Disorders of glucose metabolism in Prader-Willi syndrome: Results of a multicenter Italian cohort study.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. METHODS AND RESULTS: We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1-50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children <10 yrs; adolescents 10-18 yrs, and adults >18 yrs), Body Mass Index (BMI = kg/m(2)), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. CONCLUSION: This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program.

Gonadal status in long-term male survivors of childhood cancer.

PURPOSE: To evaluate the prevalence of gonadal dysfunction and the associated risk factors in a cohort of male childhood cancer survivors (CCS). METHODS: Gonadal function was evaluated measuring FSH, LH, inhibin B and total testosterone levels. Patients with total testosterone <3 ng/dl were considered to have hypogonadism. Patients with FSH >10 UI/l and inhibin B <100 pg/ml were considered to have spermatogenesis damage (SD). To assess the impact of risk factors, we estimated crude and adjusted OR performing logistic regression models. RESULTS: One hundred and ninety-nine male CCS were enrolled; the median follow-up time was 14.01 years. SD was diagnosed in 68 patients, 16 CCS had primary hypogonadism, and 13 had central hypogonadism. The prevalence of gonadal dysfunction (SD or primary hypogonadism) was 45 %, similar in the three considered periods of pediatric cancer diagnosis (1985-1989, 1990-1999, >2000). The adjusted risk of gonadal dysfunction was higher in patients treated with radiotherapy (OR = 8.72; 95 % CI 3.94-19.30) and in those exposed to both alkylating and platinum-derived agents (OR = 9.22; 95 % CI 2.17-39.23). Sarcomas were the cancer diagnosis associated with the higher risk of gonadal dysfunction (OR = 3.69; 95 % CI 1.11-12.22). An extremely high rate of gonadal dysfunction was detected in patients who underwent hematopoietic stem cell transplantation and/or total body irradiation. CONCLUSIONS: Gonadal dysfunction still remains a significant late effect of anticancer therapies; thus, it is mandatory to inform patients (and parents) about this risk, and semen cryopreservation should be offered to all boys who are able to produce semen.

GH replacement therapy and second neoplasms in adult survivors of childhood cancer: a retrospective study from a single institution.

PURPOSE: Growth hormone deficiency (GHD) is the most common endocrine late effect observed in childhood cancer survivors (CCS) previously submitted to cranial irradiation. Radiation therapy can also increase the risk of second neoplasms (SNs). Since in previous studies GH replacement therapy was associated with increased incidence of neoplasia, we explored the association between SNs and GH replacement therapy in a cohort of CCS with GHD. METHODS: Within the clinical cohort of CCS referred to the Transition Unit for Childhood Cancer Survivors of Turin between November 2001 and December 2012, we considered all patients who developed GHD as a consequence of cancer therapies. GHD was always diagnosed in childhood. To evaluate the quality of data, our cohort was linked to the Childhood Cancer Registry of Piedmont. RESULTS: GHD was diagnosed in 49 out of 310 CCS included in our clinical cohort. At least one SN was diagnosed in 14 patients, meningioma and basal cell carcinoma being the most common SNs. The cumulative incidence of SNs was similar in GH-treated and -untreated patients (8 SNs out of 26 GH-treated and 6 out of 23 GH-untreated patients; p = 0.331). Age, sex and paediatric cancer type had no impact on SNs development. CONCLUSIONS: In our CCS, GH replacement therapy does not seem to increase the risk of SNs. Anyway, independently from replacement therapy, in these patients we observed an elevated risk of SNs, possibly related to previous radiation therapy, which suggests the need of a close long-term follow-up.

Subclinical hyperthyroidism when presenting as initial manifestation of juvenile Hashimoto's thyroiditis: first report on its natural history.

