists, adopting common traceable calibrators and RMP-determined EQA materials is beneficial for standardization of LC-MS/MS steroid measurements.
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Hidrocortisona , Progesterona , Aldosterona , Calibración , Cromatografía Liquida/métodos , Humanos , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
OBJECTIVE: Patients with primary aldosteronism (PA) can present with high PTH levels and negative calcium balance, with some studies speculating that aldosterone could directly stimulate PTH secretion. Either adrenalectomy or mineralocorticoid receptor blockers could reduce PTH levels in patients with PA. The aim of this study was to assess the relationship between aldosterone levels and parathyroid hormone (PTH)-vitamin D-calcium axis in a cohort of patients with PA, compared with patients with nonsecreting adrenocortical tumors in conditions of vitamin D sufficiency. METHODS: We enrolled a series of 243 patients retrospectively, of whom 66 had PA and 177 had nonsecreting adrenal tumors, and selected those with full mineral metabolism evaluation and 25(OH) vitamin D levels >20 ng/mL at the time of initial endocrine screening. The final cohort was composed of 26 patients with PA and 39 patients, used as controls, with nonsecreting adrenal tumors. The relationships between aldosterone, PTH levels, and biochemistries of mineral metabolism were assessed. RESULTS: Aldosterone was positively associated with PTH levels (r = 0.260, P < .05) in the whole cohort and in the PA cohort alone (r = 0.450; P = .02). In the multivariate analysis, both aldosterone concentrations and urinary calcium excretion were significantly related to PTH levels, with no effect of 25(OH) vitamin D or other parameters of bone metabolism. CONCLUSION: PTH level is associated with aldosterone, probably independent of 25(OH) vitamin D levels and urinary calcium. Whether aldosterone interacts directly with the parathyroid glands remains to be established.
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Neoplasias de la Corteza Suprarrenal , Aldosterona/sangre , Hiperaldosteronismo , Hormona Paratiroidea/sangre , Calcio , Humanos , Estudios Retrospectivos , Vitamina DRESUMEN
PURPOSE: The best approach for minimally invasive adrenalectomy is still under debate. METHODS: A systematic search of randomized clinical trials was carried out. A frequentist random-effects network meta-analysis was made reporting the surface under the cumulative ranking (SUCRA). The primary endpoint regarded both in-hospital mortality and morbidity. The secondary endpoints were operative time (OP), blood loss (BL), length of stay (LOS), conversion, incisional hernia, and disease recurrence rate. RESULTS: Eight studies were included, involving 359 patients clustered as follows: 175 (48.7%) in the TPLA arm; 55 (15.3%) in the RPLA arm; 10 (2.8%) in the Ro-TPLA arm; 25 (7%) in the TPAA arm; 20 (5.6%) in the SILS-LA arm; and 74 (20.6%) in the RPA arm. The RPLA had the highest probability of being the safest approach (SUCRA 69.6%), followed by RPA (SUCRA 63.0%). TPAA, Ro-TPLA, SILS-LA, and TPLA have similar probability of being safe (SUCRA values 45.2%, 43.4%, 43.0%, and 38.5%, respectively). Analysis of the secondary endpoints confirmed the superiority of RPA regarding OP, BL, LOS, and incisional hernia rate. CONCLUSIONS: The best choice for patients with adrenal masses candidate for minimally invasive surgery seems to be RPA. An alternative could be RPLA. The remaining approaches could have some specific advantages but do not represent the first minimally invasive choice.
