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Aims/hypothesis Subcutaneous adipocyte hypertrophy is associated with insulin resistance and increased risk of type 2 diabetes, and predicts its future development independent of obesity. In humans, subcutaneous adipose tissue hypertrophy is a consequence of impaired adipocyte precursor cell recruitment into the adipogenic pathway rather than a lack of precursor cells. The zinc finger transcription factor known as zinc finger protein (ZFP) 423 has been identified as a major determinant of pre-adipocyte commitment and maintained white adipose cell function. Although its levels do not change during adipogenesis, ectopic expression of Zfp423 in non-adipogenic murine cells is sufficient to activate expression of the gene encoding peroxisome proliferator-activated receptor γ (Pparγ; also known as Pparg) and increase the adipogenic potential of these cells. We investigated whether the Zfp423 gene is under epigenetic regulation and whether this plays a role in the restricted adipogenesis associated with hypertrophic obesity. Methods Murine 3T3-L1 and NIH-3T3 cells were used as fibroblasts committed and uncommitted to the adipocyte lineage, respectively. Human pre-adipocytes were isolated from the stromal vascular fraction of subcutaneous adipose tissue of 20 lean non-diabetic individuals with a wide adipose cell size range. mRNA levels were measured by quantitative real-time PCR, while methylation levels were analysed by bisulphite sequencing. Chromatin structure was analysed by micrococcal nuclease protection assay, and DNA-methyltransferases were chemically inhibited by 5-azacytidine. Adipocyte differentiation rate was evaluated by Oil Red O staining. Results Comparison of uncommitted (NIH-3T3) and committed (3T3-L1) adipose precursor cells revealed that Zfp423 expression increased (p

Background and Purpose: To evaluate outcome and safety of endovascular treatment beyond 6 hours of onset of ischemic stroke due to large vessel occlusion in the anterior circulation, in routine clinical practice. Methods: From the Italian Registry of Endovascular Thrombectomy, we extracted clinical and outcome data of patients treated for stroke of known onset beyond 6 hours. Additional inclusion criteria were prestroke modified Rankin Scale score ≤2 and ASPECTS score ≥6. Patients were selected on individual basis by a combination of CT perfusion mismatch (difference between total hypoperfusion and infarct core sizes) and CT collateral score. The primary outcome measure was the score on modified Rankin Scale at 90 days. Safety outcomes were 90-day mortality and the occurrence of symptomatic intracranial hemorrhage. Data were compared with those from patients treated within 6 hours. Results: Out of 3057 patients, 327 were treated beyond 6 hours. Their mean age was 66.8±14.9 years, the median baseline National Institutes of Health Stroke Scale 16, and the median onset to groin puncture time 430 minutes. The most frequent site of occlusion was middle cerebral artery (45.1%). Functional independence (90-day modified Rankin Scale score, 0–2) was achieved by 41.3% of cases. Symptomatic intracranial hemorrhage occurred in 6.7% of patients, and 3-month case fatality rate was 17.1%. The probability of surviving with modified Rankin Scale score, 0–2 (odds ratio, 0.58 [95% CI, 0.43–0.77]) was significantly lower in patients treated beyond 6 hours as compared with patients treated earlier No differences were found regarding recanalization rates and safety outcomes between patients treated within and beyond 6 hours. There were no differences in outcome between people treated 6-12 hours from onset (278 patients) and those treated 12 to 24 hours from onset (49 patients). Conclusions: This real-world study suggests that in patients with large vessel occlusion selected on the basis of CT perfusion and collateral circulation assessment, endovascular treatment beyond 6 hours is feasible and safe with no increase in symptomatic intracranial hemorrhage.

