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Introduction: Minipuberty follows different trends in boys and girls. Aim of our study was to explore timing and dynamics of minipuberty in healthy infants, analyzing urinary levels of sexual hormones. Moreover, we analyzed the association among HPG axis activity and linear growth, ano-genital distances (AGDs) in both sexes, and penile length in males., Methods: Longitudinal cohort study in healthy term infants from birth to 6 months of life. Clinical evaluation (anthropometrics and AGDs) and urine sampling were performed at 0 (T0), 3 (T3), and 6 (T6) months. Urine samples were analyzed for gonadotropins and sex hormones., Results: 165 participants were involved. The growth trend of our population was regular, as were the AGDs. Urinary hormones were correlated each other's. Specifically, in boys, the correlation coefficient between urinary FSH (uFSH) and urinary LH (uLH) decreased from T0 to T6, while between urinary Testosterone (uT) and uFSH increased. In girls, correlations between uFSH and urinary Estradiol (uE) were observed at each time point. Notably, several correlations between hormones and anthropometrics and AGDs were found; the most interesting correlation was found in males within uLH and PL (at T0 ρ: 0.323, p < 0.05 and at T3 ρ: 0.371, p < 0.01), whereas in females uFSH at T0 showed negative correlations with both length and body weight percentile at T3 (ρ: -0.505, p < 0.01 and ρ: -0.478, p < 0.01, respectively)., Conclusion: Urinary matrix has proved to be a valuable, practical, non-invasive and cheaper method for sexual hormone assessment., Competing Interests: Declarations. Conflict of interest: The authors have no conflicts of interest to declare. Ethical approval: All procedures followed have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. This study protocol was reviewed and approved by Comitato Etico Area Vasta Emilia Nord, approval number 715/2018. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Aims: Evaluation of 'alternative' vascularisation in human cancer is considered an important prognostic parameter; the 2022 WHO classification of parathyroid tumours despite progresses in clinical triaging of patients strongly emphasises new histopathological parameters to properly stratify these lesions. 'Alternative' and 'classic' vessels were here investigated for the first time in parathyroid tumours for their possible histopathological and clinical relevance during progression., Methods: Using a double CD31/PAS staining, microvessel density (MVD, 'classic' CD31+ vessels), mosaic vessel density (MoVD, 'alternative' CD31+/-vessels) and vessel mimicry density (VMD, 'alternative' CD31-/PAS+ vessels) were evaluated in 4 normal parathyroid glands (N), 50 Adenomas (A), 35 Atypical Tumours (AT) and 10 Carcinomas (K)., Results: Compared with N, MVD significantly increased in A (p=0.012) and decreased in K (p=0.013) with vessel counts lower than in AT and A (p<0.001). MoVs and VMs, absent in normal tissue, were documented in non-benign parathyroid lesions (AT, K) (p<0.001), with MoVs and VMs most represented in AT and K, respectively (p<0.001), in peripheral growing areas. Vessel distribution was correlated to neoplastic progression (r=-0.541 MVD; r=+0.760 MoVD, r=+0.733 VMD), with MVD decrease in AT and K inversely related to MoVD and VMD increase (r=-0.503 and r=-0.456)., Conclusions: 'Alternative' vessel identification in parathyroid tumours is crucial because it: (1) explains the paradox of non-angiogenic tumours, consisting in a new bloody non-endothelial vessel network and (2) helps pathologists to unmask worrisome lesions. Furthermore, detection of alternative vascular systems in human tumours might explain the limited success of antiangiogenic therapies and encourage new oncological studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The photocatalytic non-oxidative coupling of methane (NOCM) is a highly challenging and sustainable reaction to produce H 2 and C 2+ hydrocarbons under ambient conditions using sunlight. However, there is a lack of knowledge, particularly on how to achieve high photocatalytic yield in continuous-flow reactors. To address this, we have developed a novel flow-through photocatalytic reactor for NOCM as an alternative to the conventionally used batch reactors. Me/TiO 2 photocatalysts, where Me = Au, Ag and Pd, are developed, but only those based on Pd are active. Interestingly, the preparation method significantly impacts performance, going from inactive samples (prepared by wet impregnation) to highly active samples (prepared by strong electrostatic adsorption - SEA). These photocatalysts are deposited on a nanomembrane, and the loading effect, which determines productivity, selectivity, and stability, is also analysed. Transient absorption spectroscopy (TAS) analysis reveals the involvement of holes and photoelectrons after charge separation on Pd/TiO 2 (SEA) and their interaction with methane in ethane formation, reaching a production rate of about 1000 μmol g -1 h -1 and a selectivity of almost 95% after 5 hours of reaction. Stability tests involving 24 h of continuous irradiation are performed, showing changes in productivity and selectivity to ethane, ethylene and CO 2 . The effect of a mild oxidative treatment (80 °C) to extend the catalyst's lifetime is also reported., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A task force of the United Italian society of Endocrine Surgery (SIUEC) was commissioned to review the position statement on diagnostic, therapeutic and health‑care management protocol in parathyroid surgery published in 2014, at the light of new technologies, recent oncological concepts, and tailored approaches. The objective of this publication was to support surgeons with modern rational protocols of treatment that can be shared by health-care professionals, taking into account important clinical, healthcare and therapeutic aspects, as well as potential sequelae and complications. The task force consists of 12 members of the SIUEC highly trained and experienced in thyroid and parathyroid surgery. The main topics concern diagnostic test and localization studies, mode of admission and waiting time, therapeutic pathway (patient preparation for surgery, surgical treatment, postoperative management, management of major complications), hospital discharge and patient information, outpatient care and follow-up, outpatient initial management of patients with pHPT., (© 2024. The Author(s).)

Introduction: Fluoride exposure may have various adverse health effects, including affecting thyroid function and disease risk, but the pattern of such relation is still uncertain., Methods: We systematically searched human studies assessing the relation between fluoride exposure and thyroid function and disease. We compared the highest versus the lowest fluoride category across these studies, and we performed a one-stage dose-response meta-analysis for aggregated data to explore the shape of the association., Results: Most retrieved studies (27 of which with a cross-sectional design) were conducted in Asia and in children, assessing fluoride exposure through its concentrations in drinking water, urine, serum, or dietary intake. Twenty-four studies reported data on thyroid function by measuring thyroid-related hormones in blood (mainly thyroid-stimulating-hormone - TSH), 9 reported data on thyroid disease, and 4 on thyroid volume. By comparing the highest versus the lowest fluoride categories, overall mean TSH difference was 1.05 μIU/mL. Dose-response curve showed no change in TSH concentrations in the lowest water fluoride exposure range, while the hormone levels started to linearly increase around 2.5 mg/L, also dependending on the risk of bias of the included studies. The association between biomarkers of fluoride exposure and TSH was also positive, with little evidence of a threshold. Evidence for an association between fluoride exposure and blood concentrations of thyroid hormones was less evident, though there was an indication of inverse association with triiodothyronine. For thyroid disease, the few available studies suggested a positive association with goiter and with hypothyroidism in both children and adults., Conclusions: Overall, exposure to high-fluoride drinking water appears to non-linearly affect thyroid function and increase TSH release in children, starting above a threshold of exposure, and to increase the risk of some thyroid diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Differentiated thyroid carcinoma (DTC) has an excellent prognosis; however, advanced disease is associated with a worse prognosis and is relatively common. Surgery followed by RAI treatment remains the mainstream treatment for a large majority of patients with high- and intermediate-risk DTC, but its benefits should be carefully weighed against the potential for harm. The aim of this paper is to critically review the experience in treating advanced DTC at two tertiary referral centers in Italy., Methods: Retrospective analysis of 300 patients who underwent surgery for ADTC over 30 years., Results: The complication rate was 50.33%. A total of 135 patients (45%) remained at regular follow-up, 118 (87.4%) were alive, while 17 (12.6%) were deceased. The mean overall survival at 12 years was 84.8% with a mean of 238 months. Eleven patients (8.1%) experienced a relapse after a median of 13 months., Conclusions: ADTC patients adequately treated can achieve prolonged survival even in the case of metastasis or disease relapse. Patients with ADTC should be referred to high-volume centers with the availability of an extended multidisciplinary team to receive tailored treatment.