BACKGROUND: Due to the lack of specific pediatric studies, no data are available about natural history of endogenous subclinical hyperthyroidism (SH) in childhood. AIMS: (a) To investigate for the first time the natural history of SH [suppressed thyrotropin (TSH) and normal free thyroxine free thyroxine (FT4) levels] when presenting as initial manifestation of Hashimoto's thyroiditis (HT) in childhood (group A); (b) to compare spontaneous evolution of HT-related SH with that observed in age-matched patients with HT-related frank hyperthyroidism (suppressed TSH and elevated FT4 levels), i.e., Hashitoxicosis Htx (group B). RESULTS: In the 11 patients of group A, TSH normalization spontaneously occurred 1-24 months after diagnosis, while in the 10 patients of group B it occurred 3-9 months after diagnosis, with no differences between the 2 groups in terms of time interval from entry to TSH normalization. In group A, this time interval was related to baseline thyroid peroxidase antibodies (r=0.78, p = 0.04). During follow-up, eight patients of each group remained euthyroid, whereas two became hypothyroid (in both groups) and one developed Graves' disease (in group A). CONCLUSION: (a) HT should be included among the causes of endogenous SH in pediatric age; (b) in children with HT-related SH, spontaneous normalization of TSH levels occurs within the first 24 months after diagnosis, as well as in age-matched patients with Htx; (c) in both these conditions, a further deterioration of thyroid function might re-present in some patients during follow-up; (d) Ht-related SH and Htx might be possibly seen as different biochemical stages along the same continuum.

ZnFe2O4 nanoparticles dispersed in a highly porous silica aerogel matrix: a magnetic study.

We report the detailed structural characterization and magnetic investigation of nanocrystalline zinc ferrite nanoparticles supported on a silica aerogel porous matrix which differ in size (in the range 4-11 nm) and the inversion degree (from 0.4 to 0.2) as compared to bulk zinc ferrite which has a normal spinel structure. The samples were investigated by zero-field-cooling-field-cooling, thermo-remnant DC magnetization measurements, AC magnetization investigation and Mössbauer spectroscopy. The nanocomposites are superparamagnetic at room temperature; the temperature of the superparamagnetic transition in the samples decreases with the particle size and therefore it is mainly determined by the inversion degree rather than by the particle size, which would give an opposite effect on the blocking temperature. The contribution of particle interaction to the magnetic behavior of the nanocomposites decreases significantly in the sample with the largest particle size. The values of the anisotropy constant give evidence that the anisotropy constant decreases upon increasing the particle size of the samples. All these results clearly indicate that, even when dispersed with low concentration in a non-magnetic and highly porous and insulating matrix, the zinc ferrite nanoparticles show a magnetic behavior similar to that displayed when they are unsupported or dispersed in a similar but denser matrix, and with higher loading. The effective anisotropy measured for our samples appears to be systematically higher than that measured for supported zinc ferrite nanoparticles of similar size, indicating that this effect probably occurs as a consequence of the high inversion degree.

An X-ray absorption spectroscopy study of the inversion degree in zinc ferrite nanocrystals dispersed on a highly porous silica aerogel matrix.

The structural properties of zinc ferrite nanoparticles with spinel structure dispersed in a highly porous SiO(2) aerogel matrix were compared with a bulk zinc ferrite sample. In particular, the details of the cation distribution between the octahedral (B) and tetrahedral (A) sites of the spinel structure were determined using X-ray absorption spectroscopy. The analysis of both the X-ray absorption near edge structure and the extended X-ray absorption fine structure indicates that the degree of inversion of the zinc ferrite spinel structures varies with particle size. In particular, in the bulk microcrystalline sample, Zn(2+) ions are at the tetrahedral sites and trivalent Fe(3+) ions occupy octahedral sites (normal spinel). When particle size decreases, Zn(2+) ions are transferred to octahedral sites and the degree of inversion is found to increase as the nanoparticle size decreases. This is the first time that a variation of the degree of inversion with particle size is observed in ferrite nanoparticles grown within an aerogel matrix.

Endocrine health conditions in adult survivors of childhood cancer: the need for specialized adult-focused follow-up clinics.