We examined the difference between self-reported and measured body size values and their impact on detection of left ventricular hypertrophy (LVH) by echocardiographic LV mass indexation. A total of 1963 subjects referred by their practitioners for routine echocardiographic examination to nine outpatient echocardiographic laboratories across Italy were included in the study. Left ventricular hypertrophy was defined according to two gender-specific criteria as: A) Left ventricular mass (LVM) index ≥49 g/h2.7 in men and ≥45 g/h2.7 in women; B) LVM index ≥125 g/m2 in men and ≥110 g/m2 in women. Prevalence of LVH was calculated by indexing LVM to both self-reported and measured anthropometric values. In the whole population, LVH tended to be underestimated by self-reported values by 5.4% according to criterion A (48.5% vs. 53.9%, p < 0.001) and by 1.2% according to criterion B (29.6% vs. 30.8%, p < 0.01); similar findings were observed in the hypertensive subgroup encompassing one-half of the sample. Underestimation of LVH was more pronounced in older patients than in younger patients: 8.6% vs. 3.2% (p < 0.001) by criterion A, 3.1% vs. 0.1% (p < 0.001) by criterion B, in women than in men (8.6% vs. 3.3% (p < 0.001) by criterion A and 1.8% vs. 0.5% (p < 0.01) by criterion B. In a sample of outpatients attending echocardiographic laboratories, LVH is misclassified when left ventricular mass is normalized to self-reported weight and height. The error is related to the clinical characteristics of patients and is more pronounced when LVM is normalized to height2.7. © 2011 Informa Healthcare USA, Inc.

AIMS/HYPOTHESIS: Insulin exerts a direct action on vascular cells, thereby affecting the outcome and progression of diabetic vascular complications. However, the mechanism through which insulin signalling is impaired in the endothelium of diabetic individuals remains unclear. In this work, we have evaluated the role of the AGE precursor methylglyoxal (MGO) in generating endothelial insulin resistance both in cells and in animal models. METHODS: Time course experiments were performed on mouse aortic endothelial cells (MAECs) incubated with 500 μmol/l MGO. The glyoxalase-1 inhibitor S-p-bromobenzylglutathione-cyclopentyl-diester (SpBrBzGSHCp2) was used to increase the endogenous levels of MGO. For the in vivo study, an MGO solution was administrated i.p. to C57BL/6 mice for 7 weeks. RESULTS: MGO prevented the insulin-dependent activation of the IRS1/protein kinase Akt/endothelial nitric oxide synthase (eNOS) pathway, thereby blunting nitric oxide (NO) production, while extracellular signal-regulated kinase (ERK1/2) activation and endothelin-1 (ET-1) release were increased by MGO in MAECs. Similar results were obtained in MAECs treated with SpBrBzGSHCp2. In MGO- and SpBrBzGSHCp2-exposed cells, inhibition of ERK1/2 decreased IRS1 phosphorylation on S616 and rescued insulin-dependent Akt activation and NO generation, indicating that MGO inhibition of the IRS1/Akt/eNOS pathway is mediated, at least in part, by ERK1/2. Chronic administration of MGO to C57BL/6 mice impaired whole-body insulin sensitivity and induced endothelial insulin resistance. CONCLUSIONS/INTERPRETATION: MGO impairs the action of insulin on the endothelium both in vitro and in vivo, at least in part through an ERK1/2-mediated mechanism. These findings may be instrumental in developing novel strategies for preserving endothelial function in diabetes.

Background and aim. Aortic root dilatation (ARD) is a cardiovascular phenotype of adverse prognostic value; its prevalence has been mostly investigated in population-based samples and selected hypertensive cohorts. Data from clinical practice are rather scant. Thus, we examined the prevalence and correlates of ARD in a large sample of hypertensive patients referred by general practitioners for a routine echocardiographic examination. Methods. A total of 2229 untreated and treated hypertensive subjects (mean age 62 years) referred to 17 outpatient echocardiographic laboratories across Italy for detection of hypertensive subclinical cardiac damage were included in the study. ARD was defined by aortic diameter exceeding 3.7 cm in women and 3.9 cm in men. Results. ARD was found in 263 patients, with an overall prevalence of 11.8% (16.9% in men and 6.2% in women, p < 0.05). In multivariate regression analyses, body surface area (BSA), left ventricular (LV) mass and age were in ranking order the most important correlates of aortic root size in the whole population study as well as in men. In women, LV mass and its derivative indexes were the most important independent variables associated to aortic root size. Conclusions. This multicenter nationwide survey indicates that ARD is a frequent cardiovascular phenotype in hypertensives referred to echo-labs for detection of hypertensive organ damage. BSA, LV mass and age are the most important correlates of this phenotype. The hierarchical order of these factors differs between genders, LV mass being the strongest independent variable in women. © 2011 Scandinavian Foundation for Cardiovascular Research

