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Purpose: Endocrine-disrupting compounds, including bisphenol A (BPA), may promote obesity influencing basal metabolic rate and shifting metabolism towards energy storage. The role of 1,25‑Dihydroxyvitamin D3 (VitD) in counteracting adipogenesis is still a matter of debate. Thus, the current study aims to investigate whether and how VitD exposure during adipogenesis could prevent the pro-adipogenic effect of BPA in two adipocyte models, mouse 3T3-L1 cell line and human adipose-derived mesenchymal stem cells (hAMSC)., Methods: 3T3-L1, mouse pre-adipocytes and human adipose-derived mesenchymal stem cells (hAMSC) were treated with VitD (10 -7  M) and BPA (10 -8  M and 10 -9  M), alone or in combination, throughout the differentiation in mature adipocytes. Cellular lipid droplet accumulation was assessed by Oil Red O staining, mRNA and protein expression of key adipogenic markers, transcription factors, and cytokines were investigated by RT-qPCR and WB, respectively. miRNAs involved in the regulation of adipogenic transcription factors were evaluated by RT-qPCR, and highly potent steric-blocking oligonucleotides (miRNA inhibitors) were used to modulate miRNAs expression., Results: Pre-adipocytes express VitD receptor (VDR) in basal condition, but during the differentiation process VDR expression reduces if not stimulated by the ligand. VitD significantly decreases lipid accumulation, with a consequent reduction in adipogenic marker expression, and counteracts the pro-adipogenic effect of BPA in 3T3-L1 and hAMSC during differentiation. This effect is associated to the increased expression of miR-27a-3p and miR-27b-3p. The blocking of miR-27a-3p and miR-27b-3p through miRNA inhibitors prevents the anti-adipogenic effect of VitD in both cell models., Conclusions: These results suggest that in cultured 3T3-L1 and hAMSC VitD induces an anti-adipogenic effect and prevents BPA pro-adipogenic effect by triggering at least in part epigenetic mechanisms involving miR-27-3p., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Treatment-resistant schizophrenia (TRS) is a severe psychiatric disorder that is associated with a high level of psychotic symptoms and cognitive deficit as well as poor functioning, and an increased risk of mortality for cardiometabolic diseases. Some studies suggest that lifestyle, particularly diet, could represent a risk factor for obesity and its metabolic complications in these patients., Methods: This cross-sectional study aimed to evaluate diet quality and eating habits in individuals with TRS. Seventeen participants (13M/4F aged 37.8±13 years) were recruited to assess dietary composition and food groups consumption by a 7days food record to assess. In addition, demographic and clinical data were collected., Results: Most of the participants were overweight/obese (82%) and only 35% performed physical activity. As compared to nutritional recommendations, participants presented an insufficient intake of fiber (15.9±3.2 g/day), vitamins (thiamine, riboflavin, vitamin A, D, and E), minerals (calcium, magnesium, selenium, and iron), and polyunsaturated fatty acids (2.11±0.8%), likely triggered by the low consumption plant-based foods (legumes, fruit, vegetables, and nuts) and fish. Participants exceeded the intake of saturated fatty acids (11.6±3.4%) and cholesterol (242±124 mg/day), and simple sugars (15.2±3.9%) which were mainly related to greater consumption of red meat and processed meat, and sweet foods, respectively., Conclusions: Individuals with TRS presented low diet quality and did not comply with the nutritional recommendations. These results support the importance of including nutritional assessment in the management of individuals with TRS.

