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Bone fragility is recognized as a complication of type 2 diabetes (T2D). However, the fracture risk in T2D is underestimated using the classical assessment tools. An expert panel suggested the diagnostic approaches for the detection of T2D patients worthy of bone-active treatment. The aim of the study was to apply these algorithms to a cohort of T2D women to validate them in clinical practice.The presence of T2D-specific fracture risk factors (T2D ≥ 10 years, ≥1 T2D complications, insulin or thiazolidinedione use, poor glycaemic control) was assessed at baseline in 107 postmenopausal T2D women. In all patients at baseline and in 34 patients after a median follow-up of 60.2 months we retrospectively evaluated bone mineral density and clinical and morphometric vertebral fractures. No patient was treated with bone-active drug. Following the protocols, 34 (31.8%) and 73 (68.2%) patients would have been pharmacologically and conservatively treated, respectively. Among 49 patients without both clinical fractures and major T2D-related risk factors, who would have been, therefore, conservatively followed-up without vertebral fracture assessment, only one showed a prevalent vertebral fracture (sensitivity 90%, negative predictive value 98%). The two patients who experienced an incident fracture would have been pharmacologically treated at baseline.The clinical consensus recommendations showed a very good sensitivity in identifying T2D postmenopausal women at high fracture risk. Among those with treatment indication as many as 13% of patients experienced an incident fracture, and, conversely, among those without treatment indication no incident fractures were observed.

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome due to overproduction of fibroblast growth factor 23 (FGF23), with profound effects on patient morbidity. TIO is an underdiagnosed disease, whose awareness should be increased among physicians for timely and proper management of patients. Symptoms reported by patients with TIO are usually nonspecific, thus rendering the diagnosis elusive, with an initial misdiagnosis rate of more than 95%. Biochemical features of TIO are represented by hypophosphatemia, increased or inappropriately normal levels of FGF23, and low to low normal circulating 1,25-dihydroxyvitamin D (1,25(OH)2D). Phosphaturic mesenchymal tumors are the pathological entities underlying TIO in most affected patients. There is now evidence that FN1-FGFR1 and FN1-FGF1 fusion genes are present in about half of tumors causing this paraneoplastic syndrome. Tumors causing TIO are small and grow slowly. They can occur in all parts of the body from head to toe with similar prevalence in soft tissue and bone. There are a number of functional and anatomical imaging techniques used for tumor localization; 68Ga DOTA-based technologies have better sensitivity. Surgery is the treatment of choice; several medical treatments are now available in case of inability to locate the tumor or in case of incomplete excision.

Background Similarly to cortisol-secreting adrenal tumors, also non-functioning adrenal tumors (NFAT) may be associated with an increased cardiovascular risk. We assessed in NFAT patients: (i) the association between hypertension (HT), diabetes mellitus (DM), obesity (OB), dyslipidemia (DL) and cardiovascular events (CVE) and cortisol secretion; (ii) the cut-off of the cortisol secretion parameters for identifying NFAT patients with a worse cardiometabolic profile. Patients and methods In 615 NFAT patients (with cortisol levels after 1 mg overnight dexamethasone suppression test, F-1mgDST Results HT, DM and HT plus DM were associated with F-1mgDST levels (area under the ROC curve: 0.588 ± 0.023, 0.610 ± 0.028, 0.611 ± 0.033, respectively, p plus DM was set at ≥ 1.2 µg/dL (33 nmol/L). As compared with patients with F-1mgDST plus DM (8.3% vs 16.9%, respectively, p plus DM (OR 1.96, 95% CI 1.12–3.41, p = 0.018) after adjusting for age, gender, OB and DL. Conclusions In NFAT patients, F-1mgDST 1.2–1.79 µg/dL seems to be associated with a higher prevalence of HT and DM and a worse cardiometabolic profile, even if the poor accuracy of these associations suggests caution in interpreting these results.

Objective Among patients with type 2 diabetes (T2D), the prevalence of hidden hypercortisolism (HidHyCo, formally called subclinical hypercortisolism or mild autonomous cortisol secretion) was estimated to be 2.2-12.1%. The aim of this study was to investigate whether the available literature helps to identify the characteristics of T2D patients more frequently associated with HidHyCo. Methods A meta-analysis was performed using studies that assessed both the prevalence of HidHyCo in patients with T2D and the characteristics of these patients with and without HidHyCo. The DerSimonian and Laird (DSL) and the Hartung, Knapp, Sidik and Jonkman (HKSJ) methods were utilized. Results Among the 18 available studies, 6 studies provided the necessary data. The association between HidHyCo and advanced T2D (based on the patients’ description given in each study in presence of micro/ microvascular complications, or insulin treatment plus hypertension, or hypertension treated with ≥2 drugs), hypertension, insulin treatment and dyslipidemia was reported in 5 (2184 patients), 6 (2283 patients), 3 (1440 patients), and 3 (987 patients) studies, respectively. HidHyCo was associated with advanced T2D as assessed with both DSL (odds ratio, OR, 3.47, 95% Confidence Interval, 95%CI, 2.12-5.67) and HKSJ method (OR 3.60, 95%CI 2.03-6.41) and with the prevalence of hypertension or of insulin treatment as assessed by the DSL approach (OR 1.92, 95%CI 1.05-3.50 and OR 2.29, 95%CI 1.07-4.91, respectively), but not as assessed with HKSJ method. Conclusions Patients with advanced T2D have a higher prevalence of HidHyCo. These data inform about the selection of T2D patients for HidHyCo screening.