Background: Parathyroid cancer (PC) is a rare sporadic or hereditary malignancy whose histologic features were redefined with the 2022 WHO classification. A total of 24 Italian institutions designed this multicenter study to specify PC incidence, describe its clinical, functional, and imaging characteristics and improve its differentiation from the atypical parathyroid tumour (APT)., Methods: All relevant information was collected about PC and APT patients treated between 2009 and 2021., Results: Among 8361 parathyroidectomies, 351 patients (mean age 59.0 ± 14.5; F = 210, 59.8%) were divided into the APT (n = 226, 2.8%) and PC group (n = 125, 1.5%). PC showed significantly higher rates ( p < 0.05) of bone involvement, abdominal, and neurological symptoms than APT (48.8% vs. 35.0%, 17.6% vs. 7.1%, 13.6% vs. 5.3%, respectively). Ultrasound (US) diameter >3 cm (30.9% vs. 19.3%, p = 0.049) was significantly more common in the PC. A significantly higher frequency of local recurrences was observed in the PC (8.0% vs. 2.7%, p = 0.022). Mortality due to consequences of cancer or uncontrolled hyperparathyroidism was 3.3%., Conclusions: Symptomatic hyperparathyroidism, high PTH and albumin-corrected serum calcium values, and a US diameter >3 cm may be considered features differentiating PC from APT. 2022 WHO criteria did not impact the diagnosis.

Background: While intraoperative neuromonitoring (IONM) helps the early identification of recurrent laryngeal nerve (RLN) damage, IONM's role in RLN damage prevention is not defined, given the lack of large studies on the subject., Methods: In a PRISMA-compliant framework, all original thyroid surgery prospective studies providing early postoperative endoscopic data for all patients were pooled in a random-effects meta-analysis. We compared the temporary (and definitive where available) RLN damage rates according to IONM use and IONM type (intermittent, I-IONM, or continuous, C-IONM)., Results: We identified 2358 temporary and 257 definitive RLN injuries in, respectively, 73,325 and 66,476 nerves at risk. The pooled temporary and definitive RLN injury rates were, respectively, 3.15% and 0.422% considering all procedures, 3.29% and 0.409% in cases using IONM, and 3.16% and 0.463 in cases not using IONM. I-IONM and C-IONM, respectively, showed a pooled temporary RLN injury rate of 2.48% and 2.913% and a pooled definitive injury rate of 0.395% and 0.4%. All pooled rates had largely overlapping 95% confidence intervals., Conclusions: Our data suggest that IONM does not affect the temporary or definitive RLN injury rate following thyroidectomy, though its use can be advised in selected cases and for bilateral palsy prevention.

A task force of the United Italian society of Endocrine Surgery (SIUEC) was commissioned to review the position statement on diagnostic, therapeutic and health‑care management protocol in thyroid surgery published in 2016, at the light of new technologies, recent oncological concepts, and tailored approaches. The objective of this publication was to support surgeons with modern rational protocols of treatment that can be shared by health-care professionals, taking into account important clinical, healthcare and therapeutic aspects, as well as potential sequelae and complications. The task force consists of 13 members of the SIUEC highly trained and experienced in thyroid surgery. The main topics concern clinical evaluation and preoperative workup, patient preparation for surgery, surgical treatment, non-surgical options, postoperative management, prevention and management of major complications, outpatient care and follow-up., (© 2023. The Author(s).)

Key Clinical Message: Soporous state in acute renal failure represent an atypical presentation of parathyroid cancer. Complete prompt investigations and diagnosis have a fundamental role in the management of this disease., Abstract: This report describes a case of parathyroid carcinoma (PC) with an uncommon first clinical presentation: soporous state, depression, and severe cognitive decline in association with acute renal failure. After discovering extremely high serum calcium and parathyroid hormone (PTH) levels, the diagnosis of primary hyperparathyroidism (pHPT) was made and a surgical en bloc resection was performed. After the surgical intervention, the histological examination revealed the presence of a malignant parathyroid disease, thus confirming our first preoperative suspicion., Competing Interests: The Authors declare that there is no conflict of interest., (© 2023 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours., Methods: In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186., Findings: Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78·6%] female patients and 4922 [21·4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1·4 [IQR 0·6-3·4]) compared with the prepandemic phase (2·0 [0·9-3·7]; p<0·0001) and pandemic decrease phase (2·3 [1·0-5·0]; p<0·0001). Compared with the prepandemic phase, in the pandemic decrease phase we observed an increased occurrence of thyroid tumours larger than 10 mm (2554 [69·0%] of 3704 vs 1515 [71·5%] of 2119; OR 1·1 [95% CI 1·0-1·3]; p=0·042), lymph node metastases (343 [9·3%] vs 264 [12·5%]; OR 1·4 [1·2-1·7]; p=0·0001), and tumours at high risk of structural disease recurrence (203 [5·7%] of 3584 vs 155 [7·7%] of 2006; OR 1·4 [1·1-1·7]; p=0·0039)., Interpretation: Our study suggests that the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic period could have led to an increased occurrence of aggressive thyroid tumours. However, other compelling hypotheses, including increased selection of patients with aggressive malignancies during this period, should be considered. We suggest that surgery for indeterminate thyroid nodules should no longer be postponed even in future instances of pandemic escalation., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Highly ordered TiO 2 nanotube (NT) arrays grown on Ti mesh and Ti foil were successfully prepared by a controlled anodic oxidation process and tested for water photo-electrolysis. Electrochemical impedance spectroscopy (EIS), combined with other electrochemical techniques (cyclic voltammetry and chronoamperometry) in tests performed in the dark and under illumination conditions, was used to correlate the photoactivity to the specific charge transfer resistances associated with a 3D (mesh) or 2D (foil) geometry of the support. The peculiar structure of the nanotubes in the mesh (with better light absorption and faster electron transport along the nanotubes) strongly impacts the catalytic performances under illumination. H 2 production and current density in water photo-electrolysis were over three times higher with the TiO 2 NTs/Ti mesh, compared to the foil in the same conditions. The results obtained by the EIS technique, used here for the first time to directly compare TiO 2 nanotubes on two different supports (Ti foil and Ti mesh), led to a better understanding of the electronic properties of TiO 2 nanotubes and the effect of a specific support on its photocatalytic properties.

