High levels of LIGHT/TNFSF14 in patients with Prader-Willi syndrome.

PURPOSE/METHODS: Prader-Willi syndrome (PWS) is a rare genetic disorder displaying different clinical features, including obesity and bone impairment. LIGHT/TNFSF14 is a cytokine produced by immune cells affecting both fat and bone metabolism. The present study aimed to evaluate LIGHT serum levels in 28 children and 52 adult PWS patients compared to age and sex-matched controls, as well as correlations with parameters of bone and fat metabolism. RESULTS: Median serum LIGHT levels were significantly increased in pediatric PWS with respect to controls [255.82 (284.43) pg/ml vs 168.11 (76.23) pg/ml, p ≤ 0.02] as well as in adult PWS compared to controls [296.85 (895.95) pg/ml vs 134.18 (141.18) pg/ml, p ≤ 0.001]. In pediatric PWS, LIGHT levels were positively correlated with weight-SDS, height-SDS, and glucose levels, and negatively with total 25 (OH) vitamin D, cholesterol, LDL cholesterol and triglycerides. Additionally, LIGHT levels were negatively correlated with total BMD and fat mass. In adult PWS, LIGHT levels were positively correlated with weight, HDL cholesterol and PTH, and negatively with glucose, insulin, HOMA-IR, total cholesterol, LDL cholesterol, triglycerides, calcium, phosphorus, 25(OH)Vitamin D as well as with instrumental parameters of bone and fat quality. Consistently, multiple regression analysis showed that LIGHT serum levels in pediatric and adult PWS were predicted by different parameters including 25 (OH) Vitamin D as well as DXA parameters of bone and fat quality. CONCLUSIONS: In PWS children and adults the high levels of LIGHT could represent a marker of the altered bone and fat metabolism.

Intravenous iloprost in systemic sclerosis and its effect in cardiopulmonary function: a retrospective observational study.

OBJECTIVE: This study aims at evaluating the disease progression, specifically in terms of cardiopulmonary function, in a group of consecutively enrolled systemic sclerosis (SSc) patients treated with the approved iloprost regimen. PATIENTS AND METHODS: A retrospective observational study was performed on 68 SSc patients treated with 5-6 infusions of iloprost per month for 6 hours per day at a dosage of 0.5-2.0 ng/kg/min through a portable syringe pump. All patients were evaluated for modified Rodnan skin score, systolic pulmonary arterial pressure, tricuspid annular plane systolic excursion, diffusing capacity of the lungs for carbon monoxide, forced vital capacity, alveolar volume, diffusing capacity of the lungs for carbon monoxide/alveolar volume, pro-brain natriuretic peptide (pBNP), New York Heart Association class, and the presence or absence of digital ulcers (DUs). RESULTS: After a follow-up period of 9.9±2.9 years, all patients improved in frequency and severity of the Raynaud phenomenon and showed a stabilization or improvement of cardiopulmonary parameters. The pulmonary arterial pressure and pBNP improved significantly from baseline (30.91±6.4 mmHg vs. 27.36±7.1 mmHg, and 97.20±69.3 pg/ml vs. 66.65±44.3 pg/ml, respectively; p<0.0001 for both). A significant improvement was observed in the modified Rodnan skin score in 57 patients who continued the treatment during the entire follow-up (5.09±5.7 vs. 3.30±4.2, p<0.0001). CONCLUSIONS: Despite the retrospective design and the lack of a control group, the regular and continued administration of iloprost maintained the stability of the cardiopulmonary and cutaneous parameters in SSc. It significantly reduced pBNP levels, a prognostic cardiac biomarker of SSc. Future research should be addressed to demonstrate a stronger causality of this effect.

Role of Wnt-signaling inhibitors DKK-1 and sclerostin in bone fragility associated with Turner syndrome.

