Search

TNF-related apoptosis-inducing ligand (TRAIL) is a protein that induces apoptosis in cancer cells but not in normal ones, where its effects remain to be fully understood. Previous studies have shown that in high-fat diet (HFD)-fed mice, TRAIL treatment reduced body weight gain, insulin resistance, and inflammation. TRAIL was also able to increase skeletal muscle free fatty acid oxidation. The aim of the present work was to evaluate TRAIL actions on skeletal muscle. Our in vitro data on C2C12 cells showed that TRAIL treatment significantly increased myogenin and MyHC and other hallmarks of myogenic differentiation, which were reduced by Dr5 (TRAIL receptor) silencing. In addition, TRAIL treatment significantly increased AKT phosphorylation, which was reduced by Dr5 silencing, as well as glucose uptake (alone and in combination with insulin). Our in vivo data showed that TRAIL increased myofiber size in HFD-fed mice as well as in db/db mice. This was associated with increased myogenin and PCG1α expression. In conclusion, TRAIL/DR5 pathway promotes AKT phosphorylation, skeletal muscle differentiation, and glucose uptake. These data shed light onto a pathway that might hold therapeutic potential not only for the metabolic disturbances but also for the muscle mass loss that are associated with diabetes.

Background Estimation of the balance between subendocardial oxygen supply and demand could be a useful parameter to assess the risk of myocardial ischemia. Evaluation of the subendocardial viability ratio (SEVR, also known as Buckberg index) by invasive recording of left ventricular and aortic pressure curves represents a valid method to estimate the degree of myocardial perfusion relative to left ventricular workload. However, routine clinical use of this parameter requires its noninvasive estimation and the demonstration of its reliability. Methods and Results Arterial applanation tonometry allows a noninvasive estimation of SEVR as the ratio of the areas directly beneath the central aortic pressure curves obtained during diastole (myocardial oxygen supply) and during systole (myocardial oxygen demand). However, this “traditional” method does not account for the intra‐ventricular diastolic pressure and proper allocation to systole and diastole of left ventricular isometric contraction and relaxation, respectively, resulting in an overestimation of the SEVR values. These issues are considered in the novel method for SEVR assessment tested in this study. SEVR values estimated with carotid tonometry by "traditional” and "new” method were compared with those evaluated invasively by cardiac catheterization. The “traditional” method provided significantly higher SEVR values than the reference invasive SEVR: average of differences±SD= 44±11% (limits of agreement: 23% – 65%). The noninvasive “new” method showed a much better agreement with the invasive determination of SEVR: average of differences±SD= 0±8% (limits of agreement: ‐15% to 16%). Conclusions Carotid applanation tonometry provides valid noninvasive SEVR values only when all the main factors determining myocardial supply and demand flow are considered.

Context Current data about the cardiovascular manifestations of mild primary hyperparathyroidism (pHPT) are often conflicting. Pulse wave velocity (PWV) is the gold standard for assessing aortic stiffness, and it predicts cardiovascular morbidity and mortality. Objective Primary outcomes were to investigate if mild pHPT was associated with higher PWV and if parathyroidectomy (PTX) reduced PWV in mild pHPT. Secondary outcome was to investigate blood pressure changes after PTX. Methods Sources were PubMed, Google Scholar, SCOPUS, Web of Science, and the Cochrane Library. Eligible studies included reports of PWV in patients with mild pHPT and controls, or in patients with mild pHPT before and after PTX. Two investigators independently identified eligible studies and extracted data. Pooled mean difference (MD) was the summary effect measure. Data were presented in forest plots with outlier and influential case diagnostics. Nine observational studies and one randomized clinical trial were selected, including 433 patients with mild pHPT, 171 of whom underwent PTX, and 407 controls. PWV was significantly higher in mild pHPT than in controls (MD = 1.18, 0.67 to 1.68, P < .0001). Seven studies evaluated the effect of PTX on PWV. PTX significantly reduced PWV (MD = –0.48, –0.88 to –0.07, P = .022). Conclusion Aortic stiffness is increased in patients with mild pHPT, supporting the notion that mild pHPT is also associated with adverse cardiovascular manifestations. PTX significantly reduced arterial stiffness in mild pHPT, indicating that the benefit of PTX over cardiovascular manifestations should not be dismissed but it deserves further studies.

BackgroundRadiofrequency ablation (RFA) has gained ground as an effective and well-tolerated technique to treat benign thyroid nodules. Most of the available studies have described the short-term outcomes of RFA, whereas there is a limited number of studies evaluating long-term issues, such as regrowth and the likelihood of retreatments. In addition, risk markers of regrowth and retreatment remain to be defined. The initial ablation ratio (IAR) is an index that measures the amount of ablation after RFA, which has been associated with technique efficacy (i.e. volume reduction >50% after 1 year from the procedure). This study aimed at evaluating i) IAR reproducibility and ii) IAR predictive value for RFA 5-year outcomes.Materials and MethodsThis is a retrospective single center study on patients with benign thyroid nodules treated with RFA and followed for 5 years after initial treatment. IAR interobserver reproducibility was evaluated with Bland-Altman method and Lin’s concordance correlation coefficient (ρc). IAR predictive value for RFA 5-year outcomes was evaluated with linear and logistic regression models, as well as with Cox models, while receiver operating characteristic (ROC) analyses were used for cut-offs.ResultsWe selected 78 patients with 82 benign thyroid nodules. The procedure significantly reduced nodule volume and this reduction was generally maintained over time. Technique efficacy was achieved in 92% of patients, while 23% of nodules regrew and 12% of nodules were retreated. Median IAR was 83%. Lin’s concordance and Pearson’s correlation coefficients suggested a good interobserver reproducibility of this index, consistent with the limits of agreement of the Bland-Altman plot. IAR was significantly associated with technique efficacy, 1- and 5-year volume reduction ratio, and with the likelihood of a retreatment, but not with nodule regrowth. ROC analyses showed that IAR cut-off was 49% for technique efficacy and 73% for retreatment.ConclusionsOur results show for the first time that IAR is reproducible and that it predicts the volume reduction and the likelihood of a retreatment after 5 years from RFA.

To the Editor, We read the study ‘Residual vital ratio: predicting regrowth after radiofrequency ablation for benign thyroid nodules’ with great interest [1]. The issue of regrowth after radiofrequ...