Objective: To define the conversion risk to open procedure during robot-assisted thyroid surgery (RATS) identifying potential specific subclasses of procedures or accesses at higher conversion risk., Methods: In a PRISMA-compliant framework, all original prospective studies providing RATS conversion rates from multiple databases were pooled in a random-effects meta-analysis. Conversion rates were compared between different typologies of thyroid surgery and robotic access., Results: 13 studies were deemed eligible. Four conversions from two studies were reported out of 398 procedures. No significant heterogeneity was observed (Cochran's Q p = 0.932; I2 = 0%). The pooled conversion rate was 1% (95% confidence interval, 0.1%-2%). The ANOVA-Q test failed to show significant differences when comparing type of thyroid surgery or robotic access (respectively p = 0.766 and p = 0.457)., Conclusion: While the conversion rate appears consistently low across studies, prospective data collection and systematic reporting of procedural complications are required for framing high-risk procedures and accesses., (© 2022 The Authors. The International Journal of Medical Robotics and Computer Assisted Surgery published by John Wiley & Sons Ltd.)

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) or glutaric aciduria type II is an extremely rare autosomal recessive inborn error of fatty acid beta oxidation and branched-chain amino acids, secondary to mutations in the genes encoding the electron transfer flavoproteins A and B (ETFs; ETFA or ETFB) or ETF dehydrogenase (ETFDH). The clinical manifestation of MADD are heterogeneous, from severe neonatal forms to mild late-onset forms., Case Presentation: We report the case of a preterm newborn who died a few days after birth for a severe picture of untreatable metabolic acidosis. The diagnosis of neonatal onset MADD was suggested on the basis of clinical features displaying congenital abnormalities and confirmed by the results of expanded newborn screening, which arrived the day the newborn died. Molecular genetic test revealed a homozygous indel variant c.606 + 1 &#95;606 + 2insT in the ETFDH gene, localized in a canonical splite site. This variant, segregated from the two heterozygous parents, is not present in the general population frequency database and has never been reported in the literature., Discussion and Conclusion: Recently introduced Expanded Newborn Screening is very important for a timely diagnosis of Inherited Metabolic Disorders like MADD. In some cases which are the most severe, diagnosis may arrive after symptoms are already present or may be the neonate already died. This stress the importance of collecting all possible samples to give parents a proper diagnosis and a genetic counselling for future pregnacies., (© 2022. The Author(s).)

Differentiated thyroid cancers (DTCs) are slow-growing malignant tumours, including papillary and follicular carcinomas. Overall, prognosis is good, although it tends to worsen when local invasion occurs with bulky cervical nodes, or in the case of distant metastases. Surgery represents the main treatment for DTCs. However, radical excision is challenging and significant morbidity and functional loss can follow the treatment of the more advanced forms. Literature on advanced thyroid tumours, both differentiated and undifferentiated, does not provide clear and specific guidelines. This emerges the need for a tailored and multidisciplinary approach. In the present study, we report our single-centre experience of 111 advanced (local, regional, and distant) DTCs, investigating the rate of radical excision, peri-procedural and post-procedural complications, quality of life, persistence, recurrence rates, and survival rates. Results are critically appraised and compared to the existing published evidence review., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bulfamante, Lori, Bellini, Bolis, Lozza, Castellani, Saibene, Pipolo, Fuccillo, Rosso, Felisati and De Pasquale.)

Chronic kidney disease mineral and bone disorder may persist after successful kidney transplantation. Persistent hyperparathyroidism has been identified in up to 80% of patients throughout the first year after kidney transplantation. International guidelines lack strict recommendations about the management of persistent hyperparathyroidism. However, it is associated with adverse graft and patient outcomes, including higher fracture risk and an increased risk of all-cause mortality and allograft loss. Secondary hyperparathyroidism may be treated medically (vitamin D, phosphate binders and calcimimetics) or surgically (parathyroidectomy). Guideline recommendations suggest medical therapy first but do not clarify optimal parathyroid hormone targets or indications and timing of parathyroidectomy. There are no clear guidelines or long-term studies about the impact of hyperparathyroidism therapy. Parathyroidectomy is more effective than medical treatment, although it is associated with increased short-term risks. Ideally parathyroidectomy should be performed before kidney transplantation to prevent persistent hyperparathyroidism and improve graft outcomes. We now propose a roadmap for the management of secondary hyperparathyroidism in patients eligible for kidney transplantation that includes the indications and timing (pre- or post-kidney transplantation) of parathyroidectomy, the evaluation of parathyroid gland size and the integration of parathyroid gland size in the decision-making process by a multidisciplinary team of nephrologists, radiologists and surgeons., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Transient postoperative hypocalcemia is a common complication after total thyroidectomy. Evidence on contributing metabolic factors is contradictory. Our work aims to define the role of preoperative 25-hydroxyvitaminD levels in developing transient postoperative hypocalcemia. 183 consecutive patients who underwent total thyroidectomy at our institution (May 2017-December 2019) were included in the retrospective study. We reported gender, age, estimated glomerular filtration rate, creatinine, preoperative 25-hydroxyvitaminD, serum pre- and postoperative calcium, pre- and postoperative PTH levels and transient postoperative hypocalcemia occurrences. We compared variables both among patients with and without transient postoperative hypocalcemia and between patients with different 25-hydroxyvitaminD levels (< 10 ng/ml deficitary; 11-30 ng/ml insufficient; > 30 ng/ml, normal). A binomial logistic regression model evaluating the risk for transient postoperative hypocalcemia was elaborated. Patients with transient postoperative hypocalcemia had lower levels of postoperative PTH (p < 0.001) and more frequently normal or deficitary 25-hydroxyvitaminD levels (p = 0.05). When comparing patients according to their 25-hydroxyvitaminD levels, insufficiency was associated with a lower rate of transient postoperative hypocalcemia (p = 0.05); deficiency was associated with higher preoperative PTH (p = 0.021), postoperative PTH (p = 0.043) and estimated glomerular filtration rate (p = 0.031) and lower serum creatinine (p = 0.014). In the regression model higher preoperative PTH (OR = 1.011, p = 0.041) and 25-hydroxyvitaminD deficiency (OR = 0.343, p = 0.011) significantly predicted transient postoperative hypocalcemia. Data analysis revealed a correlation between transient postoperative hypocalcemia and 25-hydroxyvitaminD levels: our work points towards the possibility to stratify the risk of transient postoperative hypocalcemia according to patients' preoperative 25-hydroxyvitaminD status., (© 2021. The Author(s).)