Prevalence of left atrial enlargement (LAE) in hypertension has been mostly assessed in population-based samples and selected hypertensive groups. A few data are available in clinical practice. We examined LAE prevalence and severity in a cohort of hypertensive patients referred by general practitioners to a routine echocardiographic examination. A total of 2170 hypertensive individuals (mean age 62 years, 53% men) referred by practitioners to 17 outpatient echocardiographic laboratories across Italy for detection of hypertensive cardiac disease were included in the study. LAE was defined as: A) absolute LA diameter >4.0 cm in men and >3.8 cm in women; B) LA diameter normalized to body surface area (BSA) >2.3 cm/m2 in both sexes. Left atrial enlargement was graded as mild, moderate, and severe according to Lang’s report. Patients with LAE were 38% by criterion A, and 20% by criterion B. A moderate/severe increase in LA size was present in 34% (A) and 32% (B) of patients with LAE. Severe LAE was 3.3-fold (A) and 2.6-fold (B) more frequent in women than in men. Left ventricular mass was the strongest correlate of absolute LA diameter as well as of normalized LA diameter, after age. Left atrial enlargement defined either by absolute or normalized LA diameter is a frequent cardiac phenotype in hypertensive patients referred to echo-labs in clinical practice. This cardiac parameter is closely related to LV mass and its severity is highly prevalent in women.

We investigated the patterns of chronic hepatitis B virus (HBV)-related disease in a large cohort of HBsAg-positive patients, in Central Italy, by collecting a screening form with demographic, clinical and laboratory data. Overall, 737 HBsAg-positive cases were included (70% male; median age 52 years): 30% were inactive HBsAg carriers, 51% had chronic hepatitis B (CHB) and 19% had HBV-related cirrhosis. Patients from non-European Union (EU) countries (n = 65) were significantly younger, had a higher prevalence of HBeAg-positive infection and hepatitis delta virus (HDV) co-infection than patients of Italian origin. Therefore, as immigration from non-EU countries continues to grow, we can expect a change in the landscape of HBV-related disease in our area.

Elderly patients with nonoperable transitional cell carcinoma of the bladder need a rather active, but less toxic treatment than full-dose polychemotherapy. This study was designed to determine whether the cisplatin-analogue carboplatin (which is less nephrotoxic and less neurotoxic than the parent compound) has sufficient activity against T 2 -T 4 neoplasms (both nonmetastatic and metastatic) to warrant further development in phase III trials. Carboplatin dose was adjusted according to creatinine clearance, with a maximum dose of 300 mg/m 2 . The patient selection for this screening for activity was adjusted by the use of the 'optimal' two-stage design. Seventeen patients were enrolled, with a median age of 78 years (range : 70-85), a median performance status of 80% (range : 70-90%) ; 13 patients were lymph node-negative (10 T 2 , 2 T 3 , 1 T 4 ) and 4 had locoregional or distant node metastases. Nine patients had a complete response (3 in the first, 9-patient, stage, and 6 in the second, 8-patient, stage), demonstrating that carboplatin had sufficient activity (at the 'desirable' target level of 35%) ; almost all responses were observed in T 2 patients. Six patients had stable disease, and 2 had disease progression during treatment. The toxicity was acceptable, with only 41% of patients having grade II-III hematologic toxicity. More than 30% of patients were estimated to be free from progressive disease (54% alive) at 24 months. In our opinion carboplatin is suitable to be tested - in a phase III testing versus full-dose radiation therapy - as adjuvant after initial transurethral resection of the prostate in elderly patients with T 2 transitional cell carcinoma of the bladder considered radically nonoperable for medical problems.