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Enfermedades de las Glándulas Suprarrenales , Laparoscopía , Humanos , Adrenalectomía , Ensayos Clínicos Fase II como Asunto , Tiempo de Internación , Metaanálisis en Red , Tempo Operativo , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Clomiphene citrate (CC) in male hypogonadism increases testosterone (T) and estrogen levels by stimulating pituitary gonadotropin release. Our group confirmed these hormonal changes in a randomized, cross-over, double-blind trial of CC versus placebo in addition to metformin, conducted in 21 obese dysmetabolic men with low T levels. However, we hypothesize that based on its mechanism of action, CC may directly or indirectly affect adrenal steroidogenesis. The aim of this sub-study was to better understand the changes in steroid levels and metabolism induced by CC treatment. We assessed 17α-hydroxypregnelone (17αOH-P5), dehydroepiandrosterone (DHEA), progesterone (P4), 17α-hydroxyprogesterone (17αOH-P4), androstenedione (A), T, dihydrotestosterone (DHT), estrone (E1), 17ß-estradiol (E2), 11-deoxycortisol (11 S), cortisol (F), and cortisone (E) by LC-MS/MS, and corticosteroid binding globulin (CBG) by ELISA, before and after each treatment. In addition, free-F and steroid product/precursor ratios were calculated. We observed a significant change in serum levels induced by CC compared with placebo for 17αOH-P4, DHT, T, E2, E1, F, E, and CBG, but not free-F. In addition, compared to placebo, CC induced higher 17αOH-P4/P4, E2/E1, 17αOH-P4/17αOH-P5, A/17αOH-P4, T/A, E1/A, F/11 S, and F/E ratios. Therefore, besides the CC stimulating effect on testis steroidogenesis, our study showed increased F, E, but not free-F, levels, indicating changes in steroid metabolism rather than adrenal secretion stimulation. The steroid profiling also revealed the CC stimulation of the Δ5 rather than the Δ4 pathway, thus indicating considerable testicular involvement in the increased androgen secretion.
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Clomifeno/farmacología , Esteroides/sangre , Testosterona/sangre , Adulto , Cromatografía Liquida , Estudios Cruzados , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Obesidad/metabolismo , Esteroides/metabolismo , Espectrometría de Masas en Tándem , Transcortina/análisisRESUMEN
BACKGROUND: Laparoscopic adrenalectomy has a well-demonstrated learning curve in the first generation of laparoscopic surgeons. Data about the second generation of laparoscopic surgeons are lacking. METHODS: In this retrospective observational study, data from patients undergoing laparoscopic adrenalectomy from 2000 to 2019 in a high-volume center were collected and analyzed. The cumulative sum of procedures of each surgeon and the operating time were evaluated. A multivariate analysis with backward stepwise logistic regression was carried out to define which factors influenced the operative time. Three surgeons performed the analyzed procedures: a senior surgeon who began his laparoscopic activity without receiving specific training or supervision and two young surgeons, who performed their procedures under the guidance of the "senior" experienced surgeon. The first 38 procedures of the three surgeons were then compared. RESULTS: A total of 244 laparoscopic adrenalectomies were performed. Age, clinical diagnosis, side of the lesion, body mass index, comorbidities, Charlson index, American Society of Anaesthesiologists (ASA) score, and lower abdominal surgery were found to have no significant relationship with the operative time (p > 0.05). Gender, symptoms, previous upper abdominal surgery, size of the lesion, and cumulative sum of procedures were independent predictors of operative time. In the comparison between different surgeons, operative time resulted significantly longer for the senior (165 min; 140-180) than for the two junior surgeons (137.5 min; 115-160; p = 0.003 and 130 min; 120-170; p = 0.001). CONCLUSIONS: The presence of a mentor in operative theater and specific training programs could be useful during the learning period. The cumulative sum of procedures related to the operative time represents a good parameter to measure the acquired expertise of a surgeon.
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Laparoscopía , Cirujanos , Adrenalectomía , Humanos , Curva de Aprendizaje , Tempo OperativoRESUMEN
PURPOSE: Preoperative imaging in patients with primary hyperparathyroidism provides important localization information, allowing the surgeon to perform a focused surgery. However there are no evidence-based guidelines suggesting which preoperative imaging should be used, resulting in a risk of excessive prescription of exams and waste of economic resources. The main purpose of this study was to describe our experience on the performance of various imaging techniques for the preoperative localization of abnormal parathyroid gland/s, with a focus on the sensitivity and specificity of each technique. Secondly, we carried out an analysis of the cost utility of each technique in order to determine the most clinical and cost-effective combination of localization studies. MATERIALS AND METHODS: Records of 336 patients who underwent parathyroidectomy were retrospectively examined comparing imaging and intraoperative/histopathologic findings to evaluate the accuracy in parathyroid detection of each imaging technique. Costs were determined by regional health system reimbursement. RESULTS: We found that the sensitivity of color Doppler US was significantly higher than SPECT (p 0,023), while the sensitivity of 4D-CT was significantly better than US (p 0,029) and SPECT (p 0,0002). CONCLUSIONS: In experienced hands color Doppler US is a highly sensitive technique especially in patients with no thyroid diseases. In patients with concomitant thyroid pathology, the combination of US and 4D-CT represents a reliable localization technique.