Background The reproductive cycle of the recently described sponge Tethya meloni was investigated for a period of 15 months (September 2018 – November 2019) in the Mar Piccolo of Taranto (Southern Italy) and was compared with data previously collected for the other two sympatric species of the same genus known for Mediterranean Sea, T. citrina and T. aurantium. Results T. meloni is a gonochoric species with a sex ratio strongly shifted towards females. Asexual budding was a seasonal process, limited to few specimens. In a specimen collected in September 2018 both oocytes and buds occurred, suggesting that in T. meloni the sexual and asexual phases may coexist both at the population and individual levels. Conclusions The data obtained from this research compared with the available literature confirm the high temporal variability of the reproductive cycles in the Mediterranean species of Tethya, but with common general characteristics. In sexual reproduction, the oocyte production period lasts several months, with a peak between summer and autumn while spermatogenesis, shorter but with greater reproductive effort, follows the onset of oogenesis. The asexual reproduction phase of T. meloni, on the other hand, occurs in a short period and seems to have less importance in the overall reproductive process.

Inadequate serum selenium levels may delay the growth and physiological changes in bone metabolism. In humans, reduced serum selenium concentrations are associated with both increased bone turnover and reduced bone mineral density. Moreover, a reduced nutritional intake of selenium may lead to an increased risk of bone disease. Therefore, selenium is an essential nutrient playing a role in bone health, probably due to specific selenium-proteins. Some selenium-proteins have an antioxidation enzymatic activity and participate in maintaining the redox cellular balance, regulating inflammation and proliferation/differentiation of bone cells too. At least nine selenium-proteins are known to be expressed by fetal osteoblasts and appear to protect bone cells from oxidative stress at bone microenvironment. Mutations of selenium-proteins and reduced circulating levels of selenium are known to be associated with skeletal diseases such as the Kashin-Beck osteoarthropathy and postmenopausal osteoporosis. In addition, the intake of selenium appears to be inversely related to the risk of hip fragility fractures. Recent data suggest that an altered selenium state may affect bone mass even in males and selenium-proteins and selenium concentrations were positively associated with the bone mass at femoral, total and trochanteric sites. However, selenium, but not selenium-proteins, seems to be associated with femoral neck bone mass after adjustment for many bone fracture risk factors. The present review summarizes the findings of observational and interventional studies, which have been designed for investigating the relationship between selenium and bone metabolism.

To evaluate the prevalence of less severe hypercortisolism (LSH) in fractured patients, and its association with hypertension, hyperglicemia, dyslipidemia, and obesity. From July 2015 to October 2018 we enrolled all fractured patients admitted in our outpatient center for metabolic bone diseases, after exclusion of patients with secondary osteoporosis apart from diabetes and taking drugs known to affect bone metabolism. In all enrolled patients we collected data regarding gonadal status, history of diabetes, high blood pressure, dyslipidemia, and measured blood pressure, lipid profile, fasting glycaemia. Bone mass was measured with DXA at lumbar spine and femoral neck and the presence of fractures was evaluated with X-ray of thoracic and lumbar spine. All patients performed twice, 1 mg overnight dexametasone suppression test (DST) and, as confirmatory, 2day low-dose DST for diagnosing hypercortisolism. We enrolled 101 fractured patients (75 females, 26 males), aged 65 ± 10.3 years. Five out of 101 (5.0%) patients were diagnosed as LSH. Fifty-five (54.5%) out of 101 were hypertensive, 57 (56.4%) dyslipidemic, 17 (16.8%) hyperglicaemic, 28(27.7%) obese patients. LSH tended to be associated to blood hypertension [5/5 vs 50/96 (Fisher exact test, p = 0.06) hypertensive patients]. Four out five LSH patients were hypogonadic. Our study confirms that a nonnegligible percentage of fractured subjects actually presents an unrecognized hypercortisolism. Accordingly, regardless of age, we suggest to screen for hypercortisolism all patients with established osteoporosis and in particular hypertensive subjects.