Background Besides providing reassurance about cardiovascular (CV) safety of newer diabetes drugs, cardiovascular outcome trials (CVOTs) have also shown encouraging benefits on some CV endpoints. The contribution of the better glycemic control in the reduction of major cardiovascular events (MACE) remains an open question. The aim of this study is to evaluate the associations between the reduction of HbA1c and risk of MACE, MACE components, hospitalization for heart failure (HF) and all-cause death in CVOTs. Methods An electronic search up to July 2021 was conducted to determine eligible trials. Systematic review identified eighteen CVOTs reporting prespecified CV outcomes. Pooled summary estimates and 95% confidence intervals (CI) were calculated according to the random effects model using the Paule-Mandel method; restricted maximum likelihood estimators were used to estimate model parameters in the metaregression. Results The eighteen CVOTs evaluated 161,156 patients and included four trials with dipeptidyl-peptidase-4 inhibitors (DPP-4i), eight trials with glucagon-like peptide-1 receptor agonists (GLP-1RA) and six trials with sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Random-effects model meta-analysis showed an association between treatment and risk of MACE (hazard ratio [HR] 0.90; 95% CI 0.86, 0.94, P 2 = 45.2%, Q statistic P = 0.040). In meta-regression, there was an association between the reduction in HbA1c at the end of the trial and the HR reduction for MACE (beta = − 0.298, P = 0.007), with significant heterogeneity (I2 = 40%, Q statistic P = 0.04); this association was totally driven by the risk reduction of non-fatal stroke, which explained 100% of between-study variance (beta = − 0.531, R2 = 100%), without heterogeneity (I2 = 24%, Q statistic P = 0.206). There was no association between the reduction in HbA1c and the HR for heart failure or all-cause death. Conclusions The reduction of HbA1c in eighteen CVOTs was significantly associated with reduction of non-fatal stroke, explaining all (R2 = 100%) of the between-study variance. While the contribution of glucose lowering in some CV benefits of newer agents does not influence their indications for the patient with type 2 diabetes, it may hopefully facilitate their use.

OBJECTIVE BEYOND trial evaluated the feasibility of either basal insulin plus glucagon-like peptide 1 receptor agonist (GLP-1RA) or basal insulin plus sodium–glucose cotransporter 2 inhibitor (SGLT2i) to replace a full basal-bolus insulin (BBI) regimen in participants with type 2 diabetes and inadequate glycemic control. RESEARCH DESIGN AND METHODS Participants were randomized (1:1:1) to: 1) intensification of the BBI regimen (n = 101), 2) fixed ratio of basal insulin plus GLP-1RA (fixed-combo group; n = 102), and 3) combination of basal insulin plus SGLT2i (gliflo-combo group; n = 102). The primary efficacy outcome was change from baseline in HbA1c at 6 months. RESULTS Baseline characteristics were similar among the three groups (mean HbA1c was 8.6% [70 mmol/mol]). At 6 months, patients experienced similar reduction in HbA1c level (−0.6 ± 0.8, −0.6 ± 0.8, and −0.7 ± 0.9%, mean ± SD, respectively; noninferiority P < 0.001 vs. BBI), and the proportion of patients with HbA1c ≤7.5% was also similar (34%, 28%, and 27%, respectively; P = 0.489). Total insulin dose increased in the BBI group (62 units/day) and decreased both in the fixed-combo and gliflo-combo groups (27 units/day and 21 units/day, respectively; P < 0.01). The proportion of patients with hypoglycemia was 17.8%, 7.8%, and 5.9%, respectively (P = 0.015). There were 12 dropouts in the fixed-combo group, 9 in the gliflo-combo group, and none in the BBI group. CONCLUSIONS BEYOND provides evidence that it is possible and safe to switch from a BBI regimen to either a once-daily fixed-combo injection or once-daily gliflozin added to basal insulin, with similar glucose control, fewer insulin doses, fewer injections daily, and less hypoglycemia.

