Semaglutide modulates prothrombotic and atherosclerotic mechanisms, associated with epicardial fat, neutrophils and endothelial cells network.

BACKGROUND: Obesity has increased in recent years with consequences on diabetes and other comorbidities. Thus, 1 out of 3 diabetic patients suffers cardiovascular disease (CVD). The network among glucose, immune system, endothelium and epicardial fat has an important role on pro-inflammatory and thrombotic mechanisms of atherogenesis. Since semaglutide, long-acting glucagon like peptide 1- receptor agonist (GLP-1-RA), a glucose-lowering drug, reduces body weight, we aimed to study its effects on human epicardial fat (EAT), aortic endothelial cells and neutrophils as atherogenesis involved-cardiovascular cells. METHODS: EAT and subcutaneous fat (SAT) were collected from patients undergoing cardiac surgery. Differential glucose consumption and protein cargo of fat-released exosomes, after semaglutide or/and insulin treatment were analyzed by enzymatic and TripleTOF, respectively. Human neutrophils phenotype and their adhesion to aortic endothelial cells (HAEC) or angiogenesis were analyzed by flow cytometry and functional fluorescence analysis. Immune cells and plasma protein markers were determined by flow cytometry and Luminex-multiplex on patients before and after 6 months treatment with semaglutide. RESULTS: GLP-1 receptor was expressed on fat and neutrophils. Differential exosomes-protein cargo was identified on EAT explants after semaglutide treatment. This drug increased secretion of gelsolin, antithrombotic protein, by EAT, modulated CD11b on neutrophils, its migration and endothelial adhesion, induced by adiposity protein, FABP4, or a chemoattractant. Monocytes and neutrophils phenotype and plasma adiposity, stretch, mesothelial, fibrotic, and inflammatory markers on patients underwent semaglutide treatment for 6 months showed a 20% reduction with statistical significance on FABP4 levels and an 80% increase of neutrophils-CD88. CONCLUSION: Semaglutide increases endocrine activity of epicardial fat with antithrombotic properties. Moreover, this drug modulates the pro-inflammatory and atherogenic profile induced by the adiposity marker, FABP4, which is also reduced in patients after semaglutide treatment.

Should we suspect primary aldosteronism in patients with hypokalaemic rhabdomyolysis? A systematic review.

Severe hypokalaemia causing rhabdomyolysis (RML) in primary aldosteronism (PA) is a rare entity, and only a few cases have been reported over the last four decades. This systematic review and case report aims to gather all published data regarding a hypokalaemic RML as presentation of PA in order to contribute to the early diagnosis of this extremely rare presentation. With the use of PubMed Central, EMBASE, and Google Scholar, a thorough internet-based search of the literature was conducted to identify articles and cases with RML secondary to hypokalaemia due to PA between June 1976 and July 2023. The case study concerns a 68-year-old male patient with hypokalaemic RML at presentation of PA. In the systematic review of the literature, 37 cases of RML secondary to hypokalaemia due to PA have been reported to date. In summary, the median age was 47.5 years, the male/female ratio was 17/21, all patients presented symptoms (weakness and/or myalgia), all the patients were hypertensive, and only four patients had complications with acute kidney injury (AKI). Although PA rarely presents with RML, it should be suspected when marked hypokalaemia and hypertension are also present. Early detection and management are essential to reduce the frequency of manifestations such as AKI.

GALIPDIA study: Reaching lipid targets in a population with type 2 diabetes (T2DM) from the Northwest of Spain.