Context: Prolactin (PRL) is a crucial mediator of glucoinsulinemic metabolism., Objective: This work aims to dissect glucose metabolism during and after pregnancy in patients with prolactinomas., Methods: A total of 52 patients treated with cabergoline (CAB) were evaluated before conception, during pregnancy, and up to 10 years after delivery. During pregnancy, CAB was discontinued, while it was restarted in 57.7% of patients after delivery, due to recurrent hyperprolactinemia (RH). Hormonal (serum PRL) and metabolic (glycated hemoglobin A1c [HbA1c], fasting glucose [FG], glucose tolerance) parameters were assessed., Results: During pregnancy, PRL gradually increased, while FG remained stable. An inverse correlation between PRL and FG was found in the first (P = .032) and third (P = .048) trimester. PRL percentage increase across pregnancy was inversely correlated with third-trimester FG. Serum PRL before conception emerged as a predictive biomarker of third-trimester FG (t = 2.603; P = .048). Older patients with lower HbA1c in the first trimester and lower FG at 3 years post partum delivered infants with reduced birth weight. Breastfeeding up to 6 months correlated with lower FG at 4 and 10 years post partum. A positive correlation between BMI and FG at 10 years after delivery (P = .03) was observed, particularly in overweight/obese patients requiring higher CAB doses. Patients with RH who had to restart CAB showed shorter breastfeeding duration and higher FG at 2 years post partum., Conclusion: Low PRL levels before pregnancy may be detrimental to FG during pregnancy. CAB duration and dose may influence long-term glucose tolerance, besides family history and BMI. Preconception metabolic management should be recommended to reduce the risk of gestational and type 2 diabetes mellitus., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Objectives: The Mediterranean Diet (MD) has been recognized for its benefits for human health and sustainability for the planet, but it has considered not easy to reproduce in other populations. The United Nations Educational, Scientific and Cultural Organization (UNESCO) Chair on Health Education and Sustainable Development is fostering a research project (Planeterranea), aiming to identify a healthy dietary pattern based on local foods with the same MD features. The aim of our study is to develop a MD-based food pyramid for Asian populations., Methods: Asia was stratified into six areas according to pedo-climatic conditions. For each region a comprehensive scoping review of local crops and typical foods was conducted on several databases such as the US Department of Agriculture (USDA)'s database, the Food and Agriculture Organization of the United Nations (FAO) website, and PubMed, focusing on both plant-based and animal-based foods. Narrative review was then conducted on the identified foods to determine their nutritional composition and planetary health impact. Finally, the collected information was used to build up the Asian food pyramid with details for each respective region., Results: We proposed a food pyramid for Asian countries, guaranteeing the same nutritional intake and health benefits as MD, by considering dietary habits and typical foods of this population. From the bottom to the top, Asian fruits and vegetables present similar nutritional profile as those in MD. Whole grains (barley) may represent valid alternative to white rice. Sesame oil represents a source of unsaturated fats and an alternative to olive oil. Legumes (soybean), edible insects, mushrooms and algae, guarantee an adequate intake of plant-based proteins with a complete amino-acid profile and a low environmental impact with respect to animal-based ones., Conclusions: This work is a new insight of healthy and sustainable local food system based on MD principles for the Asian population., (© 2024. The Author(s).)

We report the first case of a child with 16p11.2 microduplication syndrome with increased fluid in the cisterna magna seen on magnetic resonance imaging (MRI). This finding may correspond to a Blake's Pouch Cyst (BPC) or a Mega Cisterna Magna (MCM), being impossible to differentiate through image examination. The molecular duplication was diagnosed using chromosomal microarray analysis with single nucleotide polymorphism (SNP). We review the clinical and neuroimaging features in published case reports in order to observe the findings described in the literature so far and present a skull three-dimensional model to contribute to a better understanding. Despite the variable expressivity of the syndrome being well known, there is no case described in the available literature that mentions the association of 16p11.2 microduplication and the presence of BPC or MCM seen in neuroimaging exams. This finding may represent an extension of the phenotype not yet reported or may present itself as a coincidence in a child with various malformations.

In the pathogenesis of type 2 diabetes mellitus (T2DM), diet plays a key role. Individualized medical nutritional therapy, as part of lifestyle optimization, is one of the cornerstones for the management of T2DM and has been shown to improve metabolic outcomes. This paper discusses major aspects of the nutritional intervention (including macro- and micronutrients, nutraceuticals, and supplements), with key practical advice. Various eating patterns, such as the Mediterranean-style, low-carbohydrate, vegetarian or plant-based diets, as well as healthy eating plans with caloric deficits have been proven to have beneficial effects for patients with T2DM. So far, the evidence does not support a specific macronutrient distribution and meal plans should be individualized. Reducing the overall carbohydrate intake and replacing high glycemic index (GI) foods with low GI foods have been shown as valid options for patients with T2DM to improve glycemic control. Additionally, evidence supports the current recommendation to reduce the intake of free sugars to less than 10% of total energy intake, since their excessive intake promotes weight gain. The quality of fats seems to be rather important and the substitution of saturated and trans fatty acids with foods rich in monounsaturated and polyunsaturated fats lowers cardiovascular risk and improves glucose metabolism. There is no benefit of supplementation with antioxidants, such as carotene, vitamins E and C, or other micronutrients, due to the lack of consistent evidence showing efficacy and long-term safety. Some studies suggest possible beneficial metabolic effects of nutraceuticals in patients with T2DM, but more evidence about their efficacy and safety is still needed.