Introduction: Occurrence of pancytopenia in patients with untreated hyperthyroidism is extremely rare. To the best of our knowledge, only 30 cases have been reported in the English literature. Accurate diagnosis and appropriate tailored therapy are challenging due to the variegated causes of pancytopenia and the potential hematological toxicity of antithyroid drugs (ATDs). Case report: We present a 51-year-old Caucasian man with newly diagnosed Graves’ disease showing pancytopenia and liver dysfunction. Although in this context the use of ATDs is still under debate, low-dose methimazole therapy was able to induce resolution of both pancytopenia and liver dysfunction, along with euthyroidism restoration. Conclusion: Searching in the English literature for previous studies, we identified only 30 cases worldwide to form our database. A demographic as well as clinical, laboratory, and histopathological analysis was performed. In most cases, the recovery of biochemical euthyroidism through the use of ATDs induced the resolution of pancytopenia (at laboratory and histological levels). Our review provides clinical, laboratory, and histopathological features of Graves’s hyperthyroidism-related pancytopenia with a view to improving the knowledge of this rare hematological complication and assisting in the decision-making process regarding therapeutic options.

Context An improvement of some autoimmune diseases associated with celiac disease (CD) has been observed after a gluten-free diet (GFD). Objective The aim of this longitudinal study was to evaluate the effect of a GFD on autoimmune pituitary impairment in patients with CD and potential/subclinical lymphocytic hypophysitis (LYH). Design Five-year longitudinal observational study. Setting Tertiary referral center for immunoendocrinology at the University of Campania “Luigi Vanvitelli”. Patients Ninety-three newly diagnosed LYH patients (high titer of antipituitary antibodies [APA] and normal or subclinically impaired pituitary function) were enrolled from 2000 to 2013 and grouped as follows: group 1, consisting of 43 patients with LYH + CD, and group 2, consisting of 50 patients with isolated LYH only. Intervention A GFD was started in patients in group 1 after the diagnosis of CD. Main outcome measures APA titers and pituitary function were evaluated at the beginning of the study and then yearly for 5 years in both groups. Patients progressing to a clinically overt LYH were excluded from the follow-up. Results Complete remission of LYH (disappearance of APA and recovery of pituitary function in patients with previous subclinical hypopituitarism) occurred in 15 patients in group 1 after a GFD (34%) and spontaneously in only 1 patient in group 2 (2%) (P Conclusion In patients with LYH and CD, a GFD may be able to induce remission of subclinical LYH, or prevent the progression to clinical stage of this disease.

Infection is a common complication in patients with diabetic foot ulcer, leading to lower extremities amputation and healing failure. In this article, we report the case of a 39‐year‐old man with diabetes who developed a severe soft tissue infection and osteomyelitis after experiencing a major amputation for wet gangrene of both the foot and the ankle.

Background Navigated transcranial magnetic stimulation (nTMS) provides a reliable identification of “eloquent” cortical brain areas. Moreover, it can be used for diffusion tensor imaging fiber tracking of eloquent subcortical tracts. We describe the use of nTMS-based cortical mapping and diffusion tensor imaging fiber tracking for defining the “eloquence” of areas surrounding brain arteriovenous malformations (BAVMs), aiming to improve patient stratification and treatment. Methods We collected data of BAVMs suspected to be in eloquent areas treated between 2017 and 2019, and submitted to nTMS-based reconstruction of motor, language, and visual pathways for the definition of the eloquence of the surrounding brain areas. We describe the nTMS-based approach and analyze its impact on patient stratification and allocation to treatment in comparison with the standard assessment of eloquence based on anatomical landmarks. Results Ten patients were included in the study. Preliminarily, 9 BAVMs were suspected to be located in an eloquent area. After nTMS-based mapping, only 5 BAVMs were confirmed to be close to eloquent structures, thus leading to a change of the score for eloquence and of the final BAVMs grading in 60% of patients. Treatment was customized according to nTMS information, and no cases of neurological worsening were observed. Radiological obliteration was complete in 7 cases microsurgically treated, and accounted for about 70% in the remaining 3 patients 1 year after radiosurgical treatment. Conclusions The nTMS-based information allows an accurate stratification and allocation of patients with BAVMs to the most effective treatment according to a modern, customized, neurophysiological identification of the adjacent eloquent brain networks.