Background: The main challenge for treating primary hyperparathyroidism (PHPT) is to understand if it is caused by a single adenoma (80-85% of the cases) or by a multiglandular disease (15-20%), both preoperatively and intraoperatively. For this reason, some preoperative scores were proposed in the literature, to perform focused parathyroidectomy, avoiding intraoperative parathormone assay (ioPTH). The most known are the CaPTHUS test and the Wisconsin index. We applied them to our experience., Methods: A retrospective cohort study on 462 patients referred for parathyroidectomy to Thyroid and Parathyroid Unit at Santi Paolo e Carlo Hospital, Milan, Italy, from 2011 to 2021. Only patients affected with benign PHPT and neck ultrasound performed at our institution were included. Both patients for whom preoperative imaging agreed with the localization of a single diseased parathyroid and those with only ultrasound or scintigraphy positive for parathyroid localization underwent Mini-Invasive Video-assisted parathyroidectomy. In all cases, ioPTH assay was performed. The conversion to bilateral neck exploration was decided based on the drop in ioPTH. CaPTHUS score and the Wisconsin index (Win) were applied to the series. CaPTHUS score ≥3 and Win index >1600, according to the original studies of the literature, were considered at high probability of monoglandular disease. Outcomes in these two groups were examined., Results: 236 patients were eligible for the study. The pathology resulted in multiglandular disease in 24 patients (10.2%). Among these, 18 (75.0%) obtained a CaPTHUS score ≥3, and 20 (83.3%) had a Win index>1600. Intraoperative PTH allowed to identify multiglandular disease in 16 of 18 cases with CaPTHUS ≥3 and in 18 of 20 cases with win >1600, who could have been lost, based only on the results of these 2 tests., Conclusion: Based on our experience, CaPTHUS test and Wisconsin index were not so useful in predicting multiglandular disease as ioPTH., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2021 Loredana De Pasquale et al.)

Background: Parathyroid carcinoma (PC) is the rarest endocrine cancer and an infrequent cause of primary hyperparathyroidism (PHPT), responsible for less than 1% of cases. Due to its rarity, treatment is challenging., Methods: A retrospective cohort study on 462 patients referred for parathyroidectomy to Thyroid and Parathyroid Unit at Santi Paolo e Carlo Hospital, Milan, Italy, from 2011 to 2021. We identified and individually described the patients affected with PC. Then, we split all patients treated for PHPT into four groups based on the cause: PC, adenoma, atypical adenoma, and hyperplasia. Patients' demographics, preoperative evaluation results, intraoperative findings, and outcomes for the PC group were compared with groups of PHPT due to benign causes., Results: Eight cases of PC were identified, five males and three females. Seven cases presented with symptoms of hypercalcemia and one with a neck mass. Five underwent en bloc resections and three local excisions. Histopathological features showed capsular invasion in four patients, capsular and soft tissue invasion in three patients, and vascular invasion in one case. No patients had distant metastasis. One patient was classed as high risk based on the Schulte classification system. All patients treated for PC were alive and disease-free at a mean follow-up of 38.4 months. When compared with other PHPT patients, PC patients were more frequently male and had higher preoperative blood calcium and PTH and lower phosphate levels, larger and heavier parathyroids excised, lower postoperative calcium, and a higher rate of postoperative hypoparathyroidism., Conclusion: Our study highlights some aspects valuable to suspect PC and differentiate PHPT-PC from benign causes of PHPT preoperatively. Preoperative suspicion of malignancy is essential to guarantee the best course of treatment for patients. Although limited for size and follow-up, the excellent outcome of our series seems to support the value of both surgery extension and risk class according to the Schulte classification as possible prognostic factors for recurrence., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2021 Loredana De Pasquale et al.)

The surgical treatment of the intermediate-risk DTC (1-4 cm) remains still controversial. We analyzed the current practice in Italy regarding the surgical management of intermediate-risk unilateral DTC to evaluate risk factors for recurrence and to identify a group of patients to whom propose a total thyroidectomy (TT) vs. hemithyroidectomy (HT). Among 1896 patients operated for thyroid cancer between January 2017 and December 2019, we evaluated 564 (29.7%) patients with unilateral intermediate-risk DTC (1-4 cm) without contralateral nodular lesions on the preoperative exams, chronic autoimmune thyroiditis, familiarity or radiance exposure. Data were collected retrospectively from the clinical register from 16 referral centers. The patients were followed for at least 14 months (median time 29.21 months). In our cohort 499 patients (88.4%) underwent total thyroidectomy whereas 65 patients (11.6%) underwent hemithyroidectomy. 151 (26.8%) patients had a multifocal DTC of whom 57 (10.1%) were bilateral. 21/66 (32.3%) patients were reoperated within 2 months from the first intervention (completion thyroidectomy). Three patients (3/564) developed regional lymph node recurrence 2 years after surgery and required a lymph nodal neck dissection. The single factor related to the risk of reoperation was the histological diameter (HR = 1.05 (1.00-1-09), p = 0.026). Risk stratification is the key to differentiating treatment options and achieving better outcomes. According to the present study, tumor diameter is a strong predictive risk factor to proper choose initial surgical management for intermediate-risk DTC., (© 2021. Italian Society of Surgery (SIC).)

The outbreak of the COVID-19 pandemic has led to a disruption of surgical care. The aim of this multi-centric, retrospective study was to evaluate the impact of the pandemic on surgical activity for thyroid disease among the Italian Units of Endocrine Surgery. Three phases of the pandemic were identified based on the epidemiological situation and the public measures adopted from the Italian Government (1st phase: from 9th March to 3rd May 2020; 2nd phase: from 4th May to 14th June; 3rd phase: from 15th June to 31st). The patients operated upon during these phases were compared to those who underwent surgery during the same period of the previous year. Overall, 3892 patients from 28 Italian endocrine surgical units were included in the study, 1478 (38%) operated upon during COVID-19 pandemic, and 2414 (62%) during the corresponding period of 2019. The decrease in the number of operations was by 64.8%, 44.7% and 5.1% during the three phases of COVID-19 pandemic, compared to 2019, respectively. During the first and the second phases, the surgical activity was dedicated mainly to oncological patients. No differences in post-operative complications were noted between the two periods. Oncological activity for thyroid cancer was adequately maintained during the COVID-19 pandemic., (© 2021. The Author(s).)

Objectives: This study aims to evaluate the diagnostic accuracy of the VECTOR software in patients with connective tissue diseases (CTDs), compared with the reference standard of high-resolution computed tomography (HRCT)., Patients and Methods: The study included 98 consecutive patients of CTD (24 males, 74 females; median age 66 years; range, 24 to 85 years) with a recent HRCT. Patients were evaluated in a blindly manner by VECTOR and the results obtained by the algorithm were compared with the presence of interstitial lung disease (ILD) according to HRCT., Results: Interstitial lung disease was detected in 42.8% of subjects. VECTOR correctly classified 81/98 patients, with a diagnostic accuracy of 82.6%; sensitivity and specificity were 88.1% and 78.6%, respectively. Only 5/42 patients with ILD were not correctly classified by VECTOR, while false positive cases were 21.4%. No significant differences were observed according to the radiologic pattern of ILD., Conclusion: VECTOR showed high sensitivity, specificity and diagnostic accuracy, allowing selecting patients to be investigated with HRCT. The relatively high frequency rate of false positive results is acceptable if compared with the lack of effective screening methods for this complication of CTDs., Competing Interests: Conflict of Interest: The authors declared no conflicts of interest with respect to the authorship and/or publication of this article., (Copyright © 2020, Turkish League Against Rheumatism.)