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Diagnóstico por Imagen/métodos , Hipertiroidismo/diagnóstico por imagen , Hipertiroidismo/cirugía , Glándulas Paratiroides/diagnóstico por imagen , Glándulas Paratiroides/cirugía , Paratiroidectomía/métodos , Cuidados Preoperatorios , Centros de Atención Terciaria , Análisis Costo-Beneficio , Diagnóstico por Imagen/economía , Femenino , Humanos , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Sensibilidad y Especificidad , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X , Ultrasonografía Doppler en ColorRESUMEN
The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a 'phosphate perspective'.
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Neoplasia Endocrina Múltiple/patología , Osteomalacia/patología , Enfermedades de las Paratiroides/patología , Glándulas Paratiroides/metabolismo , Fosfatos/sangre , Huesos/metabolismo , Calcio/sangre , Humanos , Hiperparatiroidismo Primario/patología , Hipoparatiroidismo/patología , Hipofosfatemia/patología , Fosfatos/metabolismoRESUMEN
BACKGROUND: Clomiphene citrate (CC) has been shown to restore the hypothalamic-pituitary-gonadal (HPG) axis by increasing testosterone (T) levels to physiological levels in patients with dysmetabolic conditions such as obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). However, the data are unclear regarding the effects on Sertoli cell (SC) function. AIM: To study SC function by assessing Inhibin B (IB) and anti-Mullerian hormone (AMH) levels at baseline and after 3 months of CC treatment. MATERIALS AND METHODS: This is an ancillary study of a cross-over, randomised, double-blind, placebo-controlled trial performed to evaluate androgen response to CC treatment in dysmetabolic obese subjects with low T levels treated with metformin. We evaluated SC function by assessing IB and AMH levels at baseline and after 3 months of each treatment in ten dysmetabolic obese subjects with low T levels. In all subjects, the influence of the clinical characteristics, metabolic and hormonal baseline parameters on SC and Leydig (LC) function, evaluated respectively with AMH, IB, follicle-stimulating hormone (FSH) and T levels, was tested. RESULTS: No significant changes were observed for IB and AMH concentrations after each treatment period. Whereas T and oestradiol (E2) levels were shown to be significantly higher in the CC plus metformin phase (CC/Met) only. No clinical, metabolic or hormonal parameters showed significant effects on serum AMH at baseline or after treatments. However, baseline T, dihydrotestosterone (DHT) and E2 positively affected IB levels during CC/Met therapy (P = .003, P = .038 and P = .049, respectively). Baseline leptin and FSH had a negative (P = 031) and positive (P = .048) respectively role on T levels during CC/Met, as they were statistically significant compared to the placebo period (Plac/Met). CONCLUSION: Unlike the LC activity, CC was unable to influence SC function, as shown by the lack of IB and AMH serum modifications, thus suggesting an intrinsic nonreversible defect of SC cells in patients with dysmetabolic conditions.
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Hormona Antimülleriana/sangre , Clomifeno/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Antagonistas de Estrógenos/farmacología , Hipoglucemiantes/farmacología , Hipogonadismo/tratamiento farmacológico , Inhibinas/efectos de los fármacos , Síndrome Metabólico/tratamiento farmacológico , Metformina/farmacología , Obesidad/tratamiento farmacológico , Células de Sertoli/efectos de los fármacos , Testosterona/sangre , Adulto , Clomifeno/administración & dosificación , Estudios Cruzados , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Dihidrotestosterona/sangre , Método Doble Ciego , Quimioterapia Combinada , Estradiol/sangre , Antagonistas de Estrógenos/administración & dosificación , Estudios de Seguimiento , Humanos , Hipogonadismo/sangre , Hipogonadismo/etiología , Inhibinas/sangre , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/complicaciones , Persona de Mediana Edad , Obesidad/sangre , Obesidad/complicacionesRESUMEN
STUDY QUESTION: What are the consequences of ageing on human Leydig cell number and hormonal function? SUMMARY ANSWER: Leydig cell number significantly decreases in parallel with INSL3 expression and Sertoli cell number in aged men, yet the in vitro Leydig cell androgenic potential does not appear to be compromised by advancing age. WHAT IS KNOWN ALREADY: There is extensive evidence that ageing is accompanied by decline in serum testosterone levels, a general involution of testis morphology and reduced spermatogenic function. A few studies have previously addressed single features of the human aged testis phenotype one at a time, but mostly in tissue from patients with prostate cancer. STUDY DESIGN, SIZE, DURATION: This comprehensive study examined testis morphology, Leydig cell and Sertoli cell number, steroidogenic enzyme expression, INSL3 expression and androgen secretion by testicular fragments in vitro. The majority of these endpoints were concomitantly evaluated in the same individuals that all displayed complete spermatogenesis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testis biopsies were obtained from 15 heart beating organ donors (age range: 19-85 years) and 24 patients (age range: 