BACKGROUND: Survival rates among childhood cancer survivors (CCS) have enormously increased in the last 40 years. However, this improvement has been achieved at the expense of serious late effects that frequently involve the endocrine system. AIM: To evaluate the cumulative incidence of endocrine diseases in a cohort of long-term CCS. MATERIALS AND METHODS: We analyzed the clinical data of 310 adults, followed for a median time of 16.0 years after the first cancer diagnosis. The monitoring protocols applied to each patient were personalized on the basis of cancer diagnosis and previous treatments, according to the Children's Oncology Group guidelines. RESULTS: The cumulative incidence of endocrine late effects steadily increased over time. At the last follow-up visit available, 48.46% of females and 62.78% of males were affected by at least one endocrine disease. The most common disorders were gonadal dysfunction, primary hypothyroidism, and GH deficiency (GHD). The main risk factors for endocrine disease were male sex (hazard ratio (HR)=1.45, 95% confidence interval (95% CI) 1.05-1.99), radiotherapy (HR=1.91, 95% CI 1.28-2.84), hematopoietic stem cells transplantation (HR=3.11, 95% CI 2.23-4.34), and older age at cancer diagnosis (HR=1.89, 95% CI 1.25-2.85). Male sex was associated with a higher risk of gonadal disorders, whereas radiotherapy specifically increased the risk of GHD and thyroid dysfunction. CONCLUSIONS: Endocrine disorders among CCS have a high prevalence and increase over time. Thus, endocrinologists need to cope with an increasing demand for health care in a field that is still little developed and that, in perspective, could also be extended to some selected types of adult cancer survivors.

Metabolic syndrome in adult patients with Prader-Willi syndrome.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS), the most common genetic cause of obesity, is characterized by elevated morbility and mortality in all ages. In this context, non-obese PWS children showed low frequency of metabolic syndrome (MetS), while a comparable prevalence was observed in obese PWS and obese controls. Aim of this study was to estimate the occurrence of MetS and its components in a large group of PWS adults, according to obesity status. METHODS AND RESULTS: A cross-sectional study was performed in 108 PWS aged 18.0-43.2 years (87 obese and 21 non-obese) and in 85 controls with nonsyndromic obesity matched for age, gender, and BMI with obese PWS. Non-obese PWS showed lower waist circumference, insulin, HOMA-index, triglycerides, diastolic blood pressure, and higher HDL-C than both obese PWS and obese controls (p < 0.017). Obese PWS showed higher glucose and systolic blood pressure than both non-obese PWS and obese controls (p < 0.017). MetS was found in 1/21 (4.8%) non-obese PWS, 36/87 (41.4%) obese PWS and 39/85 (45.9%) obese controls. Non-obese PWS showed lower frequency for each MetS component as compared with obese PWS and obese controls. PWS patients with deletion of the chromosome 15q11-13 showed a lower risk for low HDL-C (p < 0.01) and a trend towards a lower MetS risk (p < 0.06) compared to subjects without deletion. CONCLUSION: Our findings suggest the main role that obesity status plays on the individual metabolic risk clustering in PWS adults. Early identification of MetS could be helpful to improve morbidity and prevent mortality in such patients.

Thyroid abnormalities in children and adolescents with McCune-Albright syndrome.

BACKGROUND: To date, there is no agreement about the frequency or the features of thyroid abnormalities in McCune-Albright syndrome (MAS). The aim of our study was to detect thyroid abnormalities in a cohort of MAS children and adolescents and to give indications for their treatment and follow-up. METHODS: In 36 patients, 22 females and 14 males, thyroid function and sonographic features of thyroid were evaluated every 6-12 months. RESULTS: Three males and 1 female had hyperthyroidism: 2 with nodular, 2 with diffuse goiters. They were treated with methimazole (0.2-0.5 mg/kg/day) with good clinical and biochemical responses. The remaining 32 patients were euthyroid, even if 7 displayed sonographic alterations, of whom 5 had nodular goiter with nodules >1 cm, and 2 micronodular goiter. Fine-needle aspiration biopsy was performed in 2 patients with nodules >1 cm, 1 showing hemorrhagic nodule and 1 colloid cystic nodule. CONCLUSIONS: Prevalence of thyroid alterations in the studied MAS series was 31%. 64% of 11 patients with thyroid alterations had nodular goiters, with nodules >1 cm. As the onset of thyroid disease ranged from 1 to 20 years, a strict monitoring of thyroid function is recommended every 6 months. Satisfactory treatment can be obtained and maintained with antithyroid drugs.