We report the case of a woman with primary hyperparathyroidism suspected of mediastinal ectopic parathyroid adenoma revealed to be a thymoma. Our aim was to focus on some possible criticisms in distinguishing between ectopic parathyroid and thymus., Competing Interests: None declared., (© 2020 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background and Objective: Recently the term "interstitial pneumonia with autoimmune features" (IPAF) has been proposed to identify patients with interstitial lung disease and autoimmune characteristics, not fulfilling the criteria for specific connective tissue diseases (CTD). Only few data are available about the clinical and serological features of IPAF patients, their survival and the possible evolution in a CTD. The aims of the study were to investigate the demographic and clinico-serologic features of patients with IPAF, their relationship to survival, and the possible evolution in a definite CTD., Patients and Methods: Fifty-two patients were consecutively enrolled and prospectively followed for 45 ± 31.6 months. Data about disease onset, serological, clinical and therapeutic features, pulmonary function tests and high-resolution computed tomography were periodically repeated. The survival of patients with IPAF was compared with that of 104 patients with idiopathic pulmonary fibrosis (IPF)., Results: The clinical domain for IPAF was satisfied in 44 patients, serological domain in 49 and the morphological domain in 29 patients. During the follow-up, a definite CTD was diagnosed in 7 patients, in particular Sjogren's syndrome in 4 patients, rheumatoid arthritis in 2, and polymyositis in the last. The estimated 5-year survival of IPAF patients 69.5 ± 7.8%, significantly higher than survival observed in IPF patients, and the baseline value of FVC and DLCO were the only factors associated to death., Conclusions: IPAF seems to a distinct entity, with a low tendency to evolve in a definite CTD. Nevertheless, further studies are needed to better define the clinical evolution and the outcome of IPAF., (Copyright © 2019. Published by Elsevier B.V.)

Background: Narrow-band imaging uses selective haemoglobin light absorption to emphasise vascular visualisation and capillary networks., Objective: This study aimed to evaluate the application of this technique to parathyroid surgery., Method: This preliminary evaluation was carried out on five consecutive patients with single parathyroid adenoma being considered for minimally invasive video-assisted parathyroidectomy. The adenomas were checked for narrow-band imaging vascular patterns. Minimally invasive video-assisted parathyroidectomy was then carried out in accordance with our standard protocol., Results: In four out of the five cases, narrow-band imaging integrated the white endoscopic light and direct vision, but in one case narrow-band imaging allowed distinction between the hidden neoplastic tissue and the surrounding structures thanks to the different vascular patterns., Conclusion: Narrow-band imaging was helpful in properly identifying adenoma. It is suggested that this technique be considered as a means for surgeons to improve their confidence in selected surgical treatments and to improve treatment quality.

Background: Cutaneous lesions are common in the neonatal period and usually physiological, transient and self-limited; infrequently, they are pathological and require treatment and collaboration between dermatologists and neonatologists. Particular conditions, like prematurity, can influence onset, type and evolution of cutaneous manifestations. Of the several articles in literature about skin findings in newborns, only few were performed in Southern European countries. We aimed to investigate dermatological findings in a sample of neonates within the first 7 days of life and to evaluate the association between skin lesions and neonatal, parental or pregnancy-related variables., Methods: A total of 259 newborns, hospitalized in the Department of Pediatrics and Neonatal Intensive Care Unit, Barone Romeo Hospital, Patti (Messina), Italy, during a six months period, were examined. All skin findings were recorded and information on neonatal, parental and pregnancy-related variables was collected and analyzed to detect statistically significant associations., Results: Skin lesions were present in 181 newborns (69.88%). Their frequency was significantly higher in those born to primigravida mothers (P=0.024). Erythema toxicum neonatorum prevalence was significantly higher (P=0.006) in term newborns., Conclusions: Skin findings are frequent in newborns and often cause concern in parents and physicians without specific experience. Thus, it is important to know and identify them promptly to avoid unnecessary diagnostic and therapeutic procedures.

Purpose: Intraoperative PTH testing (IOPTH) in treatment of primary hyperparathyroidism (PH) is debated. Some authors advise against IOPTH in patients with concordant preoperative imaging undergoing focused parathyroidectomy. This study aims to compare focused parathyroidectomy success rates with and without IOPTH in patients with concordant preoperative imaging., Methods: Retrospective cohort study involving 599 consecutive patients underwent surgery for PH from 2012 to 2017. Patients with discordant preoperative imaging were excluded. 426 patients underwent focused parathyroidectomy (214 patients without IOPTH and 212 with IOPTH) and were considered for the statistical analysis. In case of insufficient IOPTH decay (less than 50%), a bilateral exploration was carried out., Results: The IOPTH group and the non-IOPTH group were similar for demographics and preoperative PTH and calcaemia. 413 patients were cured and disease persistence rates between groups were not significantly different (p > 0.05)., Conclusions: Although further testing and randomized-controlled trials are required to validate our findings, our data show that IOPTH does not seem to improve the outcome in patients with concordant preoperative imaging undergoing focused parathyroidectomy.

Background: Thyroid nodules are a fairly common finding in general population and, even if most of them are benign, a treatment can be however necessary. In the last years, non surgical minimally invasive techniques have been developed to treat this pathology, starting from percutaneous ethanol injection (PEI), to laser ablation (LA), radiofrequency ablation (RFA) and, most recently, microwave ablation (MWA)., Methods: We reviewed all medical literature searching in pubmed.gov the terms "microwave" & "thyroid". We found three original studies concerning MWA treatment, for a total of 263 patients (mean age 51.0 years; range, 15-80 years; male to female ratio 2.55) and 522 nodules., Results: A total of 522 nodules (338 solid, 22 cystic, 162 mixed) in 263 patients were treated. Studies have shown a mean reduction in volume of thyroid nodules ranging from 45.9% to 65%. No study reported a significant and definitive change in laboratory parameters, except for one case (Heck et al. ). No studies have reported major complications after procedure., Conclusions: MWA is a new, promising technique among the minimally invasive treatments of thyroid nodules. Actually, the larger diameter of MW antenna seems to be the major limiting factor in the use of this technique. More studies are necessary to evaluate feasibility, safety and efficacy of the procedure., Competing Interests: The authors have no conflicts of interest to declare.