19-45 years) with complete spermatogenesis. Leydig cells and Sertoli cells were counted following identification by immunohistochemical staining of specific cell markers. Gene expression analysis of INSL3 and steroidogenic enzymes was carried out by qRT-PCR. Secretion of 17-OH-progesterone, dehydroepiandrosterone, androstenedione and testosterone by in vitro cultured testis fragments was measured by LC-MS/MS. All endpoints were analysed in relation to age. MAIN RESULTS AND THE ROLE OF CHANCE: Increasing age was negatively associated with Leydig cell number (R = -0.49; P < 0.01) and concomitantly with the Sertoli cell population size (R= -0.55; P < 0.001). A positive correlation (R = 0.57; P < 0.001) between Sertoli cell and Leydig cell numbers was detected at all ages, indicating that somatic cell attrition is a relevant cellular manifestation of human testis status during ageing. INSL3 mRNA expression (R= -0.52; P < 0.05) changed in parallel with Leydig cell number and age. Importantly, steroidogenic capacity of Leydig cells in cultured testis tissue fragments from young and old donors did not differ. Consistently, age did not influence the mRNA expression of steroidogenic enzymes. The described changes in Leydig cell phenotype with ageing are strengthened by the fact that the different age-related effects were mostly evaluated in tissue from the same men. LIMITATIONS, REASONS FOR CAUTION: In vitro androgen production analysis could not be correlated with in vivo hormone values of the organ donors. In addition, the number of samples was relatively small and there was scarce information about the concomitant presence of potential confounding variables. WIDER IMPLICATIONS OF THE FINDINGS: This study provides a novel insight into the effects of ageing on human Leydig cell status. The correlation between Leydig cell number and Sertoli cell number at any age implies a connection between these two cell types, which may be of particular relevance in understanding male reproductive disorders in the elderly. However aged Leydig cells do not lose their in vitro ability to produce androgens. Our data have implications in the understanding of the physiological role and regulation of intratesticular sex steroid levels during the complex process of ageing in humans. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from Prin 2010 and 2017. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.
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Células Intersticiales del Testículo , Espectrometría de Masas en Tándem , Adulto , Anciano , Anciano de 80 o más Años , Cromatografía Liquida , Humanos , Insulina , Masculino , Persona de Mediana Edad , Proteínas , Células de Sertoli , Espermatogénesis , Testículo , Adulto JovenRESUMEN
BACKGROUND: Narcolepsy is a rare chronic sleep disorder that typically begins in youth. Excessive daytime sleepiness is the main disabling symptom, but the disease is often associated with severe endocrine-metabolic and psychosocial issues, worsened by a long diagnostic delay, requiring a multidisciplinary approach. The scarcity of reference Sleep Centres forces the patient and family to travel for seeking medical consultations, increasing the economic and psychosocial burden of the disease. Growing evidence suggests that Telemedicine may facilitate patient access to sleep consultations and its non-inferiority in terms of patient satisfaction, adherence to treatment, and symptom improvement for sleep disorders. However, Telemedicine clinical and economic benefits for patients with narcolepsy are still unknown. METHODS: TENAR is a two-part project, including: 1. a cross-sectional study (involving 250 children and adults with suspected narcolepsy) evaluating the accuracy of Teletriage (i.e., a synchronous live interactive sleep assessment through a Televisit) for narcolepsy diagnosis compared to the reference standard; and 2. a two-arm, parallel, open randomized controlled trial (RCT) to demonstrate the non-inferiority of the multidisciplinary care of narcolepsy through Televisits versus standard care. In this RCT, 202 adolescents (> 14 y.o.) and adults with narcolepsy will be randomly allocated (1:1 ratio) either to Televisits via videoconference or to standard in-person outpatient follow-up visits (control arm). The primary outcome is sleepiness control (according to the Epworth Sleepiness Scale). Secondary outcomes are other symptoms control, compliance with treatment, metabolic control, quality of life, feasibility, patient and family satisfaction with care, safety, and disease-related costs. At baseline and at 12 months, patients will undergo neurologic, metabolic, and psychosocial assessments and we will measure primary and secondary outcomes. Primary outcomes will be also measured at 6 months (remotely or in person, according to the arm). DISCUSSION: TENAR project will assess, for the first time, the feasibility, accuracy, efficacy and safety of Telemedicine procedures applied to the diagnosis and the multidisciplinary care of children and adults with narcolepsy. The study may be a model for the remote management of other rare disorders, offering care access for patients living in areas lacking medical centres with specific expertise. TRIAL REGISTRATION: Number of the Tele-multidisciplinary care study NCT04316286. Registered 20 March 2020.