Background:It is unknown whether patients with interstitial lung disease (ILD) and only some features of autoimmunity have a different natural history from those with a defined connective tissue disease (CTD-ILD). The classification criteria for “ILD with autoimmune features” (IPAF) may not be able to characterize all these patients, especially those with a usual interstitial pneumonia (UIP) pattern [1].Objectives:To determine clinical characteristics and predictive factors for progression in a cohort of ILD patients with features of autoimmunity, through the application of classification criteria for IPAF and specific CTD, whenever possible.Methods:We retrospectively selected a cohort of consecutive patients with ILD as onset manifestation and features of autoimmunity (at least 1 autoantibody and/or 1 clinical sign/symptom), evaluated by our multidisciplinary unit from March 2009 to March 2020. All the final diagnoses were revised according to the latest CTD and IPAF criteria. Patients were followed up for 33 (16.5-69.5) months.Results:Of the 101 patients enrolled (67.4±10.9 yrs, F/M ratio 65/36), 53 (52.5%) and 37 (36.6%) respectively satisfied the CTD and IPAF criteria. Eleven patients (10.9%) did not satisfy IPAF criteria because of only 1 item (clinical or serologic) within the IPAF domains and a UIP pattern; we defined this group as “autoimmune” UIP (AI-UIP). All the 8 patients initially classified as undifferentiated CTD had sufficient IPAF criteria. Among the IPAF patients (68.2±10.1 years, F/M ratio 20/17), the most common findings were: Nonspecific interstitial pneumonia pattern (56.8%), antinuclear antibodies positivity (43.2%) and arthritis (24.3%). The combination of a positive morphologic and serologic domain was the most common to reach the diagnosis (48.6%). Some IPAF patients had features not included in IPAF criteria, such as non-anti-synthetase myositis-specific antibodies (21.6%), objective sicca syndrome (13.5%) and anti-myeloperoxidase antibodies (2.7%). Over a median of 17 months, 2 IPAF patients (5.4%) developed a definite UIP pattern, while 4 (10.8%) a specific CTD. Comparing the IPAF, CTD-ILD and AI-UIP groups, no statistically significant differences were found in the mean age, sex distribution, smoking habits and mean duration of the disease. However, IPAF patients had a significantly higher prevalence of arterial hypertension and left-sided heart failure and a lower predominance of UIP pattern as expected (10.8% vs. 32.1% vs. 100%, pp 0.01). Fewer IPAF patients needed oxygen support (8.6% vs. 31.4% vs. 36.4, p 0.02). Considering the overall 101 patients, having an IPAF and a UIP pattern respectively predicted a slower (OR: 0.37, p 0.04) and a faster (OR: 3.56, p 0.01) ILD progression at the multivariate analysis.Conclusion:In our cohort, IPAF criteria were useful to identify a subset of patients with a slower ILD progression and a possible evolution to CTD (10-15% of cases) [2]. These criteria do not characterize all the patients with a UIP pattern and limited features of autoimmunity, which seem to have a worse prognosis, independently from the final diagnosis. Further studies are needed to clarify if the prognosis of AI-UIP is different from that of idiopathic pulmonary fibrosis.References:[1]Graney, et al. Ann Am Thorac Soc 2019;16(5):525-33.[2]Sebastiani, et al. Biomedicines 2021,9,17.Disclosure of Interests:None declared

Background: TNF-related apoptosis-inducing ligand (TRAIL) has attracted attention not only as an anti-cancer agent, but also as a potential treatment for diabetes. Animal studies have shown that TRAIL delivery ameliorated glucose control in type 1 and type 2 diabetes. It is currently unknown whether TRAIL positive effects are maintained in more severe forms of type 2 diabetes, and whether they include renoprotection. Our study aimed at evaluating TRAIL effects in a severe form of type 2 diabetes with nephropathy. Materials and methods: A total of 20 db/db mice were treated with saline or TRAIL twice per week for 12 weeks. In parallel, renal tubular epithelial cells were cultured with TGF-β1 in the presence and absence of TRAIL, with and without silencing TRAIL-specific receptor (DR5) and leptin receptor. Results: TRAIL did not improve glucose control, but it significantly reduced circulating interleukin (IL)-6 and resistin. In the kidney, TRAIL treatment significantly ameliorated glomerular and tubular morphology with an improvement in kidney function, but no effect on proteinuria. Our in vitro studies on TGF-β1-treated cells, showed that by binding to DR5, TRAIL rescued normal tubular cell morphology, increasing E-cadherin and reducing α-smooth muscle actin (SMA) expression, with no effects on cell viability. Interestingly, both in vivo and in vitro, TRAIL reduced the accumulation of the autophagy substrate p62. Conclusions: Our data confirm TRAIL protective effects against organ damage and shed light on to promising anti-fibrotic actions, which are independent of glucose control. TRAIL anti-fibrotic actions might be due to the rescue of autophagy in diabetes.

Background: Thyroid nodules are an extremely common occurrence, as their prevalence in the general population is estimated to range between 50 and 70%. Some of these nodules are autonomously functioning such that they can cause hyperthyroidism over time. In this case, surgery and radioiodine represent the standard of care. Nevertheless, patients might have contraindications or be unwilling to undergo these treatments. Minimally-invasive ultrasound-guided techniques, such as laser and radiofrequency ablation (RFA), have been recently introduced into clinical practice as an alternative treatment for symptomatic benign thyroid nodules. Due to their efficacy and tolerability, these techniques have become increasingly available and their usage has been extended also to autonomously functioning thyroid nodules (AFTN). Methods: In this narrative review, we will describe the studies reporting the therapeutic effects of RFA on AFTN, the studies reporting how RFA compares to the other treatment modalities, as well as the current indications for the use of RFA in patients with AFTN. For this purpose, a comprehensive literature search was independently conducted by three investigators on PubMed, EMBASE, and the Cochrane Library from inception up to February 2020 to identify published articles concerning the effects of RFA on AFTN. Results and Conclusions: Current consensus statements and guidelines support the notion that RFA should be regarded as a first-line therapy for non-functioning benign thyroid nodules, while it remains a valid second-line option for AFTN treatment in case of contraindications or patient unwillingness to undergo surgery or radioiodine.

Background and aim Considering the amount of novel knowledge generated in the last five years, a team of experienced hypertensionlogists was assembled to furnish updated clinical practice guidelines for the management of primary aldosteronism. Methods To identify the most relevant studies, the authors utilized a systematic literature review in international databases by applying the PICO strategy, and then they were required to make use of only those meeting predefined quality criteria. For studies of diagnostic tests, only those that fulfilled the Standards for Reporting of Diagnostic Accuracy recommendations were considered. Results Each section was jointly prepared by at least two co-authors, who provided Class of Recommendation and Level of Evidence following the American Heart Association methodology. The guidelines were sponsored by the Italian Society of Arterial Hypertension and underwent two rounds of revision, eventually reexamined by an External Committee. They were presented and thoroughly discussed in two face-to-face meetings with all co-authors and then presented on occasion of the 36th Italian Society of Arterial Hypertension meeting in order to gather further feedbacks by all members. The text amended according to these feedbacks was subjected to a further peer review. Conclusions After this process, substantial updated information was generated, which could simplify the diagnosis of primary aldosteronism and assist practicing physicians in optimizing treatment and follow-up of patients with one of the most common curable causes of arterial hypertension.

This case report describes the clinical characteristics of a 50-year-old woman that developed SARS-CoV-2 pneumonia and was admitted at the COVID-19 dedicated unit where she developed neurological symptoms 10 days after admission. After neurological examination, including a panel of blood cerebrospinal fluid biomarkers, a diagnosis of Miller Fisher syndrome (MFS) was hypothesized and intravenous immunoglobulin therapy (IVIG) was initiated. Fourteen days after the start of IVIG treatment, the patient has been discharged at home with the resolution of respiratory symptoms and only minor hyporeflexia at the lower limbs, without any side effect.

Objective The index of maximal systolic acceleration ([AImax]: maximal systolic acceleration of the Doppler waveform divided by peak systolic velocity) shows diagnostic accuracy in screening of renal artery stenosis. This study aimed to determine whether an upstream factor of resistance, such as aortic valve stenosis (AVS), can affect Doppler parameters detected in the peripheral arteries. Methods In this prospective study, we measured the AImax in non-stenotic renal interlobar arteries of 62 patients with AVS. Patients were divided into three groups on the basis of severity of valvulopathy as follows: mild-to-moderate AVS (M-AVS; n = 24), intermediate AVS (I-AVS; n = 15), and severe AVS (S-AVS; n = 23) based on Nishimura’s criteria. Results The AImax in the renal parenchymal arteries was significantly lower in the S-AVS group (8.9 ± 3.6 s−1) than in the M-AVS (15.3 ± 3.8 s−1) and I-AVS groups (16.7 ± 5.2 s−1). The AImax was positively correlated with the aortic valve area and inversely correlated with the tranvalvular aortic pressure gradient. After aortic valve replacement, the AImax significantly increased from 10.7 ± 4.0 s−1 at baseline to 19.3 ± 4.4 s−1. Conclusions Proximal resistance can lead to diagnostic bias of Doppler parameters that are applied in the diagnosis of peripheral vasculopathies, particularly in renal artery stenosis.