Phalangeal quantitative ultrasound in 1,719 children and adolescents with bone disorders.

SUMMARY: We measured bone properties by phalangeal quantitative ultrasound in 1,719 pediatric patients with bone disorders, classifying them according to fracture status. Quantitative ultrasound discriminated fractured and nonfractured pediatric patients and enabled us to stratify fractured patients into classes according to the severity of the causative trauma (spontaneous, minimal trauma, appropriate trauma fractures). INTRODUCTION: The correlation between quantitative bone measurements and fractures is poorly established in pediatric patients with bone disorders. We correlated phalangeal quantitative ultrasound (QUS) and fracture history in children and adolescents with bone disorders and evaluated the ability of QUS to recognize fractured patients. METHODS: Amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) were measured in 1,719 pediatric patients with bone disorders and related to fracture history. The patients were classified as (1) spontaneously (77), (2) minimal trauma (101), or (3) appropriate trauma fractured (206), and (4) nonfractured (1,335). The likelihood of fracture according to QUS was calculated as odds ratio per SD decrease (OR/SD), and the effectiveness in discriminating fractured patients was evaluated by receiver operating characteristic (ROC) analysis. The influence of age, sex, puberty, height, and BMI was explored by respective adjustments and multiple logistic regression. RESULTS: Fractured patients showed significantly reduced AD-SoS and BTT standard deviation score (-0.32 ± 1.54 and -0.78 ± 1.49) compared to nonfractured subjects (0.43 ± 1.63 and -0.11 ± 1.34). QUS measurements paralleled the causative trauma severity, ranging from the lowest values in spontaneously fractured patients to normal values in appropriate trauma fractured subjects. The OR/SD were increasingly higher in appropriate trauma fractured, minimal trauma fractured, and spontaneously fractured patients. At ROC analysis, both parameters proved to have significant discrimination power in recognizing spontaneously and minimal trauma-fractured patients. CONCLUSIONS: QUS identifies fractured pediatric patients with bone disorders, reflecting the severity of the causative trauma with a high discrimination power for fragility fractures.

One-step preparation of FeCo nanoparticles in a SBA-16 matrix as catalysts for carbon nanotubes growth.

Nanocomposites containing FeCo alloy nanoparticles dispersed in a highly ordered 3D cubic Im3m mesoporous silica (SBA-16) matrix were prepared by a novel, single-step templated-assisted sol-gel technique. Two different approaches were used in the synthesis of nanocomposites; a pure SBA-16 sample was also prepared for comparison. Low-angle X-ray diffraction, transmission electron microscopy and N2 physisorption at 77 K show that after metal loading, calcination at 500 degrees C and reduction in H2 flux at 800 degrees C the nanocomposites retain the cubic mesoporous structure with pore size not very different from the pure matrix. X-ray absorption fine structure (EXAFS) analysis at Fe and Co K-edges demonstrates that the FeCo nanoparticles have the typical bcc structure. The final nanocomposites were tested as catalysts for the production of carbon nanotubes by catalytic chemical vapour deposition and high-resolution TEM shows that good quality multi-walled carbon nanotubes are obtained.