PURPOSE: Girls affected with Turner syndrome (TS) present with low bone mineral density (BMD) and osteopenia/osteoporosis. Thus, they have an increased risk to develop fractures compared to normal population. The aim of this study was to deepen the pathophysiology of skeletal fragility in TS subjects by evaluating the serum levels of Dickkopf-1 (DKK-1) and sclerostin, main regulators of bone mass, as well as the percentage of circulating osteoblast precursors (OCPs). METHODS: Thirty-four TS girls and 24 controls were recruited. All subjects underwent anthropometric measures (height, weight, body mass index-BMI). A peripheral venous blood sample was collected to determine serum levels of active intact parathyroid hormone (PTH), 25-OH vitamin D, calcium, phosphorus, bone alkaline phosphatase (bALP), osteocalcin, sclerostin, DKK-1, RANKL and OPG. OCPs were detected by flow cytometry. In TS subjects bone mineralization was measured at lumbar spine by dual energy X-ray absorptiometry (DXA). RESULTS: bALP, 25-OH Vitamin D, and osteocalcin levels were significant lower in TS subjects than in the controls. Statistically significant higher levels of sclerostin, DKK-1 and RANKL were measured in patients compared with the controls. The percentage of OCPs did not show significant differences between patients and controls. Sclerostin and DKK-1 levels were related with anthropometric parameters, bone metabolism markers, HRT, rhGH therapy, RANKL and lumbar BMAD-Z-score. CONCLUSION: TS patients showed higher levels of sclerostin and DKK-1 than controls which can be related to HRT, and to reduced bone formation markers as well as the increased bone resorption activity.

Paleogenomics illuminates the evolutionary history of the extinct Holocene "horned" crocodile of Madagascar, Voay robustus.

Ancient DNA is transforming our ability to reconstruct historical patterns and mechanisms shaping modern diversity and distributions. In particular, molecular data from extinct Holocene island faunas have revealed surprising biogeographic scenarios. Here, we recovered partial mitochondrial (mt) genomes for 1300-1400 year old specimens (n = 2) of the extinct "horned" crocodile, Voay robustus, collected from Holocene deposits in southwestern Madagascar. Phylogenetic analyses of partial mt genomes and tip-dated timetrees based on molecular, fossil, and stratigraphic data favor a sister group relationship between Voay and Crocodylus (true crocodiles). These well supported trees conflict with recent morphological systematic work that has consistently placed Voay within Osteolaeminae (dwarf crocodiles and kin) and provide evidence for likely homoplasy in crocodylian cranial anatomy and snout shape. The close relationship between Voay and Crocodylus lends additional context for understanding the biogeographic origins of these genera and refines competing hypotheses for the recent extinction of Voay from Madagascar.

Polyphenols and obesity prevention: critical insights on molecular regulation, bioavailability and dose in preclinical and clinical settings.

Obesity represents one of the most important public health challenges of the 21st century and is characterized by a multifactorial etiology in which environmental, behavioral, metabolic, and genetic factors work together. Despite the rapid increase in prevalence of obesity in the last decades, especially in children, it remains a preventable disease. To battle obesity a multisector approach promoting healthier lifestyle in terms of physical activity and nutrition is needed. Specifically, biologically active dietary compounds, as polyphenols, are able to modulate the expression of genes involved in the development and progression of obesity and its comorbidities as demonstrated by multiple studies using different obesity models. However, human studies focusing on the transcriptomic modulation by polyphenols in obese patients are still limited and do not often recapitulate the results obtained in preclinical setting likely due to the underestimation of some variables such as bioavailability, dose and form (native vs. metabolized) of polyphenols used. The aim of this review is to summarize the state-of-art of nutrigenomic in vitro, in vivo and ex vivo studies as well as clinical trials based on dietary polyphenols to fight obesity. We also critical discuss the variables to be considered to fill the gap between preclinical and clinical settings.

Prospective multicentre study on azole resistance in Aspergillus isolates from surveillance cultures in haematological patients in Italy.

OBJECTIVES: This study was conducted to assess the prevalence of azole resistance in Aspergillus isolates from patients with haematological malignancies or who were undergoing haematopoietic stem cell transplantation and to identify the molecular mechanism of resistance. METHODS: In this 28-month prospective study involving 18 Italian centres, Aspergillus isolates from surveillance cultures were collected and screened for azole resistance, and mutations in the cyp51A gene were identified. Resistant isolates were genotyped by microsatellite analysis, and the allelic profiles were compared with those of resistant environmental and clinical isolates from the same geographical area that had been previously genotyped. RESULTS: There were 292 Aspergillus isolates collected from 228 patients. The isolates belonged mainly to the section Fumigati (45.9%), Nigri (20.9%), Flavi (16.8%) and Terrei (4.8%). Three isolates showed itraconazole resistance: Aspergillus fumigatus sensu stricto, Aspergillus lentulus (section Fumigati) and Aspergillus awamori (section Nigri). The itraconazole resistance rates were 1% and 1.48% considering all Aspergillus spp. isolates and the Aspergillus section Fumigati, respectively. The prevalence of azole resistance among all the patients was 1.3%. Among patients harbouring A. fumigatus sensu stricto isolates, the resistance rate was 0.79%. The A. fumigatus isolate, with the TR34/L98H mutation, was genotypically distant from the environmental and clinical strains previously genotyped. CONCLUSIONS: In this study, the Aspergillus azole resistance rate was 1% (3/292). In addition to A. fumigatus sensu stricto, A. lentulus and A. awamori azole-resistant isolates were identified. Therefore, it is important have a correct identification at the species level to address a rapid therapy better, quickly understand the shift towards cryptic species and have an updated knowledge of the local epidemiology.