Purpose. Aim of the study was to assess the impact of the Italian Society of Anatomic Pathology and Diagnostic Cytology (SIAPEC) classification of 2014, on the treatment of indeterminate thyroid lesions (TIR3). Methods. We retrospectively analyzed patients undergoing thyroid surgery for TIR3 lesions between 2013 and 2018, at the General Surgery Department of Trieste University Hospital. According to the SIAPEC classification, patients were divided into TIR3A and TIR3B groups. All patients treated before 2014 underwent surgical treatment, and surgical specimens were retrospectively classified after revision of fine-needle aspiration cytology. Starting 2014, TIR3A patients were treated only when symptomatic (i.e., coexistent bilateral thyroid goiter or growing TIR3A nodules), whereas TIR3B patients always received surgical treatment. Hemithyroidectomy (HT) was the procedure of choice. Total thyroidectomy (TT) was performed in case of concurrent bilateral goiter, autoimmune thyroid disease, and/or presence of BRAF and/or RAS mutation. Lastly, we analyzed the malignancy rate in the two groups. Results. 29 TIR3A and 90 TIR3B patients were included in the study. HT was performed in 10 TIR3A patients and 37 TIR3B patients, respectively, with need for reoperation in 4 TIR3B (10.8%) patients due to histological findings of follicular thyroid carcinoma >1 cm. The malignancy rates were 17.2% in TIR3A and 31.1% in TIR3B, (p=0.16). Predictability of malignancy was almost 89% in BRAF mutation and just 47% in RAS mutation. Conclusions. The new SIAPEC classification in association with biomolecular markers has improved diagnostic accuracy, patient selection, and clinical management of TIR3 lesions.

Simple Summary Ultrasound (US)-guided minimally-invasive techniques, such as radiofrequency ablation (RFA) have emerged as an alternative treatment to surgery for benign and malignant thyroid nodules. Based on a systematic literature search, here we report the long-term outcomes of thyroid RFA. Available data show that US-guided RFA significantly reduced benign thyroid nodules and destroyed most PTMC, and this was generally maintained for at least 5 years after the initial treatment. Further studies addressing the risk of regrowth in patients with benign thyroid nodules, as well as the risk of recurrence in patients with PTMC are needed. Abstract Background: US-guided minimally-invasive techniques, such as radiofrequency ablation (RFA) have emerged as an alternative treatment for benign and malignant thyroid nodules. This systematic review aims to provide an overview on the long-term outcomes of US-guided RFA in patients with benign and malignant thyroid nodules. Methods: We systematically searched PubMed/MEDLINE, EMBASE, and Scopus to identify articles reporting the outcomes of thyroid RFA after a follow-up of at least 3 years. Results: A total of 20 studies met the inclusion criteria and were included in the review. In patients with benign thyroid nodules, RFA significantly reduced nodule volume and this was generally maintained for the following 5 years. However, a small but not negligible proportion of nodules regrew and some of them required further treatments over time. In patients with malignant nodules, RFA has been used not only to treat differentiated thyroid cancer (DTC) neck recurrences, but also to treat papillary thyroid microcarcinoma (PTMC). In most patients with PTMC, RFA led to complete disappearance of the tumor. When it was compared to surgery, RFA was not inferior in terms of oncologic efficacy but it had a lower complication rate. However, RFA did not allow for final pathology, disease staging and accurate risk stratification. Conclusions: US-guided RFA significantly reduces benign thyroid nodules and destroys most PTMC, and this is generally maintained for at least 5 years after the initial treatment. Further studies addressing the risk of regrowths in patients with benign thyroid nodules, as well as the risk of recurrence in patients with PTMC are needed.

Background:Endocrine and metabolic imbalance conditions can affect the development of subjective abnormal perceptions within fibromyalgia (FMR). In the case of autoimmune thyroid disease (ATD), prolonged, clinically active states of impaired glandular function may be associated with an FMR-type condition. Less clear is the association between subclinical or rapidly well-controlled states of thyroid disease and the presence of FMR, since this assessment, although analysed in some previous studies, was usually performed on cohorts of subjects where the absence of any other confusing factors was not well defined.Objectives:To evaluate the prevalence of subclinical autoimmune thyroid disease, or functionally controlled autoimmune thyroid disease, in a retrospective cohort of consecutively diagnosed patients suffering from fibromyalgia condition.Methods:Over a 2 years period of time (2018-2019) a monocentric joint evaluation was activated with the endocrinology section of our healthcare area in order to consecutively monitor the subjects belonging to both specialist clinics. Patients with ATD were not unfrequently firstly evaluated in the rheumatology ambulatory. Diagnosis of FMR was defined according to the American College of Rheumatology 2010/2011 criteria. At the same time, at the rheumatology clinics, all cases addressed with diagnosis of fatigue or chronic pain of no defined origin were analysed in order to carefully identify any associated, comorbidity problems. The diagnosis of ATD was confirmed according to recognized international criteria. The following results will focus on subjects with chronic Hashimoto type Thyroiditis (HT).Results:Among the HT patients, 98% were women, aged between 28 and 64. Over the 2 years considered period of time, 65 subjects suffering from HT, showing no active disease or unstable endocrine function were addressed to the rheumatology clinics owing to FMR related symptoms. Among them, 55 (84.6%) had a confirmed diagnosis of FMR. Within this time, we recognized 239 consecutive diagnoses of FMR in subjects aging 22-76 years, with a number of 114 found to be devoid of factors (other than ATD) able to be responsible for chronic pain, except for a modest component of situational anxiety, or mild mood depression, not requiring any specific drug intervention. Among the 114, so called “primary” FMR, 35.6% showed to suffer from TCH, under confirmed clinical/hormonal remission, or in a preclinical, early stage of onset. Within the 125 subjects, carrying a FMR condition related to previous or associated fostering pathology, 26.8% were positive for current or previous thyroid problems. The prevalence of TCH, in the “secondary” FMR conditions differed significantly (pConclusion:Although limited in number, the here reported data confirm the hypothesis of a significant association between ATD and FMR, even in subjects who were considered to be in a subclinical condition or in full clinical remission by the endocrinology colleagues. The physiopathology of this association needs further appropriate insights.Acknowledgements:We thank Dr Alberto Petterle for his previous helpful contributionDisclosure of Interests:None declared

Objective: Aortic stiffness and central pressure measurements have become increasingly important for the overall estimation of cardiovascular risk. The aim of this study is to verify whether the presence of stenosis in the carotid arteries due to atherosclerotic plaques may induce a bias in the measurement of carotid-femoral pulse wave velocity (PWV) and in the analysis of central pulse waveform variables assessed by carotid tonometry. Methods: Eighty-four patients (age: 67.1 ± 12.4 years) undergoing screening for carotid atherosclerosis were enrolled, divided into three groups according to carotid ultrasound findings (NASCET criteria): 28 patients without significant stenosis, 30 patients with bilateral plaques, and 26 patients with right or left monolateral stenosis. PWV and other variables derived from the central pulse waveform analysis (central blood pressure, augmentation index and forward and backward waves) were measured at both right and left carotid arteries by a validated PulsePen tonometer. A repeatability study was performed in 28 young healthy patients (age: 25.4 ± 2.9 years). Results: A high degree of correlation was found between bilateral measurements in all groups, and particularly in groups with monolateral carotid stenosis, with no significant difference attributable to lateralized stenosis. Right-left differences in asymmetric groups were 0.35 ± 5.12 mmHg (R2 = 0.960) for central blood pressure,-2.12 ± 7.39% (R2 = 0.743) for augmentation index, 0.64 ± 1.56 m/s (R2 = 0.947) for PWV, 0.08 ± 8.48 mmHg for forward wave (R2 = 0.742) and 0.35 ± 2.35 mmHg for backward wave (R2 = 0.907). Conclusion: Measurement of PWV and of variables derived from the central pulse waveform analysis by carotid tonometry is not biased by the presence of local atherosclerotic plaques.