Over the last years, the metabolic role of PRL has emerged. PRL excess is known to promote weight gain, obesity, metabolic syndrome, and impairment in gluco-insulinemic and lipid profiles, likely due to the suppression of physiologic dopaminergic tone. Prolactin receptors and dopamine receptors type 2 have been demonstrated to be expressed on both human pancreatic β- cell and adipocytes, supporting a key role of prolactin and dopamine in peripheral metabolic regulation. Medical treatment with the dopamine agonists bromocriptine and cabergoline has been demonstrated to decrease the prevalence of metabolic syndrome and obesity, and significantly improve gluco-insulinemic and lipid profiles. In hyperprolactinemic men with concomitant hypogonadism, correction of hyperprolactinaemia and testosterone replacement has been proven to restore metabolic impairment. In turn, low prolactin levels have also been demonstrated to exert a detrimental effect on weight gain, glucose and lipid metabolism, thus leading to an increased prevalence of metabolic syndrome. Therefore, PRL values ranging from 25 to 100 mg/L, in absence of other recognizable pathological causes, have been proposed to represent a physiological response to the request for an increase in metabolic activity, and nowadays classify the so-called HomeoFIT- PRL as a promoter of metabolic homeostasis. The current review focuses mainly on the effects of hyperprolactinemia and its control by medical treatment with DAs on the modulation of food intake, body weight, gluco-insulinemic and lipid profile. Furthermore, it provides the latest knowledge about the metabolic impact of hypoprolactinemia., 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 Pirchio, Graziadio, Colao, Pivonello and Auriemma.)

Giant pituitary adenomas are a subgroup of pituitary adenomas defined by a diameter greater than 4 cm, and they account for 5-14% of adenomas in surgical series. Because of their growth patterns and locations, often involving critical neurovascular structures, they represent a true surgical challenge, and gross total resection is difficult to achieve. There is no consensus on the optimal surgical strategy for giant pituitary adenomas, and, often, integrated multi-staged treatment strategies have been considered. Transcranial or transsphenoidal approaches, alone or combined, according to tumor and patient features are the two main routes. Each of these strategies has pros and cons. The conventional transcranial approach has for a long time been considered the first choice for the removal of giant pituitary adenomas. Currently, with endoscopic techniques, it is also possible to remove lesions that involve the intradural compartment and the adjacent neurovascular structures with the use of extended approaches. Our policy for the management of these lesions is to adopt the endoscopic endonasal approach as the first choice unless the tumor presents significant intracranial extension that results in it being outside the visibility and maneuverability of the endoscopic endonasal route. In these latter cases, we agree that the transcranial approach is more appropriate. However, accurate preoperative evaluation and refined treatment plans for each patient are mandatory to define a proper strategy in order to achieve the most effective long-term result.

Non-communicable diseases (NCDs) lead to a dramatic burden on morbidity and mortality worldwide. Diet is a modifiable risk factor for NCDs, with Mediterranean Diet (MD) being one of the most effective dietary strategies to reduce diabetes, cardiovascular diseases, and cancer. Nevertheless, MD transferability to non-Mediterranean is challenging and requires a shared path between the scientific community and stakeholders. Therefore, the UNESCO Chair on Health Education and Sustainable Development is fostering a research project-"Planeterranea"-aiming to identify a healthy dietary pattern based on food products available in the different areas of the world with the nutritional properties of MD. This review aimed to collect information about eating habits and native crops in 5 macro-areas (North America, Latin America, Africa, Asia, and Australia). The information was used to develop specific "nutritional pyramids" based on the foods available in the macro-areas presenting the same nutritional properties and health benefits of MD., 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 Vetrani, Piscitelli, Muscogiuri, Barrea, Laudisio, Graziadio, Marino and Colao.)

During the last decades, the gut microbiota has gained much interest in relation to human health. Mounting evidence has shown a strict association between gut microbiota and obesity and its related diseases. Inflammation has been appointed as the driving force behind this association. Therefore, a better understanding of the mechanisms by which gut microbiota might influence inflammation in the host could pave for the identification of effective strategies to reduce inflammation-related diseases, such as obesity and obesity-related diseases. For this purpose, we carried out an extensive literature search for studies published in the English language during the last 10 years. Most relevant studies were used to provide a comprehensive view of all aspects related to the association of gut microbiota and low-grade inflammation with obesity. Accordingly, this narrative review reports the evidence on the key players supporting the role of gut microbiota in the modulation of inflammation in relation to obesity and its complications. Moreover, therapeutic approaches to reduce microbiota-related inflammation are discussed to provide potential targets for future research.