AIM: To assess the degree of compliance with the European ESC/EAS 2016 and 2019 dyslipidaemia guidelines in patients with type 2 diabetes mellitus (T2DM). METHODS: Multicentre retrospective cross-sectional study, conducted in 380 adults with T2DM and dyslipidaemia in 7 Spanish health areas. INCLUSION CRITERIA: minimum follow-up of one year in Endocrinology Units, at least one visit in 2020 and a lipid profile measurement in the last 3 months. EXCLUSION CRITERIA: familial hypercholesterolaemia, recent hospitalisation, active oncological pathology and dialysis. RESULTS: According to the 2016 and 2019 guidelines the majority of patients were classified as being at very high cardiovascular risk (86.8% vs. 72.1%, respectively). LDL-c compliance was adequate in 62.1% of patients according to the 2016 guidelines and 39.7% according to the 2019 guidelines (p<0.001). Clinical conditions such as history of cardiovascular disease and therapy-related aspects (use of statins, especially high-potency statins, combination therapies and good adherence) were significantly associated with greater achievement of lipid targets. CONCLUSION: There is a discrepancy between dyslipidaemia guideline recommendations and the reality of lipid control in patients with T2DM, despite most of these patients being at very high cardiovascular risk. Strategies to optimise lipid-lowering treatments need to be implemented.

Gender Dimorphism in Hepatic Carcinogenesis-Related Gene Expression Associated with Obesity as a Low-Grade Chronic Inflammatory Disease.

Non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) show clear evidence of sexual dimorphism, with a significantly higher incidence in males. Among the determining factors that could explain this sex-based difference, the specific distribution of fat by sex has been suggested as a primary candidate, since obesity is a relevant risk factor. In this context, obesity, considered a low-grade chronic inflammatory pathology and responsible for the promotion of liver disease, could lead to sexual dimorphism in the expression profile of genes related to tumor development. When we compared the expression levels of genes associated with the early stages of carcinogenesis in the liver between male and female diet-induced obesity (DIO) rats, we observed that the expression pattern was similar in obese male and female animals. Interestingly, the SURVIVIN/BIRC5 oncogene showed a higher expression in male DIO rats than in female DIO and lean rats. This trend related to sexual dimorphism was observed in leukocytes from patients with obesity, although the difference was not statistically significant. In conclusion, this study evidenced a similar pattern in the expression of most carcinogenesis-related genes in the liver, except SUVIVIN/BIRC5, which could be a predictive biomarker of liver carcinogenesis predisposition in male patients with obesity.

Genetic Variants in Folate and Cobalamin Metabolism-Related Genes in Pregnant Women of a Homogeneous Spanish Population: The Need for Revisiting the Current Vitamin Supplementation Strategies.

Polymorphisms of genes involved in the metabolism and transport of folate and cobalamin could play relevant roles in pregnancy outcomes. This study assessed the prevalence of genetic polymorphisms of folate and cobalamin metabolism-related genes such as MTHFR, MTR, CUBN, and SLC19A1 in pregnant women of a homogeneous Spanish population according to conception, pregnancy, delivery, and newborns complications. This study was conducted on 149 nulliparous women with singleton pregnancies. Sociodemographic and obstetrics variables were recorded, and all patients were genotyped in the MTHFR, MTR, CUBN, and SLC10A1 polymorphisms. The distribution of genotypes detected in this cohort was similar to the population distribution reported in Europe, highlighting that more than 50% of women were carriers of risk alleles of the studied genes. In women with the MTHFR risk allele, there was a statistically significant higher frequency of assisted fertilisation and a higher frequency of preeclampsia and preterm birth. Moreover, CUBN (rs1801222) polymorphism carriers showed a statistically significantly lower frequency of complications during delivery. In conclusion, the prevalence of genetic variants related to folic acid and vitamin B12 metabolic genes in pregnant women is related to mother and neonatal outcomes. Knowing the prevalence of these polymorphisms may lead to a personalised prescription of vitamin intake.

Epigenetic Effects of Healthy Foods and Lifestyle Habits from the Southern European Atlantic Diet Pattern: A Narrative Review.