Background Several devices have been proposed to assess arterial stiffness in clinical daily use over the past few years, by estimating aortic pulse wave velocity (PWV) from a single measurement of brachial oscillometric blood pressure, using patented algorithms. It is uncertain if these systems are able to provide additional elements, beyond the contribution carried by age and blood pressure levels, in the definition of early vascular damage expressed by the stiffening of the arterial wall. Methods and Results The aim of our study was to compare the estimated algorithm‐based PWV values, provided by the Mobil‐O‐Graph system, with the standard noninvasive assessment of aortic PWV in patients with Marfan syndrome (ie, in subjects characterized by premature aortic stiffening and low blood pressure values). Aortic stiffness was simultaneously evaluated by carotid‐femoral PWV with a validated arterial tonometer and estimated with an arm cuff–based ambulatory blood pressure monitoring Mobil‐O‐Graph device on 103 patients with Marfan syndrome (50 men; mean± SD age, 38±15 years). Aortic PWV, estimated by the Mobil‐O‐Graph, was significantly ( P SD, 6.1±1.3 m/s) than carotid‐femoral PWV provided by arterial tonometry (mean± SD , 8.8±3.1 m/s). The average of differences between PWV values provided by the 2 methods (±1.96×SD) was −2.7±5.7 m/s. Conclusions The Mobil‐O‐Graph provides PWV values related to an ideal subject for a given age and blood pressure, but it is not able to evaluate early vascular aging expressed by high PWV in the individual patient. This is well shown in patients with Marfan syndrome.

Introduction: Minimally invasive nonsurgical techniques are gaining ground as alternatives to surgery for the treatment of benign thyroid nodules. Here, we aimed at comparing patient satisfaction after radiofrequency ablation (RFA) to that after surgery. Methods: In this cross-sectional study, we recruited 126 patients treated with RFA and 84 treated with surgery for a single benign thyroid nodule. All patients were contacted by phone call and were asked the following questions: Are you satisfied with the symptom resolution?; Are you satisfied with the cosmetic results?; Are you satisfied overall with the procedure?; Are you taking any medication for your thyroid? Patients’ general characteristics were collected from our database. Results: In the surgery group, there was a higher percentage of patients fully satisfied with the resolution of nodule-related symptoms (p = .02). In the RFA group, there was a higher percentage of patients fully satisfied with the cosmetic results (p = .001). In terms of overall satisfaction, there were no differences between the groups (p = .26). Nevertheless, RFA led to differing results based on thyroid nodule function. In patients with nonfunctioning thyroid nodules, RFA was as effective as surgery in terms of satisfaction with symptom resolution, while it was not in patients with autonomously functioning thyroid nodules (AFTN). Conclusion: Our data on postoperative patient satisfaction support the notion that both RFA and surgery are valid therapeutic options for nonfunctioning thyroid nodules, while surgery should be still preferred for AFTN.

Background Thyroid lymphomas are an exceptional finding in patients with thyroid nodules. Burkitt’s lymphoma is one of the rarest and most aggressive forms of thyroid lymphomas, and its prognosis depends on the earliness of medical treatment. Given the rarity of this disease, making a prompt diagnosis can be challenging. For instance, fine-needle aspiration (FNA) cytology, which is the first-line diagnostic test that is performed in patients with thyroid nodules, is often not diagnostic in cases of thyroid lymphomas, with subsequent delay of the start of therapy. Case presentation Here we report the case of a 52-year-old woman presenting with a rapidly enlarging thyroid mass. Thyroid ultrasonography demonstrated a solid hypoechoic nodule. FNA cytology was only suggestive of a lymphoproliferative disorder and did not provide a definitive diagnosis. It is core needle biopsy (CNB) that helped us to overcome the limitations of routine FNA cytology, showing the presence of thyroid Burkitt’s lymphoma. Subsequent staging demonstrated bone marrow involvement. The early start of an intensive multi-agent chemotherapy resulted in complete disease remission. At 60 months after the diagnosis, the patient is alive and has not had any recurrence. Conclusions Clinicians should be aware that thyroid Burkitt’s lymphoma is an aggressive disease that needs to be treated with multi-agent chemotherapy as soon as possible. To diagnose it promptly, they should consider to order/perform a CNB in any patient with a rapidly enlarging thyroid mass that is suspicious for lymphoma.

Background:Interstitial lung disease (ILD) can be the first manifestation of connective tissue disease (CTD) and rheumatoid arthritis (RA). Pulmonologists are usually the first referral in these patients.Objectives:To determine: 1) the prevalence of ILD as initial manifestation of CTD or RA 2) clinical characteristics of such patients.Methods:From a database of consecutive patients with CTD or RA referred to our academic hospital from 2009 and 2017, we selected all the patients with ILD as initial manifestation of the disease. Periodic multidisciplinary evaluations were performed during a median follow-up of 48 (35-50) months.Results:1) Fifty-four of the 427 patients with CTD or RA (12.6%) had ILD as initial manifestation (mean age: 63.9±12.9 yrs, F/M ratio: 20/34). Autoimmune myositis was diagnosed in 16/54 patients (29.6%), systemic sclerosis in 11 patients (20.4%), RA in 9 patients (16.7%), Sjogren syndrome in 9 patients (16.7%) and SLE in 3 patients (5.5%). Six patients remained classified as IPAF (11.1%). Among the Rheumatology patients we followed-up in the same period, autoimmune myositis had the highest prevalence of ILD as initial manifestation (63.6%), followed by Sjogren syndrome (20.5%), systemic sclerosis (20.0%), RA (3.4%), and SLE (3.3%). 2) Patients with initial ILD were all firstly evaluated by the Pulmonologist and the main reasons for Rheumatology referral were positivity for one or more autoantibodies (57.4%), mainly ANA≥1:320, and joint pain (29.6%). Thirty-six patients (66.7%) received steroid and/or immunosuppressive therapy in the six months before the first Rheumatology visit to relieve respiratory symptoms. Twenty of these patients (58.8%) had rheumatic manifestations during steroid tapering. ILD CT patterns were NSIP (25 patients, 52.1%), UIP (18 patients, 33.4%), and organizing pneumonia (5 patients, 9.3%). In four patients (4.5%), autoantibodies became positive during the follow-up. The final diagnosis of CTD- or RA-ILD was made after a median period of 16.5 (6-39) months from the clinical onset. At the time of diagnosis, average FVC was 90.4±18.7% of predicted, DLCO 55.4±20.2% and the median GAP index was 3 (2-3). During the median follow-up of 48 months, eight patients (14.8%) had a decline in DLCO of ≥ 15% predicted and/or a decline in FVC of ≥ 10% despite immunosuppressive drugs. Nine patients (17%) died and six of these patients (11.1%) for causes related to ILD.Conclusion:In our study population, the prevalence of ILD as initial manifestation of CTD or RA was 12.6%. Autoimmune myositis, systemic sclerosis and Sjogren syndrome were the most frequent diagnosis. As our data confirmed, ILD is a major cause of death in patients with systemic autoimmune diseases and can progress despite immunosuppression [1]. Furthermore, clinical features may become evident even months after the disease onset. A multidisciplinary evaluation is therefore essential, not only at the time of diagnosis but also during the follow-up [2].References:[1] A. Fischeret al.Progressive fibrosing interstitial lung disease associated with systemic autoimmune diseases.Clin Rheum(2019); 38:2673-81[2] F. Furini,et al. The role of the Multidisciplinary Evaluation of Interstitial Lung Diseases: Systematic Literature Review of the Current Evidence and Future Perspectives.Front Med(2019); 6:246Disclosure of Interests:None declared