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Narcolepsia/diagnóstico , Telemedicina , Adulto , Niño , Estudios Transversales , Diagnóstico Tardío , Estudios de Equivalencia como Asunto , Humanos , Narcolepsia/terapia , Pacientes Ambulatorios , Calidad de VidaRESUMEN
Growing evidence highlights the endocannabinoid (EC) system involvement in cancer progression. Lipid mediators of this system are secreted by hematopoietic cells, including the ECs 2-arachidonoyl-glycerol (2AG) and arachidonoyl-ethanolamide (AEA), the 2AG metabolite 1AG, and members of N-acylethanolamine (NAE) family-palmitoyl-ethanolamide (PEA) and oleoyl-ethanolamide (OEA). However, the relevance of the EC system in myeloproliferative neoplasms (MPN) was never investigated. We explored the EC plasma profile in 55 MPN patients, including myelofibrosis (MF; n = 41), polycythemia vera (PV; n = 9), and essential thrombocythemia (ET; n = 5) subclasses and in 10 healthy controls (HC). AEA, PEA, OEA, 2AG, and 1AG plasma levels were measured by LC-MS/MS. Overall considered, MPN patients displayed similar EC and NAE levels compared to HC. Nonetheless, AEA levels in MPN were directly associated with the platelet count. MF patients showed higher levels of the sum of 2AG and 1AG compared to ET and PV patients, higher OEA/AEA ratios compared to HC and ET patients, and higher OEA/PEA ratios compared to HC. Furthermore, the sum of 2AG and 1AG positively correlated with JAK2V617F variant allele frequency and splenomegaly in MF and was elevated in high-risk PV patients compared to in low-risk PV patients. In conclusion, our work revealed specific alterations of ECs and NAE plasma profile in MPN subclasses and potentially relevant associations with disease severity.
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Endocannabinoides/sangre , Etanolaminas/sangre , Trastornos Mieloproliferativos/sangre , Policitemia Vera/sangre , Mielofibrosis Primaria/sangre , Trombocitemia Esencial/sangre , Adulto , Anciano , Anciano de 80 o más Años , Amidas/sangre , Ácidos Araquidónicos/sangre , Cromatografía Liquida/métodos , Femenino , Glicéridos/sangre , Humanos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Mutación Missense , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Ácidos Oléicos/sangre , Ácidos Palmíticos/sangre , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Alcamidas Poliinsaturadas/sangre , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/genética , Espectrometría de Masas en Tándem/métodos , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/genéticaRESUMEN
Putative genetic markers have been associated with ETEC F4 (Mucine 4 [MUC4]; MUC4GG;CG as susceptible; MUC4CC as resistant) and F18 (Fucosyltransferase 1 [FUT1]; FUT1GG;AG as susceptible; FUT1AA as resistant) resistances respectively. In this study, 71 post-weaning pigs were followed from d0 (35 days old) to d42 (77 days of age) to investigate the effect of MUC4 or FUT1 genotypes on the mid-jejunal microbiota composition, pigs expression of genes related to inflammation (IL8, GPX2, REG3G, TFF3, CCL20 and LBPI) and glycomic binding pattern profile (Ulex europaeus agglutinin I [UEA] fucose-binding lectin and peanut agglutinin [PNA] galactose-specific), and on blood plasma targeted metabolomics profile, faecal score and performance parameters of growing healthy pigs. The MUC4 and FUT1 resistant genotypes improved the pigs' growth performance and had firmed faecal score susceptible genotypes in d0-d21 period. Pigs with MUC4GG genotype had a higher jejunal expression of genes relate to immune function (CCL20 and REG3G) than MUC4CG and MUC4CC pigs (p < 0.05). MUC4CG pigs had higher expression of TFF3 (implicated in mucosal integrity) than MUC4GG and MUC4CC (p < 0.05). FUT1 influenced the alpha- and beta-jejunal microbial indices. The FUT1AA group had a higher number of operational taxonomic units (OTUs) belonging to Lactobacillus genus, while FUT1GG group had a higher number of OTUs belonging to Veillonella genus. MUC4CC pigs had lower scores for UEA on brush borders and goblet cells in villi than MUC4GG (p < 0.05). FUT1AA pigs had lower UEA positivity and higher PNA positivity on brush borders and goblet cells than FUT1AG and FUT1GG (p < 0.05). Both FUT1 and MUC4 influenced the metabolic profile of healthy pigs. Results highlight the role of MUC4 and FUT1 on pig intestinal homoeostasis and improved the knowledge regarding the potential interaction between host genetics, gut microbiota composition and host metabolism in a healthy status.