Recent scientific evidence has shown the importance of diet and lifestyle habits for the proper functioning of the human body. A balanced and healthy diet, physical activity, and psychological well-being have a direct beneficial effect on health and can have a crucial role in the development and prognosis of certain diseases. The Southern European Atlantic diet, also named the Atlantic diet, is a unique dietary pattern that occurs in regions that present higher life expectancy, suggesting that this specific dietary pattern is associated with positive health effects. In fact, it is enriched with nutrients of high biological value, which, together with its cooking methods, physical activity promotion, reduction in carbon footprint, and promoting of family meals, promote these positive effects on health. The latest scientific advances in the field of nutri-epigenetics have revealed that epigenetic markers associated with food or nutrients and environmental factors modulate gene expression and, therefore, are involved with both health and disease. Thus, in this review, we evaluated the main aspects that define the Southern European Atlantic diet and the potential epigenetic changes associated with them based on recent studies regarding the main components of these dietary patterns. In conclusion, based on the information existing in the literature, we postulate that the Southern European Atlantic diet could promote healthy aging by means of epigenetic mechanisms. This review highlights the necessity of performing longitudinal studies to demonstrate this proposal.

Reducing Metabolic Syndrome through a Group Educational Intervention Program in Adults with Obesity: IGOBE Program.

Metabolic syndrome (MetS) increases the risk of cardiovascular disease, type 2 diabetes mellitus, and cancer. Despite the higher prevalence of MetS in obese adults, little is known about the effectiveness of intensive and group interventions in improving MetS prevalence. This study aimed to investigate the effectiveness of an intensive lifestyle program in reducing the prevalence of MetS in adults with obesity. Patients with obesity (n = 456, 48.8 ± 12.8 years, 18.5% male) were randomized in two groups as indicated in a prospective interventional real-life study: a control group (CG), in which patients received usual care, and an interventional group (IG), in which the patients participate in a healthy lifestyle habits program in six weekly sessions, IGOBE program. Anthropometric, body composition, medications, and MetS features data were analyzed in both groups at the pre-intervention and post-intervention stages using a completer's analysis. At 12 months of follow-up, the IG showed a relative reduction of 13.4% in the prevalence of MetS from baseline, while the CG showed a reduction of 2.1% (p < 0.001). A significant reduction was also observed in four of five MetS features. In this trial, implementation of the IGOBE program resulted in a significant reduction in MetS prevalence and better control of MetS features compared with the standard of care.

Susceptibility Genes and Chromosomal Regions Associated With Non-Syndromic Familial Non-Medullary Thyroid Carcinoma: Some Pathogenetic and Diagnostic Keys.

Thyroid cancer is the malignant tumor that is increasing most rapidly in the world, mainly at the expense of sporadic papillary thyroid carcinoma. The somatic alterations involved in the pathogenesis of sporadic follicular cell derived tumors are well recognized, while the predisposing alterations implicated in hereditary follicular tumors are less well known. Since the genetic background of syndromic familial non-medullary carcinoma has been well established, here we review the pathogenesis of non-syndromic familial non-medullary carcinoma emphasizing those aspects that may be useful in clinical and pathological diagnosis. Non-syndromic familial non-medullary carcinoma has a complex and heterogeneous genetic basis involving several genes and loci with a monogenic or polygenic inheritance model. Most cases are papillary thyroid carcinoma (classic and follicular variant), usually accompanied by benign thyroid nodules (follicular thyroid adenoma and/or multinodular goiter). The possible diagnostic and prognostic usefulness of the changes in the expression and/or translocation of various proteins secondary to several mutations reported in this setting requires further confirmation. Given that non-syndromic familial non-medullary carcinoma and sporadic non-medullary thyroid carcinoma share the same morphology and somatic mutations, the same targeted therapies could be used at present, if necessary, until more specific targeted treatments become available.

Effectiveness to promote weight loss maintenance and healthy lifestyle habits of a group educational intervention program in adults with obesity: IGOBE program.