Custom made onlay implants in peek in maxillofacial surgery: a volumetric study.

PURPOSE: Facially malformed patients often present a variable degree of facial imbalance even after basal bone correction, and resolution of the residual hard- and soft-tissue deficiencies and asymmetries of the face are of great importance for achieving a satisfactory post-implant procedure result. The use of polyether ether ketone (PEEK) implants for maxillofacial reconstruction has been documented in the literature, but the number of patients who have received them is limited. The aim of this study was to evaluate the overall volumetric results in patients with facial imbalance after onlay custom implant positioning for mandible and fronto-orbital reconstructions. Analysis was performed by confronting volumes with the use of three-dimensional (3D) photogrammetry. METHODS: Fifteen patients were eligible for PEEK implant placements, eight for mandibular angle reconstruction, and seven for fronto-orbital reconstruction. Pre- and post-surgical 3D images of each patient's face were acquired. Facial asymmetry was analyzed by comparing each face with its mirrored copy. RESULTS: Three-dimensional analyses have shown that some degree of volume imbalance was still present in the patients with only 1.32 ± 1.02 mm residual discrepancy after treatment. CONCLUSION: Results of the study were found to fall within clinically acceptable limits since an asymmetry rate of < 3 mm is considered to fall into the norm.

Synchronous bilateral adrenalectomy in ACTH-dependent hypercortisolism: predictors, biomarkers and outcomes.

INTRODUCTION: Hypercortisolism requires a prompt therapeutic management to reduce the risk of development of a potential fatal emergency. A synchronous bilateral adrenalectomy (SBA) is effective in recovering hypercortisolism. However, specific indications for an SBA are not available. We aimed to evaluate the outcome of patients who underwent an SBA and to identify biomarkers able to predict the requirements of an SBA. PATIENTS AND METHODS: A mono-centric and longitudinal study was conducted on 19 consecutive patients who underwent SBA for ACTH-dependent hypercortisolism between December 2003 and December 2017. This study population was compared to two control groups composed of patients cured after the resection of the ACTH secreting pituitary adenoma (Group A: 44 patients) and of the ACTH-secreting neuroendocrine tumours (Group B: 8 patients). RESULTS: Short- or long-term SBA complications or the recurrence of hypercortisolism did not occur. A single patient experienced Nelson syndrome. Clinical features after SBA showed improvement in the glico-metabolic assessment, hypertension, bone metabolism and the occurrence of hypokalaemia and infections. The younger the age at the time of Cushing's disease diagnosis, the longer the duration of active hypercortisolism, higher values of plasmatic ACTH and Cortisol (1 month after pituitary neurosurgery) and higher values of Ki67 in pituitary adenomas were detected in this study population as compared to Group A. CONCLUSIONS: SBA is an effective and safe treatment for patients with unmanageable ACTH-dependent hypercortisolism. A multidisciplinary team in a referral centre with a high volume of patients is strongly recommended for the management of these patients and the identification of patients, for better surgical timing.

Tentacle-shaped mesh for fixation-free repair of umbilical hernias.