Obesity is a chronic condition whose management is a critical challenge for physicians. The scientific community has increased its focus on the molecular mechanisms involved in obesity etiopathogenesis to better manage patients with obesity and its associated complications. The tight connection between adipose tissue and the immune system has been demonstrated to play a crucial role in inflammation, and melatonin is important for circadian rhythm regulation and metabolic homeostasis, in which it orchestrates several molecular mechanisms involved in obesity and associated inflammation. Melatonin also regulates innate and adaptive immunity; its antioxidant properties are linked to reduced predisposition to infection and weight gain in patients with obesity through the modulation of the immune response, which has a significant beneficial effect on inflammation and, consequently, on the metabolic state. Low melatonin levels have been linked to obesity, and melatonin supplementation can reduce body weight, improve metabolic profile, and ameliorate immune responses and pro-inflammatory stimuli. The role of melatonin in obesity is mainly related to improved oxidative stress signaling, modulation of adipokine secretion, and a switching from white-to-brown adipose tissue phenotype and activity. Moreover, the role of melatonin in obesity modulation by controlling circadian rhythm has recently emerged as a pivotal mechanism for lipid and glucose metabolism dysfunction in adipose, muscle, and liver tissues. Melatonin may also regulate the immune system by acting directly on thymus morphology and activity as well as by modulating oxidative stress and inflammatory states during infections. The tight association between melatonin and immune response regulation is coordinated by Toll-like receptors, which are rhythmically expressed during the day. Their expression may be strongly modulated by melatonin as their signaling is highly inhibited by melatonin. The current review summarizes studies of melatonin-induced mechanisms involved in infection regulation, particularly the modulation of obesity-associated inflammation and systemic complications., (© 2021 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

The current pandemic due to widespread SARS-CoV-19 infection has again highlighted the role of obesity, whose global prevalence increased up to 13%, as a risk factor for both susceptibility to infections and the occurrence of a more severe disease course. To date, this association has not been sufficiently explored. Obesity-related susceptibility to infectious diseases is mostly thought to be due to an impairment of both innate and adaptive immune responses and vitamin D deficiency. Several cofactors can indirectly favour the onset and/or worsening of infectious diseases, such as impairment of respiratory mechanics, skin and subcutaneous tissue homoeostasis, obesity-related comorbidities and inappropriate antimicrobial therapy. Subjects with obesity have a higher incidence of cutaneous infections, probably due to changes in skin barrier functions and wound healing. Excess weight is also associated with an increased risk of urinary tract infection and its recurrence, as well as with a higher prevalence of both lower and higher respiratory tract infections. Moreover, patients with obesity appear to have an increased risk of surgical site infections when undergoing general, orthopaedic, gynaecological, and bariatric surgery. Data concerning the different infectious diseases related to obesity are rather limited since anthropometric parameters are usually poorly recorded. Furthermore, specific therapeutic protocols in subjects with obesity are lacking, especially regarding antibiotic therapy and further supplements. This review summarizes etiopathogenetic and epidemiological evidence and highlights areas of uncertainty in the field of infectious diseases and obesity, which require further research. It is important to raise public awareness of this additional risk related to obesity and to raise awareness among the scientific community to develop specific clinical protocols for subjects with obesity., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Obesity is a major public health issue, and its trend is increasing worldwide. Interventions to effectively treat obesity and its related diseases are advocated. Given the complexity of obesity management, nurses need specific core skills to work in the Obesity Clinic and can act as key players in the multidisciplinary team of the Obesity Clinic. To provide practical guidelines for nurses working in Obesity Clinic for effective management of obesity and its related diseases, the current evidence on the role nurses in the obesity clinic was reviewed. Nurses can play a pivotal role in the management of patients with obesity and associated diseases that may require a stricter follow-up than usual care. Given the complexity of the treatment of obesity and its comorbidity, nurses should receive a specific training for: 1) methods and tools to effectively treat obesity and obesity-related disease; 2) patients and families education on nutrition, lifestyle changes, and prevention/management of obesity-related diseases; 3) motivation of patients towards adherence to treatment to achieve their specific goals. This review highlights the need of specific core skills for nurses working in the Obesity Clinic.