Primary aldosteronism (PA) causes cardiovascular damage in excess to the blood pressure elevation, but there are no prospective studies proving a worse long-term prognosis in adrenalectomized and medically treated patients. We have, therefore, assessed the outcome of PA patients according to treatment mode in the PAPY study (Primary Aldosteronism Prevalence in Hypertension) patients, 88.8% of whom were optimally treated patients with primary (essential) hypertension (PH), and the rest had PA and were assigned to medical therapy (6.4%) or adrenalectomy (4.8%). Total mortality was the primary end point; secondary end points were cardiovascular death, major adverse cardiovascular events, including atrial fibrillation, and total cardiovascular events. Kaplan–Meier and Cox analysis were used to compare survival between PA and its subtypes and PH patients. After a median of 11.8 years, complete follow-up data were obtained in 89% of the 1125 patients in the original cohort. Only a trend ( P =0.07) toward a worse death-free survival in PA than in PH patients was observed. However, at both univariate (90.0% versus 97.8%; P =0.002) and multivariate analyses (hazard ratio, 1.82; 95% confidence interval, 1.08–3.08; P =0.025), medically treated PA patients showed a lower atrial fibrillation–free survival than PH patients. By showing that during a long-term follow-up adrenalectomized aldosterone-producing adenoma patients have a similar long-term outcome of optimally treated PH patients, whereas, at variance, medically treated PA patients remain at a higher risk of atrial fibrillation, this large prospective study emphasizes the importance of an early identification of PA patients who need adrenalectomy as a key measure to prevent incident atrial fibrillation.

Recent studies suggest that a circulating protein called TRAIL (TNF-related apoptosis inducing ligand) may have an important role in the treatment of type 2 diabetes. It has been shown that TRAIL deficiency worsens diabetes and that TRAIL delivery, when it is given before disease onset, slows down its development. The present study aimed at evaluating whether TRAIL had the potential not only to prevent, but also to treat type 2 diabetes. Thirty male C57BL/6J mice were randomized to a standard or a high-fat diet (HFD). After 4 weeks of HFD, mice were further randomized to receive either placebo or TRAIL, which was delivered weekly for 8 weeks. Body weight, food intake, fasting glucose, and insulin were measured at baseline and every 4 weeks. Tolerance tests were performed before drug randomization and at the end of the study. Tissues were collected for further analyses. Parallel in vitro studies were conducted on HepG2 cells and mouse primary hepatocytes. TRAIL significantly reduced body weight, adipocyte hypertrophy, free fatty acid levels, and inflammation. Moreover, it significantly improved impaired glucose tolerance, and ameliorated non-alcoholic fatty liver disease (NAFLD). TRAIL treatment reduced liver fat content by 47% in vivo as well as by 45% in HepG2 cells and by 39% in primary hepatocytes. This was associated with a significant increase in liver peroxisome proliferator-activated receptor (PPAR) γ (PPARγ) co-activator-1 α (PGC-1α) expression both in vivo and in vitro, pointing to a direct protective effect of TRAIL on the liver. The present study confirms the ability of TRAIL to significantly attenuate diet-induced metabolic abnormalities, and it shows for the first time that TRAIL is effective also when administered after disease onset. In addition, our data shed light on TRAIL therapeutic potential not only against impaired glucose tolerance, but also against NAFLD.

INTRODUCTION: Primary hyperparathyroidism is associated with a cluster of cardiovascular manifestations, including hypertension, leading to increased cardiovascular risk. PURPOSE: The aim of our study was to investigate the ambulatory blood pressure monitoring-derived short-term blood pressure variability in patients with primary hyperparathyroidism, in comparison with patients with essential hypertension and normotensive controls. METHODS: Twenty-five patients with primary hyperparathyroidism (7 normotensive,18 hypertensive) underwent ambulatory blood pressure monitoring at diagnosis, and fifteen out of them were re-evaluated after parathyroidectomy. Short-term-blood pressure variability was derived from ambulatory blood pressure monitoring and calculated as the following: 1) Standard Deviation of 24-h, day-time and night-time-BP; 2) the average of day-time and night-time-Standard Deviation, weighted for the duration of the day and night periods (24-h "weighted" Standard Deviation of BP); 3) average real variability, i.e., the average of the absolute differences between all consecutive BP measurements. RESULTS: Baseline data of normotensive and essential hypertension patients were matched for age, sex, BMI and 24-h ambulatory blood pressure monitoring values with normotensive and hypertensive-primary hyperparathyroidism patients, respectively. Normotensive-primary hyperparathyroidism patients showed a 24-h weighted Standard Deviation (P

Background Current guidelines recommend use of the aldosterone‐renin ratio ( ARR ) for the case detection of primary aldosteronism followed by confirmatory tests to exclude false‐positive results from further diagnostic workup. We investigated the hypothesis that this could be unnecessary in patients with a high ARR value if the quantitative information carried by the ARR is taken into due consideration. Methods and Results We interrogated 2 large data sets of prospectively collected patients studied with the same predefined protocol, which included the captopril challenge test. We used an unambiguous diagnosis of aldosterone‐producing adenoma as reference index. We also assessed whether the post‐captopril ARR and plasma aldosterone concentration fall furnished a diagnostic gain over baseline ARR values. We found that the false‐positive rate fell exponentially, and, conversely, the specificity increased with rising ARR values. At receiver operating characteristics curves and diagnostic odds ratio analysis, the high baseline ARR values implied very high positive likelihood ratio and diagnostic odds ratio values. The baseline and post‐captopril ARR showed similar diagnostic accuracy (area under the receiver operating characteristics curve) in both the exploratory and validation cohorts, indicating lack of diagnostic gain with this confirmatory test (between‐area under the curve difference, 0.005; 95% CI , −0.031 to 0.040; P =0.7 for comparison, and 0.05; 95% CI , −0.061 to 0.064; P =0.051 for comparison, respectively). Conclusions These results indicate that the ARR conveys key quantitative information that, if properly used, can simplify the diagnostic workup, resulting in saving of money and resources. This can offer the chance of diagnosis and ensuing adrenalectomy to a larger number of hypertensive patients, ultimately resulting in better control of blood pressure.

Long-standing exposure to endogenous cortisol excess is associated with high cardiovascular risk. The aim of our study was to investigate arterial stiffness, which has been recognized as an independent predictor of adverse cardiovascular outcome, in a group of patients with Cushing's syndrome. Twenty-four patients with Cushing's syndrome (3 males, mean age 49±13 years; 20 pituitary-dependent Cushing's disease and 4 adrenal adenoma) underwent 24-h ambulatory blood pressure monitoring (ABPM) and evaluation of cardiovascular risk factors. The Ambulatory Arterial Stiffness Index (AASI) and symmetric AASI (sAASI) were derived from ABPM tracings. Cushing patients were divided into 8 normotensive (NOR-CUSH) and 16 hypertensive (HYP-CUSH) patients, and were compared with 8 normotensive (NOR-CTR) and 16 hypertensive (HYP-CTR) control subjects, matched for demographic characteristics, 24-h ABPM and cardiometabolic risk factors. The AASI and sAASI indexes were significantly higher in Cushing patients than in controls, either in the normotensive (p=0.048 for AASI and p=0.013 for sAASI) or in the hypertensive (p=0.004 for AASI and p=0.046 for sAASI) group. No difference in metabolic parameters was observed between NOR-CUSH and NOR-CTR or between HYP-CUSH and HYP-CTR groups. AASI and sAASI were both correlated with urinary cortisol in patients with endogenous hypercortisolism (Spearman's rho=0.40, p=0.05, and 0.61, p=0.003, respectively), while no correlation was found in controls. Both AASI and sAASI are increased in Cushing syndrome, independent of BP elevation, and may represent an additional cardiovascular risk factor in this disease. The role of excess cortisol in arterial stiffness has to be further clarified.