BACKGROUND: To achieve sustainable weight loss and healthy lifestyle changes is a huge challenge in the fight against obesity. The objective of this study was to evaluate the effectiveness to promote weight loss maintenance and healthy lifestyle habits of a group educational intervention program, Group Intervention in OBEsity (IGOBE), compared with a usual care therapy to lose weight. METHODS: Patients with obesity (n = 437; 18.5% men, 18-77 years and 40.4 ± 6.7 kg/m2) were randomised into two groups to follow a prospective interventional real-life study: a control group (CG), treated with usual clinical practice, and an intervention group (IG), in which the patients participate in a group intervention program on healthy lifestyle habits with weekly sessions for six weeks, after which a re-evaluation was made at six months and at 12 months of follow-up. After finishing the study dropout rates were 44.6% in CG and 43.4% in IG. Anthropometric, dietetic habits and body composition data were analysed in both groups at the pre-intervention and post-interventions of the subjects by completer's analysis. RESULTS: At 12 months of following IGOBE program, the IG achieved greater weight loss (-7.1% of the initial weight) than the CG, which exhibited a weight gain (3.0% of the initial weight). The body weight change induced in the IG was accompanied by a reduction in fat mass, particularly visceral fat and waist circumference. Relevantly, the IG adhered to a healthy dietary pattern and changed its eating habits, which correlated with the improvement in body weight. CONCLUSIONS: Intensive educational group treatment that induces a change of eating habits and adherence to healthy dietary pattern is more effective in a long-term to counteract obesity traits than a standard treatment performed individually. The IGOBE program could be a cost-effective practice in the clinical management of obesity.

Factores predictores de formas graves de COVID-19 que requieren hospitalización en pacientes con diabetes mellitus / Predictor factors of severe forms of COVID-19 requiring hospitalisation in patients with diabetes mellitus

Aims: To identify possible risk factors of hospitalisation in patients with diabetes (DM) and 2019 novel coronavirus disease (COVID-19), to establish the prevalence of DM among infected patients and that of DM in patients requiring hospitalisation. Research design and methods: Between March-May 2020, 1202 consecutive subjects in the healthcare area of Santiago de Compostela and Barbanza (Galicia, Spain) were diagnosed with COVID- 19, among whom 136 patients with DM were identified. Demographic data, DM characteristics and complications during hospitalisation were collected and analysed. Results: The prevalence of DM among COVID-19 infected subjects was 11.3%. This ascended to 21.7% in inpatients, while only 8.1% of outpatients had DM (p<0.0001). Higher levels of glycated haemoglobin significantly increased the risk of hospitalisation (OR: 1.57; 95% CI: 1.03-2.41, p=0.037), with small differences making the difference between inpatients and outpatients (7.3 ± 1.3% vs 6.8 ± 0.9% [56 ± 14 vs 51 ± 10 mmol/mol], respectively, p=0.009). Obesity (BMI ≥ 30 kg/m2) was the only comorbidity associated to hospitalization (OR: 2.94; 95% CI: 1.17-7.30, p=0.021). There were no differences in the type and duration of DM, the type of glucose-lowering drugs, or in the presence of micro/macrovascular complications. Conclusion: DM does not increase the risk of suffering from COVID-19, but it can worsen the outcome, raising the hospitalisation rate. Thus, obesity and worse chronic glycaemic control, even with small variations, are independent and determining factors for severe forms which require hospitalisation. (AU)

Relevance of nutritional assessment and treatment to counteract cardiac cachexia and sarcopenia in chronic heart failure.

Chronic heart failure (CHF) is frequently associated with the involuntary loss of body weight and muscle wasting, which can determine the course of the disease and its prognosis. While there is no gold standard malnutrition screening tool for their detection in the CHF population, several bioelectrical and imaging methods have been used to assess body composition in these patients (such as Dual Energy X-Ray Absorptiometry and muscle ultrasound, among other techniques). In addition, numerous nutritional biomarkers have been found to be useful in the determination of the nutritional status. Nutritional considerations include the slow and progressive supply of nutrients, avoiding high volumes, which could ultimately lead to refeeding syndrome and worsen the clinical picture. If oral feeding is insufficient, hypercaloric and hyperproteic supplementation should be considered. ß-Hydroxy-ß-methylbutyrate and omega-3 polyunsaturated fatty acid administration prove to be beneficial in certain patients with CHF, and several interventional studies with micronutrient supplementation have also described their possible role in these subjects. Taking into account that CHF is sometimes associated with gastrointestinal dysfunction, parenteral nutritional support may be required in selected cases. In addition, potential therapeutic options regarding nutritional state and muscle wasting have also been tested in clinical studies. This review summarises the scientific evidence that demonstrates the necessity to carry out a careful nutritional evaluation and nutritional treatment to prevent or improve cardiac cachexia and sarcopenia in CHF, as well as improve its course.