Individual differences in the chronotype, an attitude that best expresses the individual circadian preference in behavioral and biological rhythms, have been associated with cardiometabolic risk and gut dysbiosis. Up to now, there are no studies evaluating the association between chronotypes and circulating TMAO concentrations, a predictor of cardiometabolic risk and a useful marker of gut dysbiosis. In this study population (147 females and 100 males), subjects with the morning chronotype had the lowest BMI and waist circumference ( p < 0.001), and a better metabolic profile compared to the other chronotypes. In addition, the morning chronotype had the highest adherence to the Mediterranean diet ( p < 0.001) and the lowest circulating TMAO concentrations ( p < 0.001). After adjusting for BMI and adherence to the Mediterranean diet, the correlation between circulating TMAO concentrations and chronotype score was still kept (r = -0.627, p < 0.001). Using a linear regression analysis, higher chronotype scores were mostly associated with lower circulating TMAO concentrations (β = -0.479, t = -12.08, and p < 0.001). Using a restricted cubic spline analysis, we found that a chronotype score ≥59 ( p < 0.001, R 2 = -0.824) demonstrated a more significant inverse linear relationship with circulating TMAO concentrations compared with knots <59 (neither chronotype) and <41 (evening chronotype). The current study reported the first evidence that higher circulating TMAO concentrations were associated with the evening chronotype that, in turn, is usually linked to an unhealthy lifestyle mostly characterized by low adherence to the MD.

Phase angle (PhA), a noninvasive bioimpedance marker, is a useful tool for nutritional screening in several diseases. C-reactive protein (CRP), a strong risk factor for metabolic and cardiovascular diseases, is a commonly used biomarker of meta-inflammation. As both PhA and CRP are influenced by age, BMI, and nutritional status, and exhibit a clear sex dimorphism, we examined the association between PhA and CRP levels in 1855 subjects (680 males and 1175 females), aged 18-59 years, with BMIs ranging from 19.5 to 69.4 kg/m 2 , stratified according to sex. PhA values and CRP levels were significantly lower in females than males ( p < 0.001), while the adherence to the Mediterranean diet (MD) was lower in males compared to females ( p < 0.001). After adjusting for age, physical activity, BMI, waist circumference, and adherence to the MD, PhA remained negatively associated with CRP levels in both genders ( p < 0.001). In the ROC analysis, PhA ≤ 5.5° in males and ≤5.4° in females were the threshold values predicting increased hs-CRP levels. These results suggested that PhA might represent a valid predictor of CRP levels in both sexes regardless of body weight and adherence to the MD, which avoids the collection of blood sampling and expensive biochemical assays.

We aim to characterize patients with Gomez-López-Hernández syndrome (GLHS) clinically and to investigate them molecularly. A clinical protocol, including a morphological and neuropsychological assessment, was applied to 13 patients with GLHS. Single-nucleotide polymorphism (SNP) array and whole-exome sequencing were undertaken; magnetic resonance imaging was performed in 12 patients, including high-resolution, heavily T2-weighted sequences (HRT2) in 6 patients to analyze the trigeminal nerves. All patients presented alopecia; two did not present rhombencephalosynapsis (RES); trigeminal anesthesia was present in 5 of the 11 patients (45.4%); brachycephaly/brachyturricephaly and mid-face retrusion were found in 84.6 and 92.3% of the patients, respectively. One patient had intellectual disability. HRT2 sequences showed trigeminal nerve hypoplasia in four of the six patients; all four had clinical signs of trigeminal anesthesia. No common candidate gene was found to explain GLHS phenotype. RES does not seem to be an obligatory finding in respect of GLHS diagnosis. We propose that a diagnosis of GLHS should be considered in patients with at least two of the following criteria: focal non-scarring alopecia, rhombencephalosynapsis, craniofacial anomalies (brachyturrycephaly, brachycephaly or mid-face retrusion), trigeminal anesthesia or anatomic abnormalities of the trigeminal nerve. Studies focusing on germline whole genome sequencing or DNA and/or RNA sequencing of the alopecia tissue may be the next step for the better understanding of GLHS etiology., (© 2020 Wiley Periodicals LLC.)