Aim: Papillary thyroid microcarcinoma (PTMC) is increasing in incidence. Despite its excellent clinical outcomes, there is still debate regarding which surgical approach is more appropriate for PTMC, procedures including hemithyroidectomy (HT), total thyroidectomy (TT), and completion thyroidectomy (CT) after initial HT and histopathologic examination confirming a PTMC. Here we report our experience in the surgical management of PTMC. Methods: We conducted a retrospective evaluation of all patients who received a postoperative diagnosis of PTMC between January 2001 and January 2016. Every patient was divided according to the type of surgery performed (TT or HT alone). Follow-up consisted of regular clinical and neck ultrasonographic examination. Clinical and histopathological parameters (e.g. age, sex, lesion size, histological features, multifocality, lymph node metastases, BRAF status when available) as well as clinical outcomes (e.g. complications rates, recurrence, overall survival) were analyzed. Results: Group A consisted of 86 patients who underwent TT, whereas Group encompassed 19 patients who underwent HT. Mean follow-up period was 58.5 months. In Group A, one patient (1.2%) experienced recurrence in cervical lymph nodes with need for reoperation. In Group B, eight patients (42%) underwent completion thyroidectomy after histopathological examination confirming PTMC, while one patient (5.3%) developed PTMC in the contralateral lobe with need for reoperation at 2 years after initial surgery. Multifocality was found in 19 patients in Group A (22%). Of these, 14 presented bilobar involvement, whereas in 3 cases multifocality involved only one lobe. 1 patient in Group B (5.3%) presented with unilateral multifocal PTMC (p ¼ 0.11). Conclusions: Low-risk patients with PTMC may benefit from a more conservative treatment, e.g. HT followed by close follow-up. However, appropriate selection of patients based on risk stratification is the key to differentiate therapy options and gain better results.

Background Osteoprotegerin (OPG) is a glycoprotein that plays an important regulatory role in the skeletal, vascular, and immune system. It has been shown that OPG predicts chronic kidney disease (CKD) in diabetic patients. We hypothesized that OPG could be a risk marker of CKD development also in non-diabetic hypertensive patients. Methods A case-control study was carried out to measure circulating OPG levels in 42 hypertensive patients with CKD and in 141 hypertensive patients without CKD. A potential relationship between OPG and the presence of CKD was investigated and a receiver-operating characteristic (ROC) curve was designed thereafter to identify a cut-off value of OPG that best explained the presence of CKD. Secondly, to evaluate whether OPG increase could affect the kidney, 18 C57BL/6J mice were randomized to be treated with saline or recombinant OPG every 3 weeks for 12 weeks. Results Circulating OPG levels were significantly higher in hypertensive patients with CKD, and there was a significant inverse association between OPG and renal function, that was independent from other variables. ROC analysis showed that OPG levels had a high statistically predictive value on CKD in hypertensive patients, which was greater than that of hypertension. The OPG best cut-off value associated with CKD was 1109.19 ng/L. In the experimental study, OPG delivery significantly increased the gene expression of pro-inflammatory and pro-fibrotic mediators, as well as the glomerular nitrosylation of proteins. Conclusions This study shows that OPG is associated with CKD in hypertensive patients, where it might have a higher predictive value than that of hypertension for CKD development. Secondly, we found that OPG delivery significantly increased the expression of molecular pathways involved in kidney damage. Further longitudinal studies are needed not only to evaluate whether OPG predicts CKD development but also to clarify whether OPG should be considered a risk factor for CKD. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0625-3) contains supplementary material, which is available to authorized users.

Primary aldosteronism (PA), also known as Conn’s syndrome, is a frequent cause of secondary hypertension. If PA is due to a documented unilateral adrenal adenoma, adrenalectomy is the treatment of choice. Endocrine Society guidelines suggest monitoring potassium after adrenalectomy, while there is no mention of sodium disorders after surgery. Here we report the case of a patient with Conn’s syndrome who developed hyponatremia after surgery. This was an unexpected event in the course of the treatment, which sheds light on the fact that low levels of aldosterone strongly influence sodium concentration, and advises clinicians to monitor sodium after adrenalectomy.

Background. Dyslipidemia and diabetes are two of the most well established risk factors for the development of cardiovascular disease (CVD). Both of them usually activate a complex range of pathogenic pathways leading to organ damage. Here we hypothesized that dyslipidemia and diabetes could affect osteoprotegerin (OPG) and TNF-related apoptosis-inducing ligand (TRAIL) expression in the vessels and the heart. Materials and Methods. Gene and protein expression of OPG, TRAIL, and OPG/TRAIL ratio were quantified in the aorta and the hearts of control mice, dyslipidemic mice, and diabetic mice. Results. Diabetes significantly increased OPG and the OPG/TRAIL ratio expression in the aorta, while dyslipidemia was the major determinant of the changes observed in the heart, where it significantly increased OPG and reduced TRAIL expression, thus increasing cardiac OPG/TRAIL ratio. Conclusions. This work shows that both dyslipidemia and diabetes affect OPG/TRAIL ratio in the cardiovascular system. This could contribute to the changes in circulating OPG/TRAIL which are observed in patients with diabetes and CVD. Most importantly, these changes could mediate/contribute to atherosclerosis development and cardiac remodeling.

Benign thyroid nodules are an extremely common occurrence. Radiofrequency ablation (RFA) is gaining ground as an effective technique for their treatment, in case they become symptomatic. Here we review what are the current indications to RFA, its outcomes in terms of efficacy, tolerability, and cost, and also how it compares to the other conventional and experimental treatment modalities for benign thyroid nodules. Moreover, we will also address the issue of treating with this technique patients with cardiac pacemakers (PM) or implantable cardioverter-defibrillators (ICD), as it is a rather frequent occurrence that has never been addressed in detail in the literature.

Radiofrequency ablation has been advocated as an alternative to radioiodine and/or surgery for the treatment of autonomously functioning benign thyroid nodules. However, only a few studies have measured radiofrequency ablation efficacy on autonomously functioning benign thyroid nodules. The aim of this work was to evaluate the 12-month efficacy of a single session of radiofrequency ablation (performed with the moving shot technique) on solitary autonomously functioning benign thyroid nodules.Thirty patients with a single, benign autonomously functioning benign thyroid nodules, who were either unwilling or ineligible to undergo surgery and radioiodine, were treated with radiofrequency ablation between April 2012 and May 2015. All the patients underwent a single radiofrequency ablation, performed with the 18-gauge needle and the moving shot technique. Clinical, laboratory, and ultrasound evaluations were scheduled at baseline, and after 1, 3, 6, and 12 months from the procedure.A single radiofrequency ablation reduced thyroid nodule volume by 51, 63, 69, and 75 % after 1, 3, 6, and 12 months, respectively. This was associated with a significant improvement of local cervical discomfort and cosmetic score. As for thyroid function, 33 % of the patients went into remission after 3 months, 43 % after 6 months, and 50 % after 12 months from the procedure. This study demonstrates that a single radiofrequency ablation allowed us to withdraw anti-thyroid medication in 50 % of the patients, who remained euthyroid afterwards.This study shows that a single radiofrequency ablation was effective in 50 % of patients with autonomously functioning benign thyroid nodules. Patients responded gradually to the treatment. It is possible that longer follow-up studies might show greater response rates.