PD-L1 expression and immune cells in anaplastic carcinoma and poorly differentiated carcinoma of the human thyroid gland: A retrospective study.

Anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid carcinoma (PDTC) have limited treatment options, and immune profiling may help select patients for immunotherapy. The prevalence and relevance of programmed death-1 ligand (PD-L1) expression and the presence of immune cells in ATC and PDTC has not yet been well established. The present study investigated PD-L1 expression (clone 22C3) and cells in the tumor microenvironment (TME), including tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs) and dendritic cells, in whole tissue sections of 15 cases of ATC and 13 cases of PDTC. Immunohistochemical PD-L1 expression using a tumor proportion score (TPS) with a 1% cut-off was detected in 9/15 (60%) of ATC cases and 1/13 (7.7%) of PDTC cases (P=0.006). PD-L1 expression in TILs was limited to the ATC group (73.3 vs. 0% in ATC and PDTC, respectively). In the ATC group, the TPS for tumor positive PD-L1 expression revealed a non-significant trend towards worse survival, but no difference was observed when investigating PD-L1 expression in TILs and TAMs. In addition to increased PD-L1 expression, all ATC cases exhibited significantly increased CD3+ and CD8+ T cells, CD68+ and CD163+ macrophages, and S100+ dendritic cells compared with the PDTC cases. Loss of mutL homolog 1 and PMS1 homolog 2 expression was observed in one ATC case with the highest PD-L1 expression, as well as in the only PDTC case positive for PD-L1. Notably, the latter was the only PDTC case exhibiting positivity for p53 and a cellular microenvironment similar to ATC. The current results indicated that PD-L1 expression was frequent in ATC, but rare in PDTC. In addition to PD-L1, the present study suggested that microsatellite instability may serve a role in both the TME and the identification of immunotherapy candidates among patients with PDTC.

Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to R482 and N466 Variants in the LMNA Gene.

Patients with Dunnigan disease (FPLD2) with a pathogenic variant affecting exon 8 of the LMNA gene are considered to have the classic disease, whereas those with variants in other exons manifest the "atypical" disease. The aim of this study was to investigate the degree of variable expressivity when comparing patients carrying the R482 and N466 variants in exon 8. Thus, 47 subjects with FPLD2 were studied: one group of 15 patients carrying the N466 variant and the other group of 32 patients with the R482 variant. Clinical, metabolic, and body composition data were compared between both groups. The thigh skinfold thickness was significantly decreased in the R482 group in comparison with the N466 group (4.2 ± 1.8 and 5.6 ± 2.0 mm, respectively, p = 0.002), with no other differences in body composition. Patients with the N466 variant showed higher triglyceride levels (177.5 [56-1937] vs. 130.0 [55-505] mg/dL, p = 0.029) and acute pancreatitis was only present in these subjects (20%). Other classic metabolic abnormalities related with the disease were present regardless of the pathogenic variant. Thus, although FPLD2 patients with the R482 and N466 variants share most of the classic characteristics, some phenotypic and metabolic differences suggest possible heterogeneity even within exon 8 of the LMNA gene.

Varón de 30 años con hiperamonemia de 24 horas de evolución / 30-year-old man with Acute Hyperammonemia

La hiperamonemia es una de las complicaciones agudas más graves que se puede presentar en diversos trastornos congénitos del metabolismo como los defectos en el ciclo de la urea, las acidemias orgánicas o en las alteraciones en la oxidación de los ácidos grasos. Su reconocimiento y tratamiento es una emergencia clínica, dado que el efecto neurotóxico es directamente proporcional al tiempo de exposición a niveles elevados de amonio. Presentamos el caso clínico de un paciente de 30 años con deterioro del nivel de consciencia y elevación del amonio plasmático de 24 horas de evolución. (AU)

Hyperammonemia is one of the most severe acute complication that can occur in various congenital metabolic conditions such as the urea cycle disorders, organic acidemias or fatty acids oxidation defects. The prompt recognition and treatment is a clinical emergency, since the neurotoxic effect is directly proportional to the time of exposure to high levels of ammonia. We report the clinical case of a 30-year-old patient with a decreased level of consciousness and a 24-hour evolution of high plasma ammonia. (AU)

Rate of non-invasive follicular thyroid neoplasms with papillary-like nuclear features depends on pathologist's criteria: a multicentre retrospective Southern European study with prolonged follow-up.