ObjectiveThe best approach to patients with adrenal incidentaloma (AI) and possible autonomous cortisol secretion (PACS) is debated. The aim of this study was to assess the metabolic effect of adrenalectomy in AI patients with PACS in relation to cortisol secretion parameters, peripheral activation, and glucocorticoid sensitivity.DesignThis is a multicenter randomized study (NCT number: NCT04860180).MethodsSixty-two AI outpatients (40–75 years) with AI >1 cm and cortisol after overnight dexamethasone suppression test (F-1mgDST) between 50 and 138 nmol/L were randomized to adrenalectomy (Arm A) or a conservative approach (Arm B). Fifty-five patients completed the 6-month follow-up, 25 patients in Arm A (17 female patients, aged 62.5 ± 10.4 years) and 30 patients in Arm B (24 female patients, 66.1 ± 9.1 years). Plasma adrenocorticotroph hormone (ACTH), 24-h urinary free cortisol, 24-h urinary free cortisone, F-1mgDST, glucose, lipids, glycated hemoglobin (HbA1c) levels, blood pressure (BP), body weight, and treatment variations were assessed. The 24-h urinary free cortisol/cortisone ratio (an 11-beta hydroxysteroid dehydrogenase type 2 activity marker), BclI, and the N363S variants of glucocorticoid receptor (GR) polymorphisms were also evaluated.ResultsBP control improved in 68% and 13% of the subjects in Arm A and Arm B, respectively (p = 0.001), and the glycometabolic control improved in 28% and 3.3% of the subjects in Arm A and Arm B patients, respectively (p = 0.02). Arm A subjects more rarely showed the BP and/or glycometabolic control worsening than Arm B patients (12% and 40%, respectively, p = 0.03). The surgical approach was independently associated with BP amelioration (OR 3.0, 95% CI 3.8–108.3, p < 0.001) but not with age, F-1mgDST levels, BMI, and hypertension and diabetes mellitus presence at baseline. The 24-h urinary free cortisol/cortisone ratio and the presence of sensitizing GR polymorphisms were not associated with the surgical outcome. The receiver operating characteristic (ROC) curve analysis showed that the BP control amelioration was associated with F-1mgDST [area under the curve (AUC), 0.82 ± 0.09 p = 0.012]. The F-1mgDST cutoff with the best compromise in predicting the BP amelioration was set at 75 nmol/L (sensitivity 77%, specificity 75%).ConclusionsAI patients with PACS benefit from surgery in terms of BP and glycometabolic control.

The European Union (EU) has recently adopted a regulation on invasive alien species that foresees the possibility of developing lists of species of National Concern. We developed a prioritisation process for alien mammals already established in Italy, but not yet included in the EU list (n = 6 species) and a systematic horizon-scanning procedure to obtain ranked lists for those species that are already introduced worldwide or traded in Italy (n = 213). Experts were asked to score these species, by evaluating their likelihood of establishment and spread and the magnitude of their potential impacts on biodiversity, economy, human-health and society. The manageability of each species was also evaluated, both for the proritisation and the horizon-scanning processes. We produced five lists that ranked species according to their potential spread and impacts and their manageability. These will allow policy-makers to select outputs according to a balance between risk assessment and risk management, establishing priorities for alien species management at the national level.

ContextCushing’s syndrome frequently causes mental health impairment. Data in patients with adrenal incidentaloma (AI) are lacking.ObjectiveWe aimed to evaluate psychiatric and neurocognitive functions in AI patients, in relation to the presence of subclinical hypercortisolism (SH), and the effect of adrenalectomy on mental health.DesignWe enrolled 62 AI patients (64.8 ± 8.9 years) referred to our centers. Subclinical hypercortisolism was diagnosed when cortisol after 1mg-dexamethasone suppression test was >50 nmol/L, in the absence of signs of overt hypercortisolism, in 43 patients (SH+).InterventionsThe structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders-5, and 5 psychiatric scales were performed. The Brief Assessment of Cognition in Schizophrenia (Verbal and Working Memory, Token and Symbol Task, Verbal Fluency, Tower of London) was explored in 26 patients (≤65 years).ResultsThe prevalence of psychiatric disorders was 27.4% (SH+ 30.2% vs SH- 21.1%, P = 0.45). SH+ showed a higher prevalence of middle insomnia (by the Hamilton Depression Rating Scale) compared with SH- (51% vs 22%, P = 0.039). Considering the Sheehan Disability Scale, SH+ showed a higher disability score (7 vs 3, P = 0.019), higher perceived stress (4.2 ± 1.9 vs 2.9 ± 1.9, P = 0.015), and lower perceived social support (75 vs 80, P = 0.036) than SH-. High perceived stress was independently associated with SH (odds ratio [OR] = 5.46, confidence interval 95% 1.4–21.8, P = 0.016). Interestingly, SH+ performed better in verbal fluency (49.5 ± 38.9 vs 38.9 ± 9.0, P = 0.012), symbol coding (54.1 ± 6.7 vs 42.3 ± 15.5, P = 0.013), and Tower of London (15.1 vs 10.9, P = 0.009) than SH-. In 8 operated SH+, no significant changes were found.ConclusionsSubclinical hypercortisolism may influence patients’ mental health and cognitive performances, requiring an integrated treatment.