Background A meta-analysis is presented of cardiovascular outcome trials (CVOTs) comparing glucagon-like peptide-1 receptor agonists (GLP-1RA) versus placebo on cardiorenal outcomes in patients with type 2 diabetes mellitus (T2DM). Methods We did an electronic search up to June 30, 2021, for eligible trials. We did a meta-analysis of available trial data using a random-effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals). We included data from 8 CVOTs and 60,080 patients (72.4% with established cardiovascular disease). Results GLP-1RA reduced major cardiovascular events (MACE) by 14% (HR = 0.86, 95% CI 0.79–0.94, P = 0.006) with a non-significant heterogeneity between subgroups of patients with and without cardiovascular disease (P = 0.127). GLP-1RA also reduced the risk of cardiovascular death by 13% (P = 0.016), nonfatal stroke by 16% (P = 0.007), hospitalization for heart failure by 10% (P = 0.023), all-cause mortality by 12% (P = 0.012), and the broad composite kidney outcome by 17% (P = 0.012), which was driven by a reduction in macroalbuminuria only (HR = 0.74, 0.67–0.82, P Conclusions GLP-1RA have moderate benefits on MACE, and also reduce hospitalization for heart failure and all-cause mortality; they also have robust benefits on reducing the incidence of macroalbuminuria.

Hypoxic ischemic encephalopathy is one of the major causes of neonatal death and neurological disability in the child, and represents the most common birth injury claim. Intrapartum asphyxia often leads to several long-term sequalae, such as cerebral palsy and/or developmental delay, epilepsy. Through the neuroimaging it's possible to identify and define the different lesioned pictures and provide useful elements to establish the moment in which the damage occurred; indeed, timing of injury is a key element in the legal arena. Magnetic resonance imaging (MRI) is emerging as one of the most important tools in identifying the etiologic of neonatal encephalopathy as well as in predicting long-term outcomes. The aim of this study is to evaluate all MRI tests performed in a group of infants and young patients with possible neonatal encephalopathy, in order to determine the role of MRI in perinatal hypoxic-ischemic damage and the specific patterns that can point towards a diagnosis of the time of the damage's onset. Another goal is to assess the role of MRI in cases subject to legal-medical ligation. Since the advent of hypothermic neuroprotection, new malpractice allegations have arisen, including the failure to initiate cooling in a timely manner. In all cases, documentation of the status of the baby at birth, including a thorough neurologic exam, can be extremely helpful to the later defence of a malpractice claim, which might occur years later.

Background and Aims: Farnesoid X receptor (FXR) plays a key role in bile acid and lipid homeostasis. Experimental evidence suggests that it can modulate liver damage related to nonalcoholic fatty liver disease (NAFLD). We examined the impact of the NR1H4 rs35724 G>C, encoding for FXR, on liver damage in a large cohort of patients at risk of steatohepatitis. Methods: We considered 2,660 consecutive individuals at risk of steatohepatitis with liver histology. The rs35724 G>C polymorphisms were genotyped by TaqMan assays. Gene expression was evaluated by RNASeq in a subset of patients (n=124). Results: The NR1H4 rs35724 CC genotype, after adjusting for clinic-metabolic and genetic confounders and for enrolling centre, was protective against severity of steatosis (GG vs CC OR 0.77, 95% CI 0.62-0.95; P=.01), steatohepatitis (GG vs CC OR 0.62, 95% CI 0.47-0.83; P=.001) and severity of fibrosis (GG vs CC OR 0.83, 95% CI 0.67-0.98; P=.04). The C allele was associated with higher total circulating cholesterol (P=.01). Patients carrying the NR1H4 rs35724 C allele had significantly higher hepatic mRNA levels of FXR and were associated with higher hepatic FGFR4 and Cyp39A1 that are in turn involved in bile acid synthesis. Conclusions: Increased hepatic FXR expression due to the NR1H4 rs35724 C allele is linked to higher serum cholesterol but protects against steatosis, steatohepatitis and liver fibrosis. The translational relevance of these results for patient risk stratification and FXR-targeted therapy warrants further investigation.