A 46-year-old man was referred to our ear, nose and throat department after the accidental discovery of a large retrotracheal mass. In order to obtain the diagnosis and to plan treatment he underwent a full battery of tests (CT, MRI, blood tests, hormonal assays, ultrasounds, thyroid scintigraphy, urine tests and fine-needle aspiration of the mass), but none of these was able to define the true nature of such cervical mass. Only after surgical excision and histological evaluation, it was diagnosed as an exceptional case of giant non-functional parathyroid adenoma., (2016 BMJ Publishing Group Ltd.)

Purpose: The diagnostic, therapeutic and health-care management protocol (Protocollo Gestionale Diagnostico-Terapeutico-Assistenziale, PDTA) by the Association of the Italian Endocrine Surgery Units (U.E.C. CLUB) aims to help treat the patient in a topical, rational way that can be shared by health-care professionals., Methods: This fourth consensus conference involved: a selected group of experts in the preliminary phase; all members, via e-mail, in the elaboration phase; all the participants of the XI National Congress of the U.E.C. CLUB held in Naples in the final phase. The following were examined: diagnostic pathway and clinical evaluation; mode of admission and waiting time; therapeutic pathway (patient preparation for surgery, surgical treatment, postoperative management, management of major complications); hospital discharge and patient information; outpatient care and follow-up., Results: A clear and concise style was adopted to illustrate the reasons and scientific rationales behind behaviors and to provide health-care professionals with a guide as complete as possible on who, when, how and why to act. The protocol is meant to help the surgeon to treat the patient in a topical, rational way that can be shared by health-care professionals, but without influencing in any way the physician-patient relationship, which is based on trust and clinical judgment in each individual case., Conclusions: The PDTA in thyroid surgery approved by the fourth consensus conference (June 2015) is the official PDTA of U.E.C. CLUB.

Purpose: Hypoparathyroidism is one of the most common and most feared complications of total thyroidectomy (TT). The aim of this study is to detect possible markers that may facilitate early tracing of hypocalcaemia-prone patients in order to reduce clinical cost by optimizing patient discharge and to avoid unnecessary treatment., Methods: Over an 18-month period, 995 patients, 23 % male and 77 % female, aged 52.9 ± 13.4 years, underwent TT in ten Lombardy hospitals. The following parameters were analyzed: calcaemia before and 12-24 and 48 h after surgery, pre- and post-operative parathyroid hormone (PTH) at 24 h and pre-operative 25OH vitamin D., Results: Mortality was nil and morbidity was 22.4 %. Mean 24-h calcaemia and PTH were 2.17 ± 0.15 mmol/l and 31.81 ± 20.35 pg/ml, respectively; mean 24-h PTH decay was 36.7 ± 34.12 %. Four hundred seventy-three (47.5 %) patients were hypocalcaemic at discharge; 142 of whom had transient hypoparathyroidism that became permanent in 27. Patients developing hypocalcaemia had significantly higher values of PTH and calcium decay. At multiple logistic regression, only 24-h calcium decay, PTH drop and the presence of symptoms and parathyroid auto-grafting were significantly related to hypoparathyroidism. The association of these factors had a 99.2 % negative predictive value (NPV) for the development of hypoparathyroidism. A 70 % PTH drop had a 93.75 NPV for transient hypoparathyroidism. A 12 % calcaemia decay had a 95.7 NPV for hypoparathyroidism., Conclusions: Hypocalcaemic asymptomatic patients with less than 70 % PTH and 12 % calcaemia decay may be safely discharged without treatment. Symptomatic patients and those with parathyroid grafting should receive calcium and vitamin D.

The anti-inflammatory agents glucocorticoids (GC) are the only available treatment for Duchenne muscular dystrophy (DMD). However, long-term GC treatment causes muscle atrophy and wasting. Thus, targeting specific mediator of inflammatory response may be more specific, more efficacious, and with fewer side effects. The pro-inflammatory cytokine interleukin (IL) 6 is overproduced in patients with DMD and in the muscle of mdx, the animal model for human DMD. We tested the ability of inhibition of IL6 activity, using an interleukin-6 receptor (Il6r) neutralizing antibody, to ameliorate the dystrophic phenotype. Blockade of endogenous Il6r conferred on dystrophic muscle resistance to degeneration and alleviated both morphological and functional consequences of the primary genetic defect. Pharmacological inhibition of IL6 activity leaded to changes in the dystrophic muscle environment, favoring anti-inflammatory responses and improvement in muscle repair. This resulted in a functional homeostatic maintenance of dystrophic muscle. These data provide an alternative pharmacological strategy for treatment of DMD and circumvent the major problems associated with conventional therapy.

Unlabelled: Multidisciplinary approach to follicular thyroid carcinoma with giant mandibular and multiple sites metastases. Case report Metastatic tumors generally have poor prognosis, with short survival period and rarely indication to surgical treatment. In case of thyroid-differentiated cancer with distant metastases, prognosis is usually better, because of the possibility of treating metastasis by Radio Ablation by 131Iodine, after surgery. We report the case of a 65 years old woman, presenting with a giant mandibular metastasis from follicular thyroid carcinoma, originating from a cervico-mediastinal nonfunctioning goiter, with lung metastases. After the diagnostic work-up, she underwent left hemi-mandibulectomy, reconstruction by the placement of a precustomized titanium plate with condylar prosthesis and total thyroidectomy. Subsequently the Patient was treated by Radio Ablation by 131 Iodine, in four consecutive sessions. She is alive with no progression of the neoplasm after forty-six months follow-up. Even in advanced differentiated thyroid carcinoma, surgery should be taken into consideration, to treat the patient by complementary therapies and to improve the prognosis in term of survival., Key Words: Advanced differentiated thyroid carcinoma, Metastatic differentiated thyroid carcinoma.

Context: Calcitonin (CT) measurement is crucial to the early diagnosis and the follow-up of medullary thyroid cancer (MTC). If the evaluation of stimulated CT levels is required, a provocative test can be performed, being the high-dose Ca test recently reintroduced in clinical practice., Objective: Our objective was to identify gender-specific thresholds for MTC diagnosis in a large series of patients who underwent the Ca test., Patients and Methods: A total of 91 patients (49 females and 42 males) underwent the Ca test (calcium gluconate, 25 mg/kg) before thyroidectomy and both basal CT (bCT) and stimulated CT (sCT) were compared with histological results by receiver operating characteristic plot analyses. To evaluate possible side effects of Ca administration, cardiac function has been extensively studied., Results: bCT levels were found to harbor the same accuracy as sCT in the preoperative diagnosis of MTC. The best Ca thresholds for the identification of MTC were >26 and >68 for bCT and >79 and >544 pg/mL for sCT in females and males, respectively. The high tolerability and safety of the Ca test was demonstrated and advice offered to be followed before and during the test., Conclusions: Gender-specific bCT and sCT cutoffs for the identification of C-cell hyperplasia and/or MTC have been defined. The bCT and sCT were found to have a similar accuracy, indicating that serum CT assays with improved functional sensitivity may likely decrease the relevance of the stimulation test in several conditions. Finally, systematic cardiac monitoring confirms the safety of the Ca test.