Il calcio, il fosforo e il magnesio sono elementi mantenuti in uno stretto ambito di concentrazioni nei vari comparti intra- ed extracellulari del corpo umano; la preservazione di tale intervallo e necessaria per la normale funzione delle varie strutture. Alla regolazione di questo equilibrio contribuiscono vari organi e, in particolare, l’intestino, che regola con meccanismi attivi e passivi l’assorbimento, l’osso, che in rapporto alle necessita contingenti e capace di depositare o cedere gli elementi e il rene, che regola l’eliminazione degli elementi filtrati attraverso il controllo del loro riassorbimento nei vari segmenti del nefrone. Alla regolazione del sistema contribuiscono la quantita di calcio, fosforo e magnesio assunti con la dieta, altre sostanze quali ormoni e farmaci che influenzano l’assorbimento intestinale, il riassorbimento renale e il rilascio o deposito osseo. Alla luce delle attuali conoscenze, fra gli ormoni regolatori dell’omeostasi calcio-fosforica e magnesica, attivi anche attraverso influenze reciproche in termini di attivazione/secrezione/azione periferica, si annoverano il PTH, la 1-25(OH)2 Vitamina D e il FGF23.

A role for long non-coding RNAs (lncRNAs) in endocrine cancer pathogenesis is emerging. However, knowledge regarding their expression pattern, correlation with known genetic defects, and clinical implications in parathyroid tumors is still unclear. Here, we profiled 90 known lncRNAs in a first series of normal (PaN = 2), adenomatous (PAd = 12), and carcinomatous (PCa = 4) parathyroid glands and we confirmed deregulation of 11 lncRNAs using an independent cohort of patients (PaN = 4; PAd = 26; PCa = 9). Expression of lncRNAs was correlated with cytogenetic aberrations, status of genes multiple endocrine neoplasia 1 (MEN1) and cell division cycle 73 (CDC73), or clinical features. Globally, lncRNAs discriminate according to tissue histology. BC200 consistently identifies parathyroid cancers from adenomas and atypical adenomas. Loss-of-heterozygosity (LOH) at chromosomes 1, 11, 15, 21, and 22 significantly impacts expression of lncRNAs in PAds. Silencing of the key parathyroid gene MEN1 modulates the expression of six lncRNAs in primary PAds-derived cultures. Analogous levels of lncRNAs are measured in PAds with the mutation in the MEN1 gene compared with PAds with wild-type MEN1. Similarly, carcinomas with mutated CDC73 differ from PCas with wild-type protein in terms of expression of lncRNAs. PCas harboring CDC73 mutations overexpress BC200 compared to wild-type carcinomas. Overall, these findings shed light on deregulation of lncRNAs in human parathyroid tumors and propose that circuits between lncRNAs and the oncosuppressors MEN1 or CDC73 may have a role in parathyroid tumorigenesis as epigenetic modulators. © 2020 American Society for Bone and Mineral Research (ASBMR).

High-fat diet (HFD) alters the glycosylation patterns of intestinal mucins leading to several health problems. We studied by histochemical and lectin-binding methods mucin alterations in the duodenum of mice fed a HFD for 25 weeks. Histochemical methods included periodic acid–Schiff, alcian blue pH 2.5, and high-iron diamine. Lectin-binding experiments were performed with SBA, PNA, WGA, MAA-II, SNA, ConA, UEA-I, LTA, and AAA. SBA, PNA, WGA, MAA-II, and SNA were tested also after desulfation and ConA after periodate-sodium borohydrate treatments (paradoxical ConA). Duodenal mucins are secreted by Brunner’s glands and goblet cells in the villi. Brunner’s glands of HFD mice showed increased secreting activity and a general reduction of glycosylated residuals, such as fucose and terminal α1,4-linked GlcNAc. Moreover, a general reduction of glycosylated residuals in the goblet cells of villi such as the fucosylated and sulfated ones was observed. Since the cited residuals are involved in cytoprotective and cytostatic functions, as well as in interactions with the intestinal microbiota and protection against parasites and inflammatory disorders, we conclude that HFD can predispose duodenum to several possible health disorders.

Irisin is a myokine synthesized by skeletal muscle, which performs key actions on whole-body metabolism. Previous studies have hypothesized a relationship between irisin and vitamin D, but the pathway has not been thoroughly investigated. The purpose of the study was to evaluate whether vitamin D supplementation affected irisin serum levels in a cohort of 19 postmenopausal women with primary hyperparathyroidism (PHPT) treated with cholecalciferol for six months. In parallel, to understand the possible link between vitamin D and irisin, we analyzed the expression of the irisin precursor, Fndc5, in the C2C12 myoblast cell line treated with a biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Our results demonstrate that vitamin D supplementation resulted in a significant increase in irisin serum levels (p = 0.031) in PHPT patients. In vitro, we show that vitamin D treatment on myoblasts enhanced Fndc5 mRNA after 48 h (p = 0.013), while it increased mRNAs of sirtuin 1 (Sirt1) (p = 0.041) and peroxisome proliferator-activated receptor γ coactivator 1α (Pgc1α) (p = 0.017) over a shorter time course. Overall, our data suggest that vitamin-D-induced modulation of Fndc5/irisin occurs through up-regulation of Sirt1, which together with Pgc1α, is an important regulator of numerous metabolic processes in skeletal muscle.

Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing’s syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing’s syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the—nowadays—rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-βhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension.

Normocalcemic primary hyperparathyroidism (NPHPT) is diagnosed in the setting of elevated PTH concentrations with consistently normal albumin-adjusted and ionized serum calcium levels, in absence of secondary causes for elevated PTH concentrations. In order to confirm persistence of the hyperparathyroid state, PTH levels should be elevated on at least two occasions over a 3 to 6 months period. The prevalence of NPHPT depends on the population studied. Data from different studies are often not comparable; indeed, different criteria have been used to exclude secondary hyperparathyroidism. Notwithstanding such limits, the prevalence of NPHPT in studies including ionized calcium dosage was between 0.5% and 0.7%. Available data suggest that patients with NPHPT are likely to have more skeletal, kidney and metabolic complications compared to healthy subjects, but almost all studies suffer from possible misclassification of patients due to lack of ionized calcium dosage. The management of NPHPT is controversial in part due to lack of solid data about the natural history. However, surgical treatment is currently performed more frequently than in the past, although studies do not show, so far, a clear benefit from intervention.

Urothelium is a multilayer epithelium covering the inner surface of the urinary bladder that acts as a blood-urine barrier and is involved in maintaining the wellbeing of the whole organism. Glycans serve in the maturation and differentiation of cells and thus play a key role in the morphology and function of the multilayered epithelium. The aim of the present study was to examine the glycoprotein pattern of the horse urinary bladder urothelium by lectin histochemistry.The study involved urinary bladders from four horse stallions. Tissue sections were stained with a panel of eleven lectins, in combination with saponification and sialidase digestion (Ks).Basal cells displayed high-mannose N-glycans (Con A), α2,6-linked sialic acid (SNA), and O-linked sialoglycans with sialic acids linked to Galβl,3GalNAc (T antigen) (KsPNA) and terminal N-acetylgalactosamine (Tn antigen) (KsSBA). The young intermediate cells expressed terminal N-acetylglucosamine (GlcNAc) (GSA II), galactose (GSA I-BThis study showed that the glycan pattern becomes more complex from the basal to surface layer of the urothelium and that surface cells could modify the composition of urine via the secretion of glycoproteins.

PURPOSE: It has been hypothesized that specific early-life stress (ES) procedures on CD-1 male mice produce diabetes-like alterations due to the failure of negative feedback of glucocorticoid hormone in the pituitary. The aim of this study is to investigate the possible mechanism that leads to this pathological model, framing it in a more specific clinical condition.METHODS: Metabolic and hypothalamic-pituitary-adrenal-related hormones of stressed mice (SM) have been analyzed immediately after stress procedures (21 postnatal days, PND) and after 70 days of a peaceful (unstressed) period (90 PND). These data have been compared to parameters from age-matched controls (CTR), and mice treated during ES procedures with oligonucleotide antisense for pro-opiomelanocortin (AS-POMC).RESULTS: At 21 PND, SM presented an increased secretion of hypothalamic CRH and pituitary POMC-derived peptides, as well as higher plasmatic levels of ACTH and corticosterone vs. CTR. At 90 PND, SM showed hyperglycemia, with suppression of hypothalamic CRH, while pituitary and plasmatic ACTH levels, as well as plasma corticosterone, were constantly higher than in CTR. These values are accompanied by a progressive acceleration in gaining total body weight, which became significant vs. CTR at 90 PND together with a higher pituitary weight. Treatment with AS-POMC prevented all hormonal and metabolic alterations observed in SM, both at 21 and 90 PND.CONCLUSIONS: These findings show that these specific ES procedures affect the negative glucocorticoid feedback in the pituitary, but not in the hypothalamus, suggesting a novel model of ACTH-dependent hypercortisolism that can be prevented by silencing the POMC gene.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm that ectopically secretes fibroblast growth factor 23, a bone cell-derived protein that regulates phosphate homeostasis. The overproduction of fibroblast growth factor 23 causes a paraneoplastic syndrome characterized by hyperphosphaturia, hypophosphatemia, hypovitaminosis D, and vitamin D refractory rickets/osteomalacia, effects that disappear with tumor removal. The PMT may occur in several anatomic regions, mainly in the limbs, usually involving both soft tissue and bone. Acral locations occur in 10% to 15% of the cases, mostly in the feet, with 95 cases reported in this anatomic region to date. We report a case of a PMT in a young adult male who presented in 2007 with the classic constellation of signs and symptoms. A small soft-tissue tumor was detected in his right heel, 3 years after exhaustively seeking for it by various imaging techniques performed at different institutions. Before the tumor was detected, attempts to manage this patient's osteomalacia with phosphate and vitamin D (both calcitriol and ergocalciferol) supplementation were unsuccessful. Following surgical resection, the patient experienced prompt correction of the phosphaturia and gradual reconstitution of his bone mineralization. The pathologic diagnosis was (benign) PMT, mixed connective tissue type. In 2019, 12 years after resection, the patient is asymptomatic, and his bone mineral homeostasis has been restored.