PURPOSE: To determine the rate of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in a multi-institutional series from the Iberian Peninsula and describing this NIFTP cohort. METHODS: Retrospective study of papillary thyroid carcinoma (PTC) or well-differentiated tumours of uncertain malignant potential (WDT-UMP) diagnosed between 2005 and 2015 and measuring ≥5 mm in adult patients from 17 hospitals. Pathological reports were reviewed to determine the cases that fulfil the original criteria of NIFTP and histology was reassessed. Rates were correlated with the number of PTC and its follicular variant (FVPTC) of each institution. Demographic data, histology, management, and follow-up of the reclassified NIFTP cohort were recorded. RESULTS: A total of 182 cases with NIFTP criteria were identified: 174/3372 PTC (rate: 5.2%; range: 0-12.1%) and 8/19 WDT-UMP (42.1%). NIFTP rate showed linear correlation with total PTC (p: 0.03) and FVPTC (p: 0.007) identified at each centre. Ultrasound findings were non-suspicious in 60.1%. Fine-needle cytology or core biopsy diagnoses were undetermined in 49.7%. Most patients were treated with total thyroidectomy. No case had nodal disease. Among patients with total thyroidectomy, 89.7% had an excellent response evaluated 1 year after surgery. There were no structural persistence or relapses. Five patients showed residual thyroglobulin after 90 months of mean follow-up. CONCLUSIONS: NIFTP rate is low but highly variable in neighbouring institutions of the Iberian Peninsula. This study suggests pathologist's interpretation of nuclear alterations as the main cause of these differences. Patients disclosed an excellent outcome, even without using the strictest criteria.

Weight loss normalizes enhanced expression of the oncogene survivin in visceral adipose tissue and blood leukocytes from individuals with obesity.

BACKGROUND/OBJECTIVES: Survivin is an oncogene associated with a decrease in apoptosis, an increase in tumor growth, and poor clinical outcome of diverse malignancies. A correlation between obesity, cancer, and survivin is reported in the literature. To date, the impact of weight loss on change in survivin levels is understudied. This study was aimed at: (1) comparing survivin levels in adipose tissue (AT) from lean and obese animal models and evaluating changes after weight loss induced by energy restriction and/or exercise; (2) comparing survivin levels in normal weighted and obese humans and evaluating changes in survivin levels after weight loss induced by a very-low-calorie ketogenic diet (VLCKD) or bariatric surgery in AT and/or blood leukocytes (PBL/PBMCs). SUBJECTS/METHODS: Survivin expression was evaluated in subcutaneous (SAT) and visceral (VAT) AT derived from animal models of monogenic (Zucker rats) and diet-induced obesity (Sprague Dawley rats and C57BL/6J mice) and after a 4-week weight-loss protocol of energy restriction and/or exercise. Plasma was used to measure the inflammatory status. Survivin expression was also evaluated in PBMCs from patients with obesity and compared with normal weight, in PBLs after VLCKD, and in SAT and/or PBLs after bariatric surgery. RESULTS: Survivin expression was specifically higher in VAT from obese that lean animals, without differences in SAT. It decreased after weight loss induced by energy restriction and correlated with adiposity and inflammatory markers. In humans, the correlation between being obese and higher levels of survivin was confirmed. In obese subjects, survivin levels were reduced following weight loss after either VLCKD or bariatric surgery. Particularly, a decrease in PBMCs expression (not in SAT one) was found after surgery. CONCLUSIONS: Weight loss is effective in decreasing survivin levels. Also, PBL/PBMC should be regarded as appropriate mirror of survivin levels in VAT for the identification of an obesity-related protumoral microenvironment.