Nerve growth factor (NGF) levels are highly increased in inflamed tissues, but their role is unclear. We show that NGF is part of a regulatory loop in monocytes: inflammatory stimuli, while activating a proinflammatory response through TLRs, upregulate the expression of the NGF receptor TrkA. In turn, NGF, by binding to TrkA, interferes with TLR responses. In TLR-activated monocytes, NGF reduces inflammatory cytokine production (IL-1β, TNF-α, IL-6, and IL-8) while inducing the release of anti-inflammatory mediators (IL-10 and IL-1 receptor antagonist). NGF binding to TrkA affects TLR signaling, favoring pathways that mediate inhibition of inflammatory responses: it increases Akt phosphorylation, inhibits glycogen synthase kinase 3 activity, reduces IκB phosphorylation and p65 NF-κB translocation, and increases nuclear p50 NF-κB binding activity. Use of TrkA inhibitors in TLR-activated monocytes abolishes the effects of NGF on the activation of anti-inflammatory signaling pathways, thus increasing NF-κB pathway activation and inflammatory cytokine production while reducing IL-10 production. PBMC and mononuclear cells obtained from the synovial fluid of patients with juvenile idiopathic arthritis show marked downregulation of TrkA expression. In ex vivo experiments, the addition of NGF to LPS-activated juvenile idiopathic arthritis to both mononuclear cells from synovial fluid and PBMC fails to reduce the production of IL-6 that, in contrast, is observed in healthy donors. This suggests that defective TrkA expression may facilitate proinflammatory mechanisms, contributing to chronic tissue inflammation and damage. In conclusion, this study identifies a novel regulatory mechanism of inflammatory responses through NGF and its receptor TrkA, for which abnormality may have pathogenic implications for chronic inflammatory diseases.

Aim: To optimize thyroid microcarcinoma approach, through a retrospective examination of Authors' experience and literature review., Materials: Characteristics, treatment and outcomes of patients affected with thyroid microcarcinoma were examined: among 1733 patients operated on for thyroid diseases at Endocrine Surgery Unit of San Paolo Hospital in Milan, from 2001 to 2011, 104 (6.0%) resulted affected with microcarcinoma. Twenty (19.2%) had pre-operative and 84 (80.8%) post-operative diagnosis, 11 with (N+) and 93 without (N0) lymph node metastasis. Eighty-five patients underwent total thyroidectomy, 11 (N+) total thyroidectomy with lymphoadenectomy and 8 lobectomy, 2 radicalized in thyroidectomy. All patients underwent Levo-thyroxine suppressive therapy, 25 (24.0%) 131I ablation. Differences between N0 and N+ patients were researched., Results: Neither recurrences nor death at a mean follow-up of 5.6 years. Tumour was multifocal and in thyroid with no other diseases in N+, in a greater rate than in N0 patients., Discussion: Microcarcinoma generally has an indolent course, but sometimes it presents with nodal metastasis. For this reason its treatment in literature is still largely debated., Conclusion: In cases of pre-operative diagnosis of microcarcinoma without lymph node metastasis, we propose total thyroidectomy; otherwise, total thyroidectomy with lymphoadenectomy. In cases of post-operative diagnosis, after a partial resection, only selected cases on the basis of patients' and tumour features require a completion total thyroidectomy. We propose Levo-thyroxine suppressive therapy to all patients, 131I ablation in cases of lymphatic metastasis and only in selected cases without metastasis, on the basis of patients' and tumour aspects (age, sex, histological variant, multifocality).

This study was conducted to evaluate whether ultrasound characteristics of thyroid nodules with a known cytologic diagnosis of "follicular pattern" (indicative of follicular hyperplasia, follicular adenoma or follicular carcinoma) can be used to define a nodule malignancy score to limit surgery to selected, higher-risk cases. In pre-operative ultrasound results of patients diagnosed with a "follicular pattern" on cytology who subsequently underwent surgery, each nodule feature was given a score from 0 (most likely benign) to 2 (most likely malignant), resulting in a total score ranging from 0 to 11. The total nodule score (total malignancy score) was then compared with the definitive histologic diagnosis. According to our results, surgery is advisable in patients with score ≥4 (79% of carcinomas), ultrasound follow-up seems to be appropriate for patients with a score of 3 (21% of carcinomas) and no action is recommended for patients with score <3 (only benign nodules)., (Copyright © 2013 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

X-linked adrenoleukodystrophy is a rare inherited demyelinating disorder characterized by an abnormal accumulation of very long chain fatty acids, mainly hexacosanoic acid (26:0), due to a mutation of the gene encoding for a peroxisomal membrane protein. The only available, and partially effective, therapeutic treatment consists of dietary intake of a 4:1 mixture of triolein and trierucin, called Lorenzo's oil (LO), targeted to inhibit the elongation of docosanoic acid (22:0) to 26:0. In this study we tested whether, besides inhibiting elongation, an enhancement of peroxisomal beta oxidation induced by conjugated linoleic acid (CLA), will improve somatosensory evoked potentials and modify inflammatory markers in adrenoleukodystrophy females carriers. We enrolled five heterozygous women. They received a mixture of LO (40 g/day) with CLA (5 g/day) for 2 months. The therapeutic efficacy was evaluated by the means of plasma levels of 26:0, 26:0/22:0 ratio, modification of cerebrospinal fluid (CSF) inflammatory markers and somatosensory evoked potentials. Changes of fatty acid profile, and in particular CLA incorporation, were also evaluated in CSF and plasma. The results showed that CLA promptly passes the blood brain barrier and the mixture was able to lower both 26:0 and 26:0/22:0 ratio in plasma. The mixture improved somatosensory evoked potentials, which were previously found unchanged or worsened with dietary LO alone, and reduced IL-6 levels in CSF in three out of five patients. Our data suggest that the synergic activity of CLA and LO, by enhancing peroxisomal beta-oxidation and preventing 26:0 formation, improves the somatosensory evoked potentials and reduces neuroinflammation.

Objective: To investigate whether prolonged exposure to interleukin-6 (IL-6) affects the inflammatory response induced by Toll-like receptor (TLR) ligands., Methods: IL-6-transgenic mice and wild-type mice were stimulated with different TLR ligands; survival rates, blood cell counts, and biochemical parameters were analyzed. Murine splenic mononuclear cells and peritoneal macrophages were stimulated with lipopolysaccharide (LPS), lipoteichoic acid, poly(I-C), or CpG. Human macrophages were cultured for 4 days in the presence of IL-6 and then stimulated with LPS. Inflammatory cytokine expression was measured by enzyme-linked immunosorbent assay or reverse transcription-polymerase chain reaction. Activation of STAT-3, ERK-1/2 (MAPK), and p65 NF-κB was evaluated by Western blotting or confocal analysis., Results: Treatment of IL-6-transgenic mice with TLR ligands led to an increased fatality rate and elevated levels of IL-1β, tumor necrosis factor α (TNFα), IL-6, and IL-18. Macrophages from IL-6-transgenic mice produced increased levels of inflammatory cytokines, which were associated with increased phosphorylation of STAT-3 and ERK-1/2 and with increased NF-κB nuclear translocation. Human macrophages treated with IL-6 and then stimulated with LPS showed elevated levels of cytokines and similarly elevated signaling pathway activation. After LPS administration, IL-6-transgenic mice showed an increase in ferritin and soluble CD25 levels, as well as a decrease in platelet and neutrophil counts and in hemoglobin levels compared to wild-type mice., Conclusion: Our findings indicate that prolonged exposure to IL-6 in vivo and in vitro leads to an exaggerated inflammatory response to TLR ligands. Hematologic and biochemical abnormalities in IL-6-transgenic mice treated with LPS show striking similarities to macrophage activation syndrome., (Copyright © 2012 by the American College of Rheumatology.)