Purpose The diagnosis of vitamin D deficiency is based on the determination of total plasma 25-hydroxyvitamin D (25-OHD) concentrations, but the regulation of vitamin D 25-hydroxylation is not a major consideration and very little information is available on this activity. To check what factors could interfere with the activity of vitamin D-25-hydroxylase and thus alter the 25-OHD concentrations, we looked for potential correlations between 25-OHD and results of liver function tests in healthy adults. Methods This single-centre study was retrospective and consisted of evaluating the correlations between 25-OHD and the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and bone alkaline phosphatase (BALP) in 349 healthy subjects aged from 18 to 65 years. In particular, in Group 1 (n = 119), we looked for correlations between 25OHD and all liver function tests and in Group 2 (n = 230) the correlation between 25OHD and BALP. Results In Group 1, we found no correlation between 25OHD and AST (r = − 0.03; p = 0.8), ALT (r = − 0.02; p = 0.91), GGT (r = − 0.08; p = 0.68), direct bilirubin (r = − 0.02; p = 0.89), indirect bilirubin (r = − 0.24; p = 0.21), and total bilirubin (r = − 0.24; p = 0.21) but one between 25OHD and ALP (r = − 0.2; p = 0.007); in Group 2, we found a significant negative correlation between 25-OHD and BALP (r = − 0.2; p = 0.0008). Conclusions The correlations that we found suggest that ALP and BALP might be involved in the regulation of vitamin D-25-hydroxylase activity, but further studies are mandatory to confirm our assumptions.

In the GIOIA study, users of both SGLT-2i and DPP-4i improved glycometabolic control, after 12 months, independently from baseline eGFR levels. Moreover, both classes led to a significant decrease in eGFR in participants with eGFR ≥ 90 ml/min/1.73 m2 and no deterioration in case of mild impairment of renal function.

Hospitalization for major diabetes complications, including myocardial infarction, stroke, lower-extremity amputation, and end-stage kidney disease, is on the rise and represents a great health burden for patients with type 2 diabetes (T2D), in particular for older people. Newer glucose-lowering medications have generated some optimism on the possibility to influence the natural history of cardiorenal complications of T2D. This review summarizes work in the area of sodium–glucose cotransporter 2 inhibitors (SGLT-2i) treatment and prevention of cardiorenal complications in patients with T2D (major adverse cardiovascular events, hospitalization for heart failure, kidney outcomes), with a particular emphasis on the effect of age, the role of primary versus secondary prevention and the possible extension of their cardiorenal benefits to the entire class of SGLT-2i.

A meta-analysis of cardiorenal outcomes of sodium-glucose co-transporter-2 inhibitors (SGLT-2is) available in Europe or the United States in patients with type 2 diabetes (T2D) is presented. An electronic search up to 6 January 2021 was conducted to determine eligible trials. A total of eight cardiorenal outcomes trials of SGLT-2is (empagliflozin, canagliflozin, dapagliflozin, ertugliflozin and sotagliflozin) were identified, with 65,587 patients. Data were analysed using a random effects model. Overall, SGLT-2is were associated with a 12% reduced risk of major adverse cardiovascular events (MACE; HR = 0.88; 95% CI, 0.83-0.93; Q statistic, p = .19), with no significant heterogeneity (p for interaction = .465) between subgroups of patients with or without cardiovascular disease (CVD). The risk of the composite renal outcome was significantly reduced by treatment with SGLT-2is (HR = 0.61, 95% CI, 0.54-0.70), with no significant heterogeneity of associations with outcome (I2 = 37%, p = .11), and no difference in the risk between patients with or without CVD (p for interaction = .665). SGLT-2is have moderate benefits on MACE and major benefits on the progression of diabetic kidney disease.