The distinction between pseudo-Cushing's states (PCS) and Cushing's syndrome (CS) poses a significant clinical challenge even for expert endocrinologists. A patient's clinical history can sometimes help to distinguish between them (as in the case of alcoholic individuals), but the overlap in clinical and laboratory findings makes it difficult to arrive at a definitive diagnosis. We aim to describe the most common situations that can give rise to a condition resembling overt endogenous hypercortisolism and try to answer questions that physicians often face in clinical practice. It is important to know the relative prevalence of these different situations, bearing in mind that most of the conditions generating PCS are relatively common (such as metabolic syndrome and polycystic ovary syndrome), while CS is rare in the general population. Physicians should consider CS in the presence of additional features. Appropriate treatment of underlying conditions is essential as it can reverse the hormonal abnormalities associated with PCS. Close surveillance and a thorough assessment of a patient's hormone status will ultimately orient the diagnosis and treatment options over time.

We investigated 113 adult Brazilian patients with glioblastoma (GBM) for comparison with patients from distinct geographical areas and evaluation of suitability for novel targeted therapies. Patients were assessed for clinical features and tumor genomic characteristics such as ROS1 and NTRK1 rearrangements, KIT, PDGFRA, and KDR amplification, and RB1 deletion using multicolor fluorescence in situ hybridization. The majority of patients were male (53%), over 40 years (94%), with tumor located in single site (64%), in the right cerebral hemisphere (60%), and underwent partial resection (71%); 14% presented complications after surgery. The main clinical sign at diagnosis was focal abnormality (57%); frontal (31%); and temporal (20%) regions were most commonly affected. Median hospitalization time was 20 days, median survival was 175 days. One tumor was positive for rearrangement in NTRK1 and another in ROS1 (0.9% each). PDGFRA was amplified in 20% of cases, often co-amplified with KDR (>90%) and KIT (>60%). RB1 was deleted in 16% of patients. There was no association between these molecular abnormalities and patient survival. However, older age, complications after surgery, and right-sided tumors were independent variables associated with patient survival. This study contributes information on the molecular profile of glioblastomas in Latin America possibly supporting new target therapies., (2019 American Association of Neuropathologists, Inc.)

Secondary adrenal insufficiency (SAI) is a potentially life-threatening endocrine disorder due to an impairment of corticotropin (ACTH) secretion from any process affecting the hypothalamus or pituitary gland. ACTH deficit can be isolated or associated with other pituitary failures (hypopituitarism). An increased mortality due to cardiovascular, metabolic, and infectious diseases has been described in both primary and secondary adrenal insufficiency. However, few studies have provided compelling evidences on the underlying mechanism in SAI, because of the heterogeneity of the condition. Recently, some studies suggested that inappropriate glucocorticoid (GCs) replacement therapy, as for dose and/or timing of administration, may play a role. Hypertension, insulin resistance, weight gain, visceral obesity, increased body mass index, metabolic syndrome, impaired glucose tolerance, diabetes mellitus, dyslipidemia have all been associated with GC excess. These conditions are particularly significant when SAI coexists with other pituitary alterations, such as growth hormone deficiency, hypogonadism, and residual tumor. Novel regimen schemes and GC preparations have been introduced to improve compliance and better mimick endogenous cortisol rhythm. The controlled trials on the improved replacement therapies, albeit in the short-term, show some beneficial effects on cardiovascular risk, glucose metabolism, and quality of life. This review examines the current evidence from the available clinical trials investigating the association between different glucocorticoid replacement therapies (type, dose, frequency, and timing of treatment) and glycometabolic alterations in SAI.

Context: Adrenal insufficiency (AI) requires lifelong glucocorticoid (GC) replacement. Conventional therapies do not mimic the endogenous cortisol circadian rhythm. Clock genes are essential components of the machinery controlling circadian functions and are influenced by GCs. However, clock gene expression has never been investigated in patients with AI., Objective: To evaluate the effect of the timing of GC administration on circadian gene expression in peripheral blood mononuclear cells (PBMCs) of patients from the Dual Release Hydrocortisone vs Conventional Glucocorticoid Replacement in Hypocortisolism (DREAM) trial., Design: Outcome assessor-blinded, randomized, active comparator clinical trial., Participants and Intervention: Eighty-nine patients with AI were randomly assigned to continue their multiple daily GC doses or switch to an equivalent dose of once-daily modified-release hydrocortisone and were compared with 25 healthy controls; 65 patients with AI and 18 controls consented to gene expression analysis., Results: Compared with healthy controls, 19 of the 68 genes were found modulated in patients with AI at baseline, 18 of which were restored to control levels 12 weeks after therapy was switched: ARNTL [BMAL] (P = 0.024), CLOCK (P = 0.016), AANAT (P = 0.021), CREB1 (P = 0.010), CREB3 (P = 0.037), MAT2A (P = 0.013); PRKAR1A, PRKAR2A, and PRKCB (all P < 0.010) and PER3, TIMELESS, CAMK2D, MAPK1, SP1, WEE1, CSNK1A1, ONP3, and PRF1 (all P < 0.001). Changes in WEE1, PRF1, and PER3 expression correlated with glycated hemoglobin, inflammatory monocytes, and CD16+ natural killer cells., Conclusions: Patients with AI on standard therapy exhibit a dysregulation of circadian genes in PBMCs. The once-daily administration reconditions peripheral tissue gene expression to levels close to controls, paralleling the clinical outcomes of the DREAM trial (NCT02277587).