Objectives: Duchenne muscular dystrophy (DMD) is a degenerative muscle wasting disease caused by mutations in the dystrophin gene. Dystrophic muscle is characterized by chronic inflammation, and inflammatory mediators could be promising targets for innovative therapeutic interventions. We analyzed muscle biopsy samples of DMD-affected children to characterize interleukin (IL)-17 and Forkhead box P3 (Foxp3) expression levels and to identify possible correlations with clinical status., Methods: Expression levels of IL-17, Foxp3, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), IL-6, and transforming growth factor-β (TGF-β) were analyzed by real-time PCR in muscle biopsy samples from patients with DMD (n = 27) and juvenile dermatomyositis (JDM) (n = 8). Motor outcome of patients with DMD was evaluated by North Star Ambulatory Assessment score., Results: In DMD, we found higher levels of IL-17 and lower levels of Foxp3 mRNA compared with those for a typical inflammatory myopathy, JDM. Moreover, the IL-17/Foxp3 ratio was higher in DMD than in JDM biopsy samples. IL-17 mRNA levels appeared to be related to the expression levels of other proinflammatory cytokines (TNF-α and MCP-1) and significantly associated with clinical outcome of patients., Conclusions: The association of IL-17 expression with levels of other inflammatory cytokines and with the clinical course of DMD suggests a possible pathogenic role of IL-17.

Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro-computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-βA, and TGFβ2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients., (Copyright © 2011 American Society for Bone and Mineral Research.)

Purpose: The purpose of our study was to assess the role of ultrasonography (US) before surgical treatment of primary hyperparathyroidism., Materials and Methods: We retrospectively evaluated 77 patients (60 women, 17 men; mean age 59 years) with primary hyperparathyroidism who underwent parathyroid US prior to surgery. Sixty-five of 77 (84%) patients had undergone (99m)Tc- sestamibi (MIBI) scintigraphy. The results were correlated with the surgical and histopathological findings., Results: Surgery revealed 85 abnormal parathyroid glands in 77 patients (70 adenomas, 15 hyperplasias). The locations of the parathyroid glands were typical cervical (n=77), thyrothymic ligament (n=3), carotid sheath (n=2), and mediastinum (n=3). In two patients, intrathyroid microadenoma was diagnosed by histopathology. Seventy-four enlarged glands in 64 patients were correctly identified at US. Per-patient sensitivity and positive predictive values, respectively, were 84% (64/76) and 99% (64/65) for US, 68% (44/65) and 100% (44/44) for scintigraphy and 91% (59/65) and 98% (59/60) for both techniques combined. We weighed 63 out of 85 glands, obtaining a value of 1,004+/-1,564 mg; 460 mg (mean+/-standard deviation; median)., Conclusions: Preoperative detection and localisation of enlarged parathyroid glands can be based on US, an inexpensive and widely available method, limiting the use of scintigraphy to those cases with negative and/or doubtful findings on US.

Background: Intra-operative PTH testing in the operating theatre has proven to be an accurate way to verify the removal of all pathological parathyroid tissue in primary hyperparathyroidism. Its limitation is the high cost. An alternative, more cost-effective procedure is proposed: intra-operative PTH dosage at the Central Laboratory., Patients and Methods: Fifty-four patients underwent parathyroidectomy with intraoperative dosage of PTH at the Central Laboratory. Three blood samples were taken from each patient: just after the induction of anesthesia, 5 and 10 min after parathyroidectomy. The samples were sent to the Central Laboratory and analysed simultaneously. The results were phoned back to the theatre. The procedure was considered effective when PTH drop was >/=50% from basal value, 10 min after parathyroidectomy., Results: 98.1% of patients proved recovered (average follow- up 31.1 months). The procedure had 3 false negatives, 1 false positive, with sensitivity, specificity, accuracy, positive predictive value and negative predictive value of 94.0%, 75.0%, 92.6%, 97.9%, and 50.0%, respectively., Discussion and Conclusion: The main disadvantage of the presented procedure is the long waiting time. Nevertheless this time is the same as that required for results from intra-operative histological examination, the only alternative to determine surgery effectiveness in centres where portable instrumentation for intra-operative PTH dosage in the operating theatre is not available. The advantage of intra-operative PTH at the Central Laboratory is the very low cost. If results in terms of sensitivity, specificity, accuracy, and cost are taken into consideration, intra-operative dosage of PTH at the Central Laboratory may be deemed a viable alternative to the operating theatre.

Subcutaneous fat necrosis of the newborn is an uncommon, self-limiting panniculitis that usually occurs in full-term infants as a consequence of perinatal asphyxia. The cutaneous involvement may be associated with metabolic complications such as hypoglycaemia, thrombocytopenia, hypertriglyceridemia, anemia and hypercalcaemia. The delayed onset of hypercalcaemia, 1-6 months after the development of the skin manifestations, imposes a prolonged follow-up to avoid its acute toxic effects on cardiovascular and renal systems and the more durable metastatic calcifications.

We report the simultaneous occurrence of medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC), presenting as spatially distinct and well-defined tumour components, in three cases. In the first patient, histology, immunohistochemistry and electron microscopy demonstrated an MTC in the one nodule and PTC in two additional lesions. Non-neoplastic thyroid parenchyma separated the three nodules. Metastasis from PTC was diagnosed in a regional lymph node. Genetic analysis of both tumour components showed a distinctive mutational pattern: in the MTC a Cys634Arg substitution in exon 11 of the RET gene and in the two PTC foci a Val600Glu substitution in exon 15 of the BRAF gene. The other two patients are members of a large multigenerational family affected with familial MTC due to a germline mutation of the RET gene (Ala891Ser). Both patients harboured, besides medullary cancer and C-cell hyperplasia, distinct foci of papillary thyroid cancer, which was positive for Val600Glu BRAF mutation. Review of the literature disclosed 18 similar lesions reported and allowed the identification of different patterns of clinical presentation and biological behaviour. So far, the pathogenesis of these peculiar cases of thyroid malignancy has been completely unknown, but an underlying common genetic drive has been hypothesised. This is the first report in which two mutations, in the RET and BRAF genes, have been identified in three cases of MTC/PTC collision tumour, thus documenting the different genetic origin of these two coexisting carcinomas.