PURPOSE: Mesh fixation and broad overlap represent an open issue in umbilical hernia repair. A proprietary-designed implant with tentacle straps at its boundary has been developed to ensure a suture-free repair and a broader coverage of the abdominal wall. The study describes the results of umbilical hernia procedures carried out with the tentacle-shaped implant and the related surgical technique. METHODS: A proprietary tentacle-shaped flat mesh having a central body with integrated radiating arms at its edge was used to repair large umbilical hernias in 62 patients. The implant was placed in preperitoneal sublay. The friction of the straps, crossing the abdominal wall thanks to a special needle passer, was intended to assure adequate grip to hold the implant in place assuring a fixation-free procedure and broad overlap of the hernia defect. RESULTS: In a mean follow-up of 48 months (range 10-62 months), 4 seromas and 2 ischemia of the navel skin occurred. No infections, hematomas, chronic pain, mesh dislocation, or recurrence has been reported. CONCLUSIONS: The tentacle strap system of the prosthesis effectively ensured an easier implant placement avoiding the need for suturing the mesh. The arms of the implant ensured a proper orientation and stabilization of the mesh in association with a broad defect overlap. The specifically developed surgical procedure showed a quick postoperative recovery, a very low complication rate, and no recurrences even in the long term.

Design optimization through thermomechanical finite-element analysis of a hybrid piston-clamped anvil cell for nuclear magnetic resonance experiments.

The investigation of materials under extreme pressure conditions requires high-performance cells whose design invariably involves trade-offs between the maximum achievable pressure, the allowed sample volume, and the possibility of real-time pressure monitoring. With a newly conceived hybrid piston-clamped anvil cell, we offer a relatively simple and versatile system, suitable for nuclear magnetic resonance experiments up to 4.4 GPa. Finite-element models, taking into account mechanical and thermal conditions, were used to optimize and validate the design prior to the realization of the device. Cell body and gaskets were made of beryllium-copper alloy and the pistons and pusher were made of tungsten carbide, while the anvils consist of zirconium dioxide. The low-temperature pressure cell performance was tested by monitoring in situ the pressure-dependent 63Cu nuclear-quadrupole-resonance signal of Cu2O.

Skeletal stability in orthognathic surgery with the surgery first approach: a systematic review.

The surgery first approach (SFA) is a therapeutic strategy used in orthognathic surgery that is constantly evolving. With this approach, the pre-surgical orthodontic treatment can be eliminated, the maxilla and the mandible are surgically repositioned into the desired position, and the therapy is ended with a short orthodontic phase. Several studies have reported that the SFA is an acceptable approach, but postoperative stability is unclear. In this study, a systematic review on the SFA was performed. The PubMed, Google Scholar, Scopus, LexisNexis, Web of Science, and Cochrane Library databases were accessed. Studies from which data could be extracted on skeletal stability based on specific cephalometric points were included. The search yielded 2766 publications. Application of the selection criteria resulted in a final group of 14 articles. Five hundred and sixty patients with class III malocclusion underwent orthognathic surgery, 339 with the SFA. Study parameters such as evaluation time points and reference planes varied, making it impossible to perform a meta-analysis. The studies suggest that surgery with the SFA is as stable as surgery with the conventional approach. However, all articles described stability using a penultimate time point of 'after surgery' and not 'after debonding'; hence orthodontic movements and consequent mandibular movements could have influenced cephalometric measurements. Thus, to verify the real stability of the SFA, further research with longer follow-up periods is required, with evaluation at the same time points.

Identification of extracellular vesicles and characterization of miRNA expression profiles in human blastocoel fluid.

In this study, for the first time, we demonstrated the presence of microRNAs and extracellular vesicles in human blastocoel fluid. The bioinformatic and comparative analyses identified the biological function of blastocoel fluid microRNAs and suggested a potential role inside the human blastocyst. We found 89 microRNAs, expressed at different levels, able to regulate critical signaling pathways controlling embryo development, such as pluripotency, cell reprogramming, epigenetic modifications, intercellular communication, cell adhesion and cell fate. Blastocoel fluid microRNAs reflect the miRNome of embryonic cells and their presence, associated with the discovery of extracellular vesicles, inside blastocoel fluid, strongly suggests their important role in mediating cell communication among blastocyst cells. Their characterization is important to better understand the earliest stages of embryogenesis and the complex circuits regulating pluripotency. Moreover, blastocoel fluid microRNA profiles could be influenced by blastocyst quality, therefore, microRNAs might be used to assess embryo potential in IVF cycles.

The seminiferous tubule caliber pattern as evaluated at high magnification during microdissection testicular sperm extraction predicts sperm retrieval in patients with non-obstructive azoospermia.