Metabolic syndrome in children with Prader-Willi syndrome: the effect of obesity.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS), the most frequent syndromic obesity, is associated with elevated morbidity and mortality in pediatric and adult ages. In PWS, the presence of metabolic syndrome (MS) has not yet been established. The aim of the study was to estimate the frequency of MS and its components in pediatric subjects according to obesity status. METHODS AND RESULTS: A cross-sectional study was performed in 109 PWS children aged 2-18 years (50 obese and 59 non-obese) and in 96 simple obese controls matched for age, gender, and also for BMI with obese PWS. Obesity was defined when SDS-BMI was >2. Non-obese PWS showed significantly lower frequency of hypertension (12%) than obese PWS (32%) and obese controls (35%)(p=0.003). The same was observed for low HDL-cholesterol (3% vs 18% and 24%, p=0.001) and high triglycerides (7% vs 23% and 16%, p=0.026). Frequency of altered glucose metabolism was not different among groups (2% vs 10% and 5%), but type 2 diabetes (four cases) was present only in obese PWS. Non-obese PWS showed lower insulin and HOMA-index respect to obese PWS and obese controls (p ≤ 0.017). Overall MS frequency in PWS was 7.3%. None of the non-obese PWS showed MS compared with 16% of obese PWS and controls (p<0.001). When obesity was excluded from the analysis, a significantly lower frequency for clustering of ≥ 2 factors was still found in non-obese PWS (p=0.035). CONCLUSION: Non-obese PWS showed low frequency of MS and its components, while that observed in obese PWS was very close to those of obese controls, suggesting the crucial role of obesity status. Prevention of obesity onset remains the most important goal of PWS treatment. Early identification of MS could be helpful to improve morbidity and mortality in such patients.

Characterization of stoichiometric nanocrystalline spinel ferrites dispersed on porous silica aerogel.

Stoichiometric magnetic nanosized ferrites MFe2O4 (M = Mn, Co, Ni) were prepared in form of nearly spherical nanocrystals supported on a highly porous silica aerogel matrix, by a sol-gel procedure. X-ray diffraction and transmission electron microscopy indicate that these materials are made out of non-agglomerated ferrite nanocrystals having size in the 5-10 nm range. Investigation by Mössbauer Spectroscopy was used to gain insights on the superparamagnetic relaxation and on the inversion degree. Magnetic ordering at room temperature varies from superparamagnetic in the NiFe2O4 sample, highly blocked (approximately 70%) in the MnFe2O4 sample and nearly fully blocked in the CoFe2O4 sample. A fitting procedure of the Mössbauer data has been used in order to resolve the spectrum into the tetrahedral and octahedral components; in this way, an inversion degree of 0.68 (very close to bulk values) was obtained for 6 nm silica-supported CoFe2O4 nanocrystals.

Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: from experiments to computer simulations.

In this paper, we illustrate how advanced computational modelling and simulation can be used to investigate drug-induced effects on cardiac electrophysiology and on specific biomarkers of pro-arrhythmic risk. To do so, we first perform a thorough literature review of proposed arrhythmic risk biomarkers from the ionic to the electrocardiogram levels. The review highlights the variety of proposed biomarkers, the complexity of the mechanisms of drug-induced pro-arrhythmia and the existence of significant animal species differences in drug-induced effects on cardiac electrophysiology. Predicting drug-induced pro-arrhythmic risk solely using experiments is challenging both preclinically and clinically, as attested by the rise in the cost of releasing new compounds to the market. Computational modelling and simulation has significantly contributed to the understanding of cardiac electrophysiology and arrhythmias over the last 40 years. In the second part of this paper, we illustrate how state-of-the-art open source computational modelling and simulation tools can be used to simulate multi-scale effects of drug-induced ion channel block in ventricular electrophysiology at the cellular, tissue and whole ventricular levels for different animal species. We believe that the use of computational modelling and simulation in combination with experimental techniques could be a powerful tool for the assessment of drug safety pharmacology.

Synthesis and microstructure of manganese ferrite colloidal nanocrystals.