Objective The aim of this study was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma. Design We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants. Methods Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses. Results A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitrotranscriptional activity, including increased stimulation of the PTH promoter. Conclusions We provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.

Bone remodelling is a complex mechanism regulated by osteoclasts and osteoblasts and perturbation of this process leads to the onset of diseases, which may be characterised by altered bone erosion or formation. In this review, we will describe some bone formation-related disorders as sclerosteosis, van Buchem disease, hypophosphatasia and Camurati–Engelmann disease. In the past decades, the research focused on these rare disorders offered the opportunity to understand important pathways regulating bone formation. Thus, the identification of the molecular defects behind the etiopathology of these diseases will open the way for new therapeutic approaches applicable also to the management of more common bone diseases including osteoporosis.

Mitochondria are subcellular organelles involved in cell metabolism and cell life-cycle. Their role in apoptosis regulation makes them an interesting target of new drugs for dealing with cancer or rare diseases. Several peptides and proteins isolated from animal and plant sources are known for their therapeutic properties and have been tested on cancer cell-lines and xenograft murine models, highlighting their ability in inducing cell-death by triggering mitochondrial apoptosis. Some of those molecules have been even approved as drugs. Conversely, many other bioactive compounds are still under investigation for their proapoptotic properties. In this review we report about a group of peptides, isolated from animal venoms, with potential therapeutic properties related to their ability in triggering mitochondrial apoptosis. This class of compounds is known with different names, such as mitochondriotoxins or mitocans.

A role for long non-coding RNAs (lncRNAs) in endocrine cancer pathogenesis is emerging. However, knowledge regarding their expression pattern, correlation with known genetic defects, and clinical implications in parathyroid tumors is still unclear. Here, we profiled 90 known lncRNAs in a first series of normal (PaN = 2), adenomatous (PAd = 12), and carcinomatous (PCa = 4) parathyroid glands and we confirmed deregulation of 11 lncRNAs using an independent cohort of patients (PaN = 4; PAd = 26; PCa = 9). Expression of lncRNAs was correlated with cytogenetic aberrations, status of genes multiple endocrine neoplasia 1 (MEN1) and cell division cycle 73 (CDC73), or clinical features. Globally, lncRNAs discriminate according to tissue histology. BC200 consistently identifies parathyroid cancers from adenomas and atypical adenomas. Loss-of-heterozygosity (LOH) at chromosomes 1, 11, 15, 21, and 22 significantly impacts expression of lncRNAs in PAds. Silencing of the key parathyroid gene MEN1 modulates the expression of six lncRNAs in primary PAds-derived cultures. Analogous levels of lncRNAs are measured in PAds with the mutation in the MEN1 gene compared with PAds with wild-type MEN1. Similarly, carcinomas with mutated CDC73 differ from PCas with wild-type protein in terms of expression of lncRNAs. PCas harboring CDC73 mutations overexpress BC200 compared to wild-type carcinomas. Overall, these findings shed light on deregulation of lncRNAs in human parathyroid tumors and propose that circuits between lncRNAs and the oncosuppressors MEN1 or CDC73 may have a role in parathyroid tumorigenesis as epigenetic modulators. © 2020 American Society for Bone and Mineral Research (ASBMR).

Purpose. Cortisol secretion, peripheral activation and sensitivity seem to be associated with hypertension (HY), type-2 diabetes (T2D) and fragility fractures (FX) even in eucortisolemic subjects. The aim of the present study was to determine the cut-off(s) of the parameters of cortisol secretion and peripheral activation for predicting the presence of HY, T2D and FX (comorbidities). Methods. In 206 postmenopausal females (157 with ≥1 comorbidities and 49 without any), we assessed the ratio between 24-hour urinary free cortisol and cortisone (R-UFF/UFE, cortisol activation index), cortisol after 1mg-overnight-dexamethasone (F-1mgDST, cortisol secretion index), and the GC receptor N363S single-nucleotide polymorphism (N363S-SNP, cortisol sensitivity index). Results. The cut-offs for F-1mgDST and R-UFF/UFE set at 0.9 μg/dL (Area Under the Curve, AUC 0.634±0.43, p=0.005) and 0.17 (AUC 0.624±0.5, p=0.017) respectively, predicted the presence of ≥1 comorbidities. The presence of F-1mgDST >0.9 μg/dL plus R-UFF/UFE >0.17 showed 82.1% specificity for predicting the presence of ≥1 comorbidities, while the simultaneous presence of F-1mgDST ≤0.9 μg/dL and R-UFF/UFE ≤0.17 showed 88% sensitivity for predicting the absence of comorbidities. The F-1mgDST >0.9 μg/dL or R-UFF/UFE >0.17 was associated with 2.8 and 2.1 fold increased risk of having ≥1 comorbidities, respectively. The F-1mgDST ≤0.9 μg/dL plus R-UFF/UFE ≤0.17 or F-1mgDST >0.9 μg/dL plus R-UFF/UFE >0.17 was associated with 2.8 fold reduced or 4.9 fold increased risk of having ≥1 comorbidities regardless of age, BMI and N363S-SNP. Conclusions. F-1mgDST >0.9 μg/dL and R-UFF/UFE >0.17 may be used for predicting the presence of ≥1 among HY, T2D and fragility FX.