Background: Conventional treatment of patients with adrenal insufficiency involves administration of glucocorticoids multiple times a day and has been associated with weight gain and metabolic impairment. The optimal glucocorticoid replacement therapy for these patients is highly debated because of the scarcity of evidence from randomised trials. We aimed to establish whether the timing and pharmacokinetics of glucocorticoid replacement therapy affect the metabolism and immune system of patients with adrenal insufficiency., Methods: We did a single-blind randomised controlled trial at two reference university hospitals in Italy. Eligible patients (aged 18-80 years) with adrenal insufficiency were on conventional glucocorticoid therapy and had been stable for at least 3 months before enrolment. Patients were randomly assigned (1:1) with a computer-generated random sequence stratified by type of adrenal insufficiency and BMI to continue conventional glucocorticoid therapy (standard treatment group) or to switch to an equivalent dose of once-daily, modified-release oral hydrocortisone (switch treatment group). Outcome assessors were masked to treatment allocation. The primary outcome was bodyweight change from baseline to 24 weeks. Secondary outcomes included immune cell profiles, susceptibility to infections, and quality of life. Efficacy analyses included all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02277587., Findings: Between March 1, 2014, and June 30, 2016, 89 patients with adrenal insufficiency were randomly assigned to continue standard glucocorticoid therapy (n=43) or to switch to once-daily, modified-release hydrocortisone (n=46). At 24 weeks, bodyweight reduction was superior in patients in the once-daily hydrocortisone group compared with those in the standard treatment group (-2·1 kg [95% CI -4·0 to -0·3] vs 1·9 kg [-0·1 to 3·9]; treatment difference -4·0 kg, 95% CI -6·9 to -1·1; p=0·008). Additionally, patients in the once-daily hydrocortisone group had more normal immune cell profiles, reduced susceptibility to infections, and improved quality of life compared with the standard glucocorticoid therapy group. We observed no difference in frequency or severity of adverse events between the two intervention groups, although a lower cumulative number of recurrent upper respiratory tract infections was observed with once-daily hydrocortisone than with standard treatment (17 vs 38; p=0·016). Most adverse events were mild; three serious adverse events occurred in each group, of which one adverse advent (arthritis) in the switch treatment group could be considered drug related., Interpretation: Patients with adrenal insufficiency on conventional glucocorticoid replacement therapy multiple times a day exhibit a pro-inflammatory state and weakened immune defence. Restoration of a more physiological circadian glucocorticoid rhythm by switching to a once-daily, modified-release regimen reduces bodyweight, normalises the immune cell profile, reduces recurrent infections, and improves the quality of life of patients with adrenal insufficiency., Funding: Italian Ministry of University and Research., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Glioblastoma stands out as the most frequent central nervous system neoplasia, presenting a poor prognosis. The aim of this study was to verify the frequency and clinical significance of the aneuploidy of chromosomes 7 and 10, EGFR amplification, PTEN and TP53 deletions and 1p/19q deficiency in adult patients diagnosed with glioblastoma. The sample consisted of 40 patients treated from November 2011 to March 2015 at two major neurosurgery services from Southern Brazil. Molecular cytogenetic analyses of the tumor were performed through fluorescent in situ hybridization (FISH). The clinical features evaluated consisted of age, sex, tumor location, clinical symptoms, family history of cancer, type of resection and survival. The mean age of the patients was 59.3 years (ranged from 41 to 83). Most of them were males (70%). The median survival was 145 days. Chromosome 10 monosomy was detected in 52.5% of the patients, chromosome 7 polysomy in 50%, EGFR amplification in 42.5%, PTEN deletion in 35%, TP53 deletion in 22.5%, 1p deletion in 5% and 19q deletion in 7.5%. Age was shown to be a prognostic factor, and patients with lower age presented higher survival (p = 0.042). TP53 and PTEN deletions had a negative impact on survival (p = 0.011 and p = 0.037, respectively). Our data suggest that TP53 and PTEN deletions may be associated with a poorer prognosis. These findings may have importance over prognosis determination and choice of the therapy to be administered.