Since the advent of insulin, the improvements in diabetes detection and the therapies to treat hyperglycemia have reduced the mortality of acute metabolic emergencies, such that today chronic complications are the major cause of morbidity and mortality among diabetic patients. More than half of the mortality that is seen in the diabetic population can be ascribed to cardiovascular disease (CVD), which includes not only myocardial infarction due to premature atherosclerosis but also diabetic cardiomyopathy. The importance of renin-angiotensin-aldosterone system (RAAS) antagonism in the prevention of diabetic CVD has demonstrated the key role that the RAAS plays in diabetic CVD onset and development. Today, ACE inhibitors and angiotensin II receptor blockers represent the first line therapy for primary and secondary CVD prevention in patients with diabetes. Recent research has uncovered new dimensions of the RAAS and, therefore, new potential therapeutic targets against diabetic CVD. Here we describe the timeline of paradigm shifts in RAAS understanding, how diabetes modifies the RAAS, and what new parts of the RAAS pathway could be targeted in order to achieve RAAS modulation against diabetic CVD.

Deficiency of ACE2 (angiotensin-converting enzyme 2), which degrades Ang (angiotensin) II, promotes the development of glomerular lesions. However, the mechanisms explaining why the reduction in ACE2 is associated with the development of glomerular lesions have still to be fully clarified. We hypothesized that ACE2 may regulate the renoprotective actions of ANP (atrial natriuretic peptide). The aim of the present study was to investigate the effect of ACE2 deficiency on the renal production of ANP. We evaluated molecular and structural abnormalities, as well as the expression of ANP in the kidneys of ACE2-deficient mice and C57BL/6 mice. We also exposed renal tubular cells to AngII and Ang-(1–7) in the presence and absence of inhibitors and agonists of RAS (renin–angiotensin system) signalling. ACE2 deficiency resulted in increased oxidative stress, as well as pro-inflammatory and profibrotic changes. This was associated with a down-regulation of the gene and protein expression on the renal production of ANP. Consistent with a role for the ACE2 pathway in modulating ANP, exposing cells to either Ang-(1–7) or ACE2 or the Mas receptor agonist up-regulated ANP gene expression. This work demonstrates that ACE2 regulates renal ANP via the generation of Ang-(1–7). This is a new mechanism whereby ACE2 counterbalances the renal effects of AngII and which explains why targeting ACE2 may be a promising strategy against kidney diseases, including diabetic nephropathy.

ObjectiveAcromegaly is associated with increased cardiovascular morbidity and mortality and with specific heart and vascular abnormalities. The aim of our study was to investigate arterial stiffness using the ambulatory arterial stiffness index (AASI) and symmetric AASI (Sym-AASI), two indexes derived from 24-h ambulatory blood pressure monitoring (ABPM), in a group of normotensive and hypertensive patients with active acromegaly, compared with normotensive controls (NOR-CTR) or hypertensive controls (HYP-CTR).Subjects and methodsNinety-six consecutive patients with active acromegaly (46 males, mean age 49±14 years) underwent 24-h ABPM and evaluation of cardiovascular risk factors. Based on ABPM measurement, acromegalic patients were divided into 64 normotensive (normotensive acromegalic patients (NOR-ACRO)) and 32 hypertensive (hypertensive acromegalic patients (HYP-ACRO)) patients, and were compared with 35 normotensive (NOR-CTR) and 34 hypertensive (HYP-CTR) age-, sex,- and ABPM-matched control subjects.ResultsThe AASI and Sym-AASI indexes were significantly higher in acromegalic patients than in controls, either in the normotensive (NOR-ACRO vs NOR-CTR, PP=0.005 for Sym-AASI) or in the hypertensive (HYP-ACRO vs HYP-CTR, P=0.01 for AASI and P=0.01 for Sym-AASI) group. Multiple logistic regression analysis showed a significant association of the highest AASI tertile with serum IGF1 (P=0.034) in the whole acromegalic group.ConclusionAASIs are increased in acromegaly, independent of blood pressure (BP) elevation, and may have an important role in predicting cardiovascular risk in this disease.

Recent clinical trials carried out in patients with advanced cancer have shown that recombinant TRAIL administration is usually safe and well tolerated when used either alone or in association with chemotherapeutic drugs. Notably, anticancer chemotherapy can be associated to cardiomiopathy. We have here demonstrated that TRAIL (administrated as either recombinant soluble TRAIL or as AAV-TRAIL expression viral vector) reduced the development of cardiomyopathy in the ApoE(-/-) diabetic mouse model. These data suggest, for the first time, that therapeutically administration of TRAIL might have a cardioprotective effect.

Background. The mechanisms of uraemia-induced atherosclerosis have not been fully delineated. The aims of this study were (i) to investigate the extent and the phenotype of atherosclerosis, including the activation of local renin―angiotensin system (RAS), in a mouse model of mild uraemia and (ii) to determine the effects of angiotensin II typel (AT1) receptor blockade on the uraemic atherosclerosis, clarifying the mechanisms of its action. Methods. Mild uraemia was induced by 5/6 nephrectomy in 8-week-old apo E-deficient mice (apoE-KO). After nephrectomy, the animals received either treatment with candesartan or no treatment for 12-weeks. Sham-operated apoE-KO mice were used as controls. Results. Uraemia led to a two-fold increase in aortic plaque area. This was associated with a significant upregulation of aortic angiotensin-converting enzyme (ACE), AT1 receptor, connective tissue growth factor (CTGF), monocyte chemoattractant protein (MCP)-1 and vascular cell adhesion molecule (VCAM)-1. Candesartan significantly reduced aortic atherosclerosis, prevented the upregulation of the uraemia-induced genes and led to changes predicting greater stability of the plaques, without influencing blood pressure or serum lipids. Conclusions. This study indicates that uraemia leads to an acceleration of aortic atherosclerosis. The upregulation of aortic RAS and the reduced atherosclerosis following AT1 receptor blocker treatment highlights the pivotal role of the local RAS in the development and acceleration of atherosclerosis in uraemia.

OBJECTIVE To evaluate the potential therapeutic effect of recombinant human tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) treatment in a model of type 1 diabetes. RESEARCH DESIGN AND METHODS Recombinant TRAIL was added in vitro to primary human and mouse peripheral blood mononuclear cells (PBMCs) and isolated human islets to evaluate the expression of the immunoregulatory gene SOCS1. Diabetes was induced by five consecutive daily injections of low-concentration (50 mg/kg) streptozotocin (STZ) in C57 black mice (n = 24). A group of these mice (n = 12) was co-injected with recombinant TRAIL (20 μg/day) for 5 days, and the diabetic status (glycemia and body weight) was followed over time. After 6 weeks, circulating levels of insulin, TNF-α, and osteoprotegerin (OPG) were measured, and animals were killed to perform the histological analysis of the pancreas. RESULTS The in vitro exposure of both PBMCs and human islets to recombinant TRAIL significantly upregulated the expression of SOCS1. With respect to STZ-treated animals, mice co-injected with STZ+TRAIL were characterized by 1) lower levels of hyperglycemia, 2) higher levels of body weight and insulinemia, 3) a partial preservation of pancreatic islets with normal morphology, and 4) a lower expression of both systemic (TNF-α and OPG) and pancreatic (vascular cell adhesion molecule [VCAM]-1) inflammatory markers. CONCLUSIONS Overall, these data demonstrate that the administration of recombinant TRAIL ameliorates the severity of STZ-induced type 1 diabetes, and this effect was accompanied by the upregulation of SOCS1 expression.