BACKGROUND: microTESE proved to be the gold standard surgical approach for patients with non-obstructive azoospermia (NOA), but sperm retrieval rates (SRRs) vary considerably among centers. Some authors compared their SRRs with the pattern of seminiferous tubule caliber found at high magnification, but none provided diagnostic accuracy measures. OBJECTIVE: The present retrospective study sought to verify the diagnostic accuracy of the pattern of seminiferous tubule caliber in predicting the sperm retrieval in NOA patients. MATERIALS AND METHODS: Data from 143 infertile NOA men undergoing unilateral (64) or bilateral (79) microTESE (222 testes) were retrospectively evaluated. During microTESE, if present, dilated tubules (DTs) were retrieved, otherwise tubules with slightly larger caliber (SDT) (×24) than that of the surroundings were removed. When no DT or SDT were found, not dilated tubules (NDTs) were excised. RESULTS: Spermatozoa were retrieved in 95 of 222 testes (42.8%); sperm retrieval was successful in 90% of testes with DTs, in 47% of those with SDTs, and only in 7% of those with NDTs (p < 0.0001). Stepwise binary logistic regression revealed that the combination of seminiferous tubule pattern and testis histology was significantly predictive of SSR, being able to classify 86.8% of testes, with an excellent diagnostic accuracy (AUC 0.93). The median number of spermatozoa retrieved was significantly higher in DTs compared with SDTs and NDTs. DISCUSSION: The results of the present study provide reliable accuracy measures in support of the relationship between seminiferous tubule caliber pattern and SSR in patients with non-obstructive azoospermia. We are proposing for the first time that spermatozoa may be retrieved even from slightly dilated tubules in about half of cases. The pattern of tubules retrieved, together with histology, may represent an additional outcome measure of microTESE. CONCLUSION: The pattern of seminiferous tubules together with testis histology predicts sperm retrieval with an excellent diagnostic accuracy.

Severe asthma in adolescents and adults: a national, multicenter registry in real life.

Summary: The number of patients with uncontrolled asthma is growing especially in young people. Although current therapies improve the disease management, the heterogeneity of clinical outcomes results in patients whose asthma is refractory to standard therapies. To understand not responsive phenotypes, we instituted a web-registry aimed to collect real life data of adolescent and adult patients. One-hundred and five Italian medical Centers are part of the network. Participants above 14 years and affected by severe asthma will be included in the study. Demographic and clinical data will be collected for 5 years on a dedicated electronic database. For the first time in Italy, our study will provide information on epidemiological, clinical and therapeutic aspects related to the natural course of the disease, filling the gap between adolescents and adults.

Lipoma of the fossa femoralis mimicking a femoral hernia. Report of 2 cases.

INTRODUCTION: Lipoma of the femoral fossa is uncommon. Often asymptomatic, femoral lipoma may growth within the circumscribed space of the femoral fossa causing pain and discomfort. A worsening pain caused by a lipomatous mass in the femoral area is a clinical feature that can mislead the diagnosis, resembling the more common condition of femoral hernia. METHODS: Two cases of symptomatic lipomas of the femoral fossa mimicking an incarcerated femoral hernia are presented. In both, Caucasian female, patients clinical examination and ultrasound of the femoral region revealed a painful neoplasm suspected for incarcerated femoral hernia. RESULTS: Intraoperatively, a mass of encapsulated fat arising from the bottom of the fossa femoralis was found. No visceral protrusion through the femoral ring could be documented. The neoplasms were removed in toto. Histology of the excised specimens evidenced the diagnosis of femoral lipomas suffering by chronic compressive damages. In a midterm postoperative follow up, both patients were symptom- free. DISCUSION: A correct preoperative diagnosis of femoral lipoma is challenging, even following an accurate diagnostic pathway. The cases highlighted herewith seem to confirm that lipoma of the femoral fossa can be mistaken with a femoral hernia. CONCLUSIONS: The clinical and histological features evidenced could result helpful in the differentiation of a lipomatous mass of the femoral fossa from a genuine femoral hernia.

Fixation free femoral hernia repair with a 3D dynamic responsive implant. A case series report.