The atomic level structure of a series of monodisperse single crystalline nanoparticles with a magnetic core of manganese ferrite was studied using X-ray absorption fine structure (EXAFS) and X-ray absorption near edge structure (XANES) techniques at both the Fe and Mn K-edges, and conventional and high resolution transmission electron microscopy (TEM and HRTEM). In particular, insights on the non-stoichiometry and on the inversion degree of manganese ferrite nanocrystals of different size were obtained by the use of complementary structural and spectroscopic characterization techniques. The inversion degree of the ferrite nanocrystals, i.e. the cation distribution between the octahedral and tetrahedral sites in the spinel structure, was found to be much higher (around 0.6) than the literature values reported for bulk stoichiometric manganese ferrite (around 0.2). The high inversion degree of the nanoparticles is ascribed to the partial oxidation of Mn(2+) to Mn(3+) which was evidenced by XANES, leading to non-stoichiometric manganese ferrite.

A survey on Prader-Willi syndrome in the Italian population: prevalence of historical and clinical signs.

Clinical criteria for the diagnosis of Prader-Willi Syndrome (PWS) were established by consensus in 1993 (Holm et al.). Specific molecular testing is now available and the purpose of diagnostic criteria has shifted to identify individuals to test, thus avoiding the expense of unnecessary analysis. The aim of this study was to find clinical indicators to select patients with suspected PWS for laboratory testing. We analyzed the prevalence of clinical signs and symptoms in 147 genetically diagnosed Italian patients with PWS (67 males and 80 females), aged from 9 months to 34.6 years (13.6 +/- 8.3 years), using the consensus diagnostic criteria, and according to age, sex and type of genetic abnormality. The prevalence of several clinical features changed significantly with age, but very few with sex. According to genetic subtypes (deletion vs UPD), only hypopigmentation and acromicria were more frequent in patients with deletion. Some criteria considered as minor or supportive by Holm et al. have higher prevalence than some major criteria. In conclusion, in order to identify patients with suspected PWS to submit to laboratory testing, we recommend a classification of clinical criteria according to age, giving more attention to those so-called minor or supportive criteria.

Mutations in TAZ/WWTR1, a co-activator of NKX2.1 and PAX8 are not a frequent cause of thyroid dysgenesis.

AIM: In 80-85% of cases, congenital hypothyroidism is associated with thyroid dysgenesis (TD), but only in a small percentage of cases mutations in thyroid transcription factors (NKX2.1, PAX8, FOXE1, and NKX2.5) have been associated with the disease. Several studies demonstrated that the activity of the transcription factors can be modulated by the interaction with other proteins, such as coactivators and co-repressors, and TAZ (transcriptional co-activator with PDZ-binding motif or WWTR1) is a co-activator interacting with both NKX2.1 and PAX8. In the present study we investigate the role of TAZ in the pathogenesis of TD. MATERIAL AND METHODS: By Single Stranded Conformational Polymorphism, we screened the entire TAZ coding sequence for mutations in 96 patients with TD and in 96 normal controls. RESULTS: No mutations were found in patients and controls, but we found several polymorphisms in both groups. No significant differences could be demonstrated in the prevalence of the mutations between patients and controls. CONCLUSIONS: Our data indicate that TAZ mutations are not a cause of TD in the series of patients studied.

Pituitary height and neuroradiological alterations in patients with Prader-Labhart-Willi syndrome.

Prader-Willi syndrome (PWS), a genetic disorder due to an alteration in the paternally derived long arm of chromosome 15, is characterized by a complex clinical picture (short stature, obesity, hypogonadism) that seems to be referable to as a central hypothalamic/pituitary dysfunction. To determine whether there is any diminution in the anterior pituitary gland or other neuroradiological alterations, we retrospectively analysed 91 patients with PWS (42 females, 49 males; age range: 0.7-16.8 years) by cerebral magnetic resonance imaging (MRI). Of these 91 patients, MRI analysis showed a reduction in pituitary height in 45 patients (49.4%), a complete absence of the posterior pituitary bright spot in six patients (6.6%) and other neuroradiological alterations in ten patients (11%). Altogether, neuroradiological alterations were present in 61 of the 91 (67%) patients. Our results indicate that neuroradiological alterations are more frequent in PWS patients than has been reported to date.