Background Malignant hypertension is a condition characterized by severe hypertension and multi-organ ischemic complications. Albeit mortality and renal survival have improved with antihypertensive therapy, progression to end-stage renal disease remains a significant cause of morbidity and mortality. The underlying cause of malignant hypertension, which can be primary or secondary hypertension, is often difficult to identify and this can substantially affect the treatment outcomes, as we report here. Case presentation A 33-year-old woman presented with severe hypertension and acute renal failure. Initial evaluation demonstrated hyperreninemia with hyperaldosteronism and a possible renal artery stenosis at the contrast-enhanced CT scan. Although this data suggested the presence of a secondary form of hypertension, further exams excluded our first diagnosis of renal artery stenosis. Consequently, the patient did not undergo renal angiography (and the contrast media infusion associated with it), but she continued to be medically treated to achieve a tight blood pressure control. Our conservative approach was successful to induce renal function recovery over 2 years of follow-up. Conclusion This case highlights the difficulty in differentiating between primary and secondary forms of malignant hypertension, particularly when the patient presents with acute renal failure. Clinicians should consider renal artery ultrasound as a first level diagnostic technique, given that the presentation of primary malignant hypertension can often mimic a renal artery stenosis. Secondly, adequate control of blood pressure is essential for kidney function recovery, although this may require a long time.

Background: The association between chronic lymphocytic thyroiditis (CLT) and papillary thyroid car- cinoma (PTC) has been investigated for several years from different perspectives. In spite of that, there were only few attempts to design a common frame of references to understand the complex mutual interactions between the various pathways of inflammatory response and of thyroid tumor induction and progression. This study compares two independent groups of patients aiming to determine the frequency and the prognostic significance of CLT in patients with PTC. Material and methods: From January 2005 to September 2013, we conducted a retrospective study on 160 patients with PTC who underwent thyroidectomy. CLT was diagnosed histopathologically. Age, sex, tu- mor features (dimensions, angioinvasion, capsular infiltration, mono/multifocality and lymph node metastases) pathologic findings and outcome were considered. Mean follow-up (metastasis, completeness-of-resection, serum thyroglobulin levels, tumor recurrence) period was 61 months (ranged from 18 to 132 months). A p < 0.05 was considered statistically significant. Results: Patients were divided in 2 groups. In group A there were 90 patients affected by PTC alone, and in group B there were 70 patients affected with PTC associated with CLT. Our data showed that the presence of CLT correlate with a lower grade of PTC (p < 0.05). Considering the sex of the patients there were a statistically significant correlation (p < 0.02) and the presence of CLT associated with PTC was most representative in female patients. Conclusions: The presence of CLT in patients with PTC correlated with a lower grade of PTC, but it does not affect the overall survival of papillary thyroid cancers.

TRAIL or tumor necrosis factor (TNF) related apoptosis-inducing ligand is a member of the TNF superfamily of proteins, whose best characterized function is the induction of apoptosis in tumor, infected, or transformed cells through activation of specific receptors. In nontransformed cells, however, the actions of TRAIL are less well characterized. Recent studies suggest that TRAIL may be implicated in the development and progression of diabetes. Here we review TRAIL biological actions, its effects on the immune system, and how and to what extent it has been shown to protect against diabetes.

Introduction: At this time, good quality randomized clinical trials assessing the effects of vitamin D supplementation on cardiometabolic outcomes are lacking in the international literature. Aim: To fill this gap, the Working Group on Vitamin D and Cardiorenal Disorders established jointly by the Italian Society of Hypertension (SIIA) and the Forum in Bone and Mineral Research conceived the HYPODD study (HYPOvitaminosis D and organ Damage). Methods: HYPODD is a no-profit multicenter 12-month parallel-group double-blind placebo controlled randomized trial aiming to assess the effects of cholecalciferol supplementation on blood pressure control, antihypertensive drugs consumption and progression of target organ damage in patients with essential hypertension and 25-hydroxyvitamin D serum level lower than 20 ng/ml (vitamin D deficiency). HYPODD is coordinated by the European Society Excellence Center of Hypertension of Federico II University, Naples, and involves 12 academic institutions in Italy (Ancona, Milan, Padua, Perugia, Rome, Siena, Trieste, Turin, Udine, Varese, and Verona). Results and conclusion: The HYPODD study has been registered at the Agenzia Italiana del Farmaco-Osservatorio sulla Sperimentazione Clinica del Farmaco (AIFA-OsSC) and EUDRACT sites (n° 2012-003514-14) and has been approved by the Ethical Committees of all the Centers involved in the study. The patients' recruitment is currently underway.

Background. Radiofrequency ablation (RFA) has been recently advocated as an effective technique for the treatment of symptomatic benign thyroid nodules. It is not known to what extent it may affect any subsequent thyroid surgery and/or histological diagnosis.Materials and Methods. RFA was performed on 64 symptomatic Thy2 nodules (benign nodules) and 6 symptomatic Thy3 nodules (follicular lesions/follicular neoplasms). Two Thy3 nodules regrew after the procedure, and these patients accepted to undergo a total thyroidectomy. Here we present how RFA has affected the operation and the final pathological features of the surgically removed nodules.Results and Conclusions. RFA is effective for the treatment of Thy2 nodules, but it should not be recommended as first-line therapy for the treatment of Thy3 nodules (irrespective of their mutational status), as it delays surgery in case of malignancy. Moreover, it is unknown whether RFA might promote residual tumor progression or neoplastic progression of Thy3 lesions. Nevertheless, here we show for the first time that one session of RFA does not affect subsequent thyroid surgery and/or histological diagnosis.

Objective: Experimental evidence suggests that aldosterone directly contributes to organ damage by promoting cell growth, fibrosis, and inflammation. Based on these premises, this work aimed to assess the glomerular effects of aldosterone, alone and in combination with salt. Methods: After undergoing uninephrectomy, 75 rats were allocated to five groups: control, salt diet, aldosterone, aldosterone + salt diet, aldosterone + salt diet and eplerenone, and they were all studied for four weeks. We focused on glomerular structural, functional, and molecular changes, including slit diaphragm components, local renin–angiotensin system activation, as well as pro-oxidative and profibrotic changes. Results: Aldosterone significantly increased systolic blood pressure, led to glomerular hypertrophy, mesangial expansion, and it significantly increased the glomerular permeability to albumin and the albumin excretion rate, indicating the presence of glomerular damage. These effects were worsened by adding salt to aldosterone, while they were reduced by eplerenone. Aldosterone-induced glomerular damage was associated with glomerular angiotensin-converting enzyme (ACE) 2 downregulation, with ACE/ACE2 ratio increase, ANP decrease, as well as with glomerular pro-oxidative and profibrotic changes. Conclusions: Aldosterone damages not only the structure but also the function of the glomerulus. ACE/ACE2 upregulation, ACE2 and ANP downregulation, and pro-oxidative and profibrotic changes are possible mechanisms accounting for aldosterone-induced glomerular injury.

Transsexualism refers to a condition where an individual identifies with a gender that differs from the assigned sex. Transsexual subjects may suffer from gender dysphoria, which is the distress caused by the feeling of being born to the wrong biologic sex. Gender dysphoria is undoubtedly a complex and multifaceted problem that requires a multidisciplinary approach for its diagnosis and treatment. It goes without saying that the goal of the therapy is to harmonize physical appearance with gender identity. In order to do so, treatments need to be customized, as some individuals need cross-sex hormone therapy and surgery to alleviate their gender dysphoria, others need only one of these treatment options, and some need neither.

The aim of this study was to investigate the short‐term blood pressure (BP) variability (BPV) derived from ambulatory blood pressure monitoring (ABPM) in patients with primary aldosteronism (PA), either idiopathic hyperaldosteronism (IHA) or aldosterone‐producing adenoma (APA), in comparison with patients with essential hypertension (EH) and normotensive (NT) controls. Thirty patients with PA (16 with IHA and 14 with APA), 30 patients with EH, and 30 NT controls, matched for sex, age, body mass index, and antihypertensive therapy, were studied. The standard deviation (SD) of 24‐hour, daytime, and nighttime BP; 24‐hour weighted SD of BP; and 24‐hour BP average real variability were not different between patients with PA and those with EH (P=not significant). All BPV indices were higher in patients with PA, either IHA or APA subtypes, and patients with EH, compared with NT controls (P