Parathyroid carcinoma (PC) is a rare disease with an indolent behavior due to the low malignant potential. The etiology is unknown. Somatic mutations of CDC73 gene, the same gene involved in the hyperparathyroidism-jaw tumor syndrome, can be identified in up to 70% of patients with PC and in one-third of cases the mutations are germline. Therefore, in patients who carry germline CDC73 gene mutations, its finding permits to identify the carriers among relatives and sometimes to early detect a parathyroid lesion in such subjects. The diagnosis of PC is commonly made after surgery, however there are some clinical/biochemical features that should raise the suspicion of PC, namely markedly elevated serum calcium and PTH levels, a large parathyroid lesion with suspected ultrasonographic features of malignancy, the damages of kidney and bones. The best chance of cure is the complete surgical resection with the en-bloc excision at the first operation, however several recurrences are often observed during the follow-up. Since PC is an indolent tumor with long-lasting survival and the death is due to complications of untreatable hypercalcemia, multiple surgical interventions with debulking of tumoral tissues along with medical treatment for reducing hypercalcemia are often needed. Patients with PC should be followed up along their lifetime.

Sarcopenia is a common geriatric syndrome, whose diagnosis implies the assessment of muscle mass. Dual-energy x-ray absorptiometry (DXA) is the reference method for clinical practice, but it is not universally available. We compared DXA with 2 anthropometry-based methods to assess muscle mass in older adults.Cross-sectional.Ambulatory patients.148 (87 female and 61 male) white older adults.Mid-arm muscle circumference (MAMC), whole skeletal muscle mass estimated by the Lee's formula (eTSMM), and relative skeletal muscle index (RSMI).Men and women did not differ for MAMC and RSMI, whereas eTSMM was higher (P .001) in men. MAMC and eTSMM correlated with RSMI, in the whole sample as in men and women separately (P .001). According to the McNemar test, the frequencies of older men and women with low muscle mass identified by eTSMM did not differ from those detected by RSMI (P = .066) at variance with MAMC. Using EWGSOP (European Working Group on Sarcopenia in Older People) criteria for RSMI as standard reference, the receiver operating characteristic (ROC) curves provided redefined cut-offs of reduced muscle mass: 18.6 cm in women and 22.3 cm in men for MAMC, and 17.7 kg in women and 28.3 kg in men for eTSMM. The areas under the ROC curves (AUCs) for MAMC were 0.882 in women (sensitivity 89%, specificity 84%) and 0.826 in men (sensitivity 94%, specificity 67%). The AUCs for eTSMM were 0.8913 in women (sensitivity 95%, specificity 81%) and 0.878 in men (sensitivity 97%, specificity 67%). No significant difference was found between the ROC curves of MAMC and eTSMM in both sexes.Two simple anthropometric methods, possibly used in every clinical setting, could be valuable screening tools for low muscle mass in older subjects.

The previous studies suggested a possible increased risk of hypercalcaemia and reduced bone mineral density (BMD) in Williams’ syndrome (WS). However, an extensive study regarding bone metabolism has never been performed. To investigate bone health in young adults with WS. Cross-sectional study. Endocrinology and Metabolic Diseases and Medical Genetic Units. 29 WS young adults and 29 age- and sex-matched controls. In all subjects, calcium, phosphorus, bone alkaline phosphatase (bALP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHVitD), osteocalcin (OC), carboxyterminal cross-linking telopeptide of type I collagen (CTX), 24-h urinary calcium and phosphorus, femoral-neck (FN) and lumbar-spine (LS) BMD and vertebral fractures (VFx) were assessed. In 19 patients, serum fibroblast growth factor-23 (FGF23) levels were measured. WS patients showed lower phosphorus (3.1 ± 0.7 vs 3.8 ± 0.5 mg/dL, p = 0.0001) and TmP/GFR (0.81 ± 0.32 vs 1.06 ± 0.25 mmol/L, p = 0.001), and an increased prevalence (p = 0.005) of hypophosphoremia (34.5 vs 3.4%) and reduced TmP/GFR (37.9 vs 3.4%). Moreover, bALP (26.3 ± 8.5 vs 35.0 ± 8.0 U/L), PTH (24.5 ± 12.6 vs 33.7 ± 10.8 pg/mL), OC (19.4 ± 5.3 vs 24.5 ± 8.7 ng/mL), and FN-BMD (− 0.51 ± 0.32 vs 0.36 ± 0.32) were significantly lower (p