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Fucosiltransferasas/metabolismo , Microbioma Gastrointestinal/fisiología , Variación Genética , Homeostasis/genética , Mucina 4/metabolismo , Porcinos/genética , Animales , Bacterias/clasificación , Femenino , Fucosiltransferasas/genética , Regulación de la Expresión Génica , Genotipo , Homeostasis/fisiología , Masculino , Mucina 4/genética , Porcinos/microbiología , Porcinos/fisiología , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
Familial aggregation is a significant risk factor for the development of thyroid cancer and familial non-medullary thyroid cancer (FNMTC) accounts for 5-7% of all NMTC. Whole exome sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a novel heterozygous mutation (c.400G > A, NM_012335; p.Gly134Ser) in exon 5 of MYO1F, mapping to the linkage locus. In the thyroid FRTL-5 cell model stably expressing the mutant MYO1F p.Gly134Ser protein, we observed an altered mitochondrial network, with increased mitochondrial mass and a significant increase in both intracellular and extracellular reactive oxygen species, compared to cells expressing the wild-type (wt) protein or carrying the empty vector. The mutation conferred a significant advantage in colony formation, invasion and anchorage-independent growth. These data were corroborated by in vivo studies in zebrafish, since we demonstrated that the mutant MYO1F p.Gly134Ser, when overexpressed, can induce proliferation in whole vertebrate embryos, compared to the wt one. MYO1F screening in additional 192 FNMTC families identified another variant in exon 7, which leads to exon skipping, and is predicted to alter the ATP-binding domain in MYO1F. Our study identified for the first time a role for MYO1F in NMTC.
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Proliferación Celular , Embrión no Mamífero/patología , Mitocondrias/patología , Mutación , Miosina Tipo I/genética , Cáncer Papilar Tiroideo/patología , Neoplasias de la Tiroides/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Células Cultivadas , Niño , Cromosomas Humanos Par 19 , Embrión no Mamífero/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Mitocondrias/metabolismo , Miosina Tipo I/química , Miosina Tipo I/metabolismo , Consumo de Oxígeno , Linaje , Conformación Proteica , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Adulto Joven , Pez CebraRESUMEN
Similarities in neural activation patterns in obese and substance-dependent subjects led to the food addiction concept, but studies exploiting this issue for obesity stratification are missing. We assessed brain activation in response to food cues using 18 F-2-fluoro-2-deoxy-glucose-PET in 36 overweight women, stratified by low or high food addiction groups according to the Yale Food Addiction Scale (YFAS). Assessments were repeated after a 3-month diet. We found greater activation in thalamus, hypothalamus, midbrain, putamen, and occipital cortex (reward), but not in prefrontal and orbitofrontal cortices (control/reward receipt) in the high-YFAS versus low-YFAS group. In high-YFAS subjects, orbitofrontal responsiveness was inversely related to YFAS severity and hunger rating, and positive associations were observed between regional brain activation and lipid intake. A 3-month diet abolished group differences in brain activation. Our data suggest that food addiction distinguishes an overweight phenotype that can be reversed by diet, opening to personalized strategies in obesity treatment.