Pituitary Tumors Centers of Excellence.

Pituitary tumors are common and require complex and sophisticated procedures for both diagnosis and therapy. To maintain the highest standards of quality, it is proposed to manage patients in pituitary tumors centers of excellence (PTCOEs) with patient-centric organizations, with expert clinical endocrinologists and neurosurgeons forming the core. That core needs to be supported by experts from different disciplines such as neuroradiology, neuropathology, radiation oncology, neuro-ophthalmology, otorhinolaryngology, and trained nursing. To provide high-level medical care to patients with pituitary tumors, PTCOEs further pituitary science through research publication, presentation of results at meetings, and performing clinical trials.

Ketogenic diets as treatment of obesity and type 2 diabetes mellitus.

During the last decades, several interventions for the management of overweight and obesity have been proposed. Among diets, the first studies focused on the effect of water only and total fasting diets with or without proteins. Unfortunately, they were found to be associated with adverse events which lead to the abandon of these strategies. Interestingly, despite the radical approach, total fasting was effective and generally well tolerated. A strict connection between protein-calorie malnutrition and increased in morbidity and mortality in hospitalized patients was found at that time. Then, the seminal works of Blackburn and his collaborators lead to the introduction of the protein-sparing modified fast. Encouraged by the early results using this intervention, diets evolved to the current very-low-calorie ketogenic diets (VLCKD). In the present review, results of studies on the VLCKDs are presented and discussed, with a particular reference to the protocolled VLCKD. Also, a recent proposal on the nomenclature on the ketogenic diets is reported. Available evidence suggests VLCKDs to be effective in achieving a rapid and significant weight loss by means of an easily reversible intervention which could be repeated, if needed. Muscle mass and strength are preserved, resting metabolic rate is not impaired, hunger, appetite and mood are not worsened. Symptoms and abnormal laboratory findings can be there, but they have generally been reported as of mild intensity and transient. Preliminary studies suggest VLCKDs to be a potential game-changer in the management of type 2 diabetes too. Therefore, VLCKDs should be considered as an excellent initial step in properly selected and motivated patients with obesity or type 2 diabetes, to be delivered as a part of a multicomponent strategy and under strict medical supervision.

Thyroid Papillary Microtumor: Validation of the (Updated) Porto Proposal Assessing Sex Hormone Receptor Expression and Mutational BRAF Gene Status.

Given the high incidence and excellent prognosis of many papillary thyroid microcarcinomas, the Porto proposal uses the designation papillary microtumor (PMT) for papillary microcarcinomas (PMCs) without risk factors to minimize overtreatment and patients' stress. To validate Porto proposal criteria, we examined a series of 190 PMC series, also studying sex hormone receptors and BRAF mutation. Our updated Porto proposal (uPp) reclassifies as PMT incidental PMCs found at thyroidectomy lacking the following criteria: (a) detected under the age of 19 years; (b) with multiple tumors measuring >1 cm adding up all diameters; and (c) with aggressive morphologic features (extrathyroidal extension, angioinvasion, tall, and/or hobnail cells). PMCs not fulfilling uPp criteria were considered "true" PMCs. A total of 102 PMCs were subclassified as PMT, 88 as PMC, with no age or sex differences between subgroups. Total thyroidectomy and iodine-131 therapy were significantly more common in PMC. After a median follow-up of 9.6 years, lymph node metastases, distant metastases, and mortality were only found in the PMC subgroup. No subgroup differences were found in calcifications or desmoplasia. Expression of estrogen receptor-α and estrogen receptor-ß, progesterone receptor, and androgen receptor was higher in PMC than in nontumorous thyroid tissue. BRAF mutations were detected in 44.7% of PMC, with no differences between subgroups. In surgical specimens, the uPp is a safe pathology tool to identify those PMC with extremely low malignant potential. This terminology could reduce psychological stress associated with cancer diagnosis, avoid overtreatment, and be incorporated into daily pathologic practice.