Oculoauriculovertebral spectrum (OAVS), also known as Goldenhar syndrome, is considered a condition associated to failing of embryogenesis involving the first and second branchial arches, leading to structural abnormalities arising from it. The aim of this study is to verify the hearing features presented by patients with OAVS and provide additional information that may contribute to improvement of speech therapy. The sample consisted of 10 individuals diagnosed with OAVS and cared for by the Clinical Genetics Service. All patients underwent objective assessment of auditory function through tonal and vocal audiometry. This evaluation was completed using TOAE and BERA. The patient's age ranged from 1 year and 9 months to 27 years and 4 months. At physical examination it was found that 10 had microtia, 7 preauricular tags, 6 low-set ears, 6 ear canal atresia, and 2 preauricular pits. Among the patients, five presented with abnormal hearing. Three patients had conductive hearing loss ranging from mild to moderate, and two patients had sensorineural hearing loss from mild to profound. Three patients had hearing loss in both ears. Speech-language disorders are common in children with OAVS. Thus, the referral to the audiologist and speech pathologist is indicated as soon as possible. Early recognition and detailed understanding of aspects related to the etiology, clinical features, and outcome of patients with OAVS are essential for their proper management. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Rationale: The case reported the rapid remission of disease recurrence achieved adding foscarnet, a DNA polymerase inhibitor that interacts with fibroblast growth factor 2, to low molecular weight heparin and sunitinib for the first time in a patient with an anaplastic thyroid cancer (ATC)., Patient Concerns: A 65-year-old woman with a multinodular goiter referred for a rapid enlargement of a nodule. Histological examination revealed an ATC with a little area of papillary thyroid cancer (PTC). The patient was resistant to selective single-target treatment., Diagnoses: Immunophenotyping and gene analyses found a significant increase in FGF2 and FGFR1 expression in the primary ATC area (FGF2 = 38.2 ± 6.2% in ATC vs 34.6 ± 6.0% in the differentiated area of PTC, P < 0.05; FGFR1: 41.7 ± 6.0% in ATC vs 34.4 ± 4.2% in PTC, P < 0.001) and in metastatic neck lymph nodes (P < 0.001 vs normal control tissues). Unlike conventional imaging, F-FDG PET/CT with PERCIST 1.0 criteria promptly and quantitatively detected disease recurrence and remission before and after multitarget therapy, combining anatomic, metabolic, and functional data., Interventions: Foscarnet was administered given the positivity for FGF2, FGFR1 and FGFR4 in ATC. Low molecular wight heparin and Sunitinib were coadministere to limiti metastatic progression and on neck tumor masse, respectively., Outcomes: The rationale for the clinical response to this innovative multitarget association with foscarnet is based on the histological and genetic finding that fibroblast growth factors and their receptor super-family are up-regulated in the primary anaplastic thyroid tumor and in the metastatic lymph node of our patient., Lessons: We propose that fibroblast growth factors and their receptor super-family play a key role as potential therapeutic targets in anaplastic thyroid cancer and the positive relevance of this suggestion for patient care, especially for an individualized management.

Calcitonin is the hallmark of medullary thyroid carcinoma. However, extrathyroidal neuroendocrine tumors can also release calcitonin.We report 2 cases of calcitonin-secreting pancreatic tumors found in asymptomatic patients with thyroid nodules referred to our center within 11 months.Case 1: A man initially referred for thyroid nodule characterization was found to have hypercalcitoninemia (>200 pg/mL) during non-neoplastic fine-needle aspiration.Case 2: A woman evaluated for liver metastasis was found to have hypercalcitoninemia and multinodular goiter.Our research emphasizes that marked hypercalcitoninemia in the presence of thyroid nodules is not necessarily due to medullary thyroid carcinoma; awareness of this could avoid unnecessary thyroidectomy. The lack of specific symptoms related to hypercalcitoninemia may be the reason that the prevalence of calcitonin-secreting pancreatic tumors is underestimated., Competing Interests: The authors have no conflicts of interest to disclose.