Parathyroid tumors deregulate microRNAs belonging to the two clusters on the chromosome 19, the C19MC and miR-371-373 clusters. Here, we report that the embryonic miR-372 is aberrantly expressed in half of parathyroid adenomas (PAds) in most of atypical adenomas and carcinomas (n = 15). Throughin situhybridization, we identified that miR-372-positive parathyroid tumor cells were scattered throughout the tumor parenchyma. In PAd-derived cells, ectopic miR-372 inhibited the expression of its targetsCDKN1A/p21 and LATS2 at both mRNA and protein levels. Although the viability of parathyroid cells was not affected by miR-372 overexpression, the miRNA blunted camptothecin-induced apoptosis in primary PAd-derived cultures. miR-372 overexpression in parathyroid tumor cells increased parathormone (PTH) mRNA levels, and it positively correlatedin vivowith circulating PTH levels. Conversely, the parathyroid-specific genesTBX1andGCM2were not affected by miR-372 mimic transfection. Finally, miR-372 dampened the Wnt pathway in parathyroid tumor cells through DKK1 upregulation. In conclusion, miR-372 is a novel mechanism exploited by a subset of parathyroid tumor cells to partially decrease sensitivity to apoptosis, to increase PTH synthesis and to deregulate Wnt signaling.

Transcription factors active in embryonic parathyroid cells can be maintained in adult parathyroids and be involved in tumorigenesis. TBX1, the candidate gene of 22q11.2-DiGeorge syndrome, which includes congenital hypoparathyroidism, is involved in parathyroid embryogenesis. The study aimed to investigate expression, function, and regulation of the parathyroid embryonic transcription factor TBX1 in human parathyroid adult normal and tumor tissues. TBX1 transcripts were detected in normal parathyroids and were deregulated in parathyroid tumors. Using immunohistochemistry, TBX1 protein was detected, mainly at the nuclear level, in a consistent proportion of cells in normal adult parathyroids, whereas TBX1 immunoreactivity was absent in fetal parathyroids. TBX1-expressing cells were markedly reduced in about a half of adenomas (PAds) and two-thirds of carcinomas and the proportion of TBX1-expressing cells negatively correlated with the serum albumin-corrected calcium levels in the analyzed tumors. Moreover, a subset of TBX1-expressing tumor cells coexpressed PTH. TBX1 silencing in HEK293 cells, expressing endogenous TBX1, increased the proportion of cells in the G0/G1 phase of cell cycle; concomitantly, CDKN1A/p21 and CDKN2A/p16 transcripts increased and ID1 mRNA levels decreased. TBX1 silencing exerted similar effects in PAd-derived cells, suggesting cell cycle arrest. Moreover, in PAd-derived cells GCM2 and PTH mRNA levels were unaffected by TBX1 deficiency, whereas it was associated with reduction of WNT5A, an antagonist of canonical WNT/β-catenin pathway. WNT/β-catenin activation by lithium chloride inhibited TBX1 expression levels both in HEK293 and PAd-derived cells. In conclusion, TBX1 is expressed in adult parathyroid cells and deregulated in parathyroid tumors, where TBX1 deficiency may potentially contribute to the low proliferative nature of parathyroid tumors.

Skin filaments are present on the heads of several Hippocampus species. Their clipping is a useful, non-lethal technique for marking individuals and sampling tissue. Little is known about the consequences of clipping on behaviour and details of regeneration. We present the results of a study on the effects of filament clipping on activity patterns and the regeneration of this structure at the macroscopic and microscopic level in Hippocampus guttulatus Cuvier, 1801 from the Gulf of Taranto (Apulia, Ionian Sea). Twelve individuals of both sexes underwent filament clipping, and their behaviour sequences (expressed as percent of total time spent swimming, resting, food searching, and swinging) were monitored for 10 wk in water tanks. In the first week, individuals spent significantly more time food searching and swimming compared to controls, whereas in the following weeks, no differences between groups were observed. Regeneration was observed in 12 other individuals reclipped after 3, 5, and 7 wk. Sections of paraffin-embedded filaments were stained with Mallory’s trichrome, alcian blue pH 2.5, periodic acid-Schiff (PAS), and PAS with diastase. Epidermal cells and basal membranes were the first to recover fully. Basal epidermal cells were filled with glycogen. In the dermis, the arrangement of bundles of fibres surrounded by melanocytes took longer to reconstitute. After 10 wk, the filaments grew to about 36.7% of their original length, whereas at the microscopic level, the tissues recovered fully. It is concluded that filament clipping does not significantly affect the general behavioural patterns of H. guttulatus, and regeneration at the microscopic level is fully accomplished.