BACKGROUND: To date, no gold standard for the surgical treatment of femoral hernia exists. Pure tissue repair as well as mesh/plug implantation, open or laparoscopic, are the most performed methods. Nevertheless, all these techniques need sutures or mesh fixation. This implies the risk of damaging sensitive structures of the femoral area, along with complications related to tissue tear and postoperative discomfort consequent to poor quality mesh incorporation. The present retrospective multicenter case series highlights the results of femoral hernia repair procedures performed with a 3D dynamic responsive implant in a cohort of 32 patients during a mean follow up of 27 months. MATERIALS AND METHODS: Aiming to simplify the surgical procedure and reduce complications, a 3D dynamic responsive implant was delivered for femoral hernia repair, in a patient cohort. After returning the hernia sack to the abdominal cavity, the implant was simply delivered into the hernia defect where it remained, thanks to its inherent centrifugal expansion, obliterating the hernia opening without need of fixation. Postoperative pain assessment was determined using the VAS score system. RESULTS: The use of the 3D prosthetic device allowed for easier and faster surgical repair in a fixation free fashion. None of the typical fixation related complications occurred in the examined patients. Postoperative pain assessment with VAS score showed a very low level of pain, allowing the return of patients to normal activities in extremely reduced times. In the late postoperative period, no discomfort or chronic pain was reported. CONCLUSIONS: Femoral hernia repair with the 3D dynamic revealed a quick and safe placement procedure. The reduced pain intensity, as well as the absence of adverse events consequent to sutures or mesh fixation, seems to be a significant benefit of the motile compliance of the device. Furthermore, this 3D prosthesis has already proven to induce an enhanced probiotic response showing ingrowth in the implant of the typical tissue components of the abdominal wall, instead of the low quality tissue ingrowth typical in conventional meshes and plugs. The highlighted features seem to represent a more physiologic and updated repair concept of femoral protrusions.

News on Climate Change, Air Pollution, and Allergic Triggers of Asthma.

The rising frequency of obstructive respiratory diseases during recent years, in particular allergic asthma, can be partially explained by changes in the environment, with the increasing presence in the atmosphere of chemical triggers (particulate matter and gaseous components such as nitrogen dioxide and ozone) and biologic triggers (aeroallergens). In allergic individuals, aeroallergens stimulate airway sensitization and thus induce symptoms of bronchial asthma. Over the last 50 years, the earth's temperature has risen markedly, likely because of growing concentrations of anthropogenic greenhouse gas. Major atmospheric and climatic changes, including global warming induced by human activity, have a considerable impact on the biosphere and on the human environment. Urbanization and high levels of vehicle emissions induce symptoms of bronchial obstruction (in particular bronchial asthma), more so in people living in urban areas compared than in those who live in rural areas. Measures need to be taken to mitigate the future impact of climate change and global warming. However, while global emissions continue to rise, we must learn to adapt to climate variability.

Analysis of Circulating Mediators of Bone Remodeling in Prader-Willi Syndrome.

We tested the hypothesis that the levels of bone remodeling mediators may be altered in Prader-Willi syndrome (PWS). We assessed RANKL, OPG, sclerostin, DKK-1 serum levels, and bone metabolism markers in 12 PWS children (7.8 ± 4.3 years), 14 PWS adults (29.5 ± 7.2 years), and 31 healthy controls matched for sex and age. Instrumental parameters of bone mineral density (BMD) were also evaluated. Lumbar spine BMD Z-scores were reduced in PWS children (P < 0.01), reaching osteopenic levels in PWS adults. PWS patients showed lower 25(OH)-vitamin D serum levels than controls (P < 0.001). Osteocalcin was increased in PWS children but reduced in adults respect to controls (P < 0.005 and P < 0.01, respectively). RANKL levels were higher in both pediatric and PWS adults than controls (P < 0.004), while OPG levels were significantly reduced (P < 0.004 and P < 0.006, respectively). Sclerostin levels were increased in children (P < 0.04) but reduced in adults compared to controls (P < 0.01). DKK-1 levels did not show significant difference between patients and controls. In PWS patients, RANKL, OPG, and sclerostin significantly correlated with metabolic and bone instrumental parameters. Consistently, with adjustment for age, multiple linear regression analysis showed that BMD and osteocalcin were the most important predictors for RANKL, OPG, and sclerostin in children, and GH and sex steroid replacement treatment in PWS adults. We demonstrated the involvement of RANKL, OPG, and sclerostin in the altered bone turnover of PWS subjects suggesting these molecules as markers of bone disease and new potential pharmacological targets to improve bone health in PWS.