Fingers have preferential associations with relative spatial locations. Tactile localisation is faster when the fingers are in these locations, such as when the index finger is in a relatively higher spatial position, and the thumb in a relatively lower position. However, it is unclear whether these associations are related to hands specifically, or are a more general characteristic of limbs. The present study therefore investigated whether toes have similar spatial associations. If these associations reflect the statistics of natural limb usage, very different patterns of association would be expected for the fingers and toes, given their different functional roles in daily behaviour. We measured reaction time (RT) and error rates of responses to tactile stimuli applied to the middle finger/toe or thumb/big toe, when they were positioned in a relative upper or lower location. We replicated the finding that fingers have preferential associations that facilitates localisation—RT and error rate were lower when the index finger was in the top position, and the thumb in the bottom position. We found that toes do not hold the same spatial information, though it remains unclear whether toes hold different spatial information or none at all. These results demonstrate spatial information held by the fingers is stronger and more reliable than for the toes, so is not a general characteristic of limbs, but possibly related to hand use.

Background Female sexual dysfunctions (FSDs) are frequent concerns in women with type 1 diabetes (T1D), which is frequently associated with other autoimmune diseases (ADs). Aim To assess sexual function in young type 1 diabetic women with or without additional ADs. Methods Women with T1D aged 18–35 years with a stable couple relationship and no oral contraceptive use were enrolled. Diabetic women with concomitant ADs were also identified. All women completed the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale. Outcomes The main outcome was the prevalence of FSD. The FSFI-single domain scores were also evaluated in diabetic women with or without additional ADs. Results The global population included 154 diabetic women, of whom 66 (42%) had at least one additional AD. The prevalence of FSD was similar among diabetic women with and those without (30% vs 32%, P = .980) additional ADs. The FSFI-desire score was significantly lower among diabetic women with concomitant ADs than those without ADs [median (interquartile range), 4.1 (3.6, 4.8) vs 4.6 (4.0, 5.0), P = .042]. Clinical Implications An early evaluation of sexual function in women with T1D and concomitant ADs should be encouraged. Strengths & Limitations Major strengths are the use of 2 validated tools to diagnose FSD and the relatively large number of subjects investigated. The limitations include the cross-sectional nature of the study, which does not allow to make inference regarding the cause and effect. Conclusion Diabetic women with additional ADs show an impairment in sexual desire as compared with those suffering only from diabetes. Longo M, Cirillo P, Scappaticcio L, et al. Female Sexual Function in Young Women With Type 1 Diabetes and Additional Autoimmune Diseases. J Sex Med 2021;18:219–223.

Purpose This study is aimed at evaluating changes in metrics of glucose control in home-isolated patients with type 1 diabetes and COVID-19 using a continuous glucose monitoring (CGM) system. Methods We included adults aged 18–45 years with type 1 diabetes, using CGM, followed by telemedicine at a Southern Italian University Hospital. Thirty-two home-quarantined subjects with SARS-CoV-2 positive swab constituted the COVID-19 group. Thirty age-matched diabetic individuals without COVID-19 formed the control group. The effects of COVID-19 on glycemic control in patients infected were assessed at different time points [2 weeks before-COVID-19 (Time 1), 2 weeks during-COVID-19 (Time 2) and 2 weeks after COVID-19 (Time 3)] and compared with those without infection. Results A significant reduction of TIR (Time 1 vs Time 2, %, 60.1 ± 16.6 vs 55.4 ± 19.2, P = 0.03), associated with a significant increase of TAR level 2 (10.1 ± 7.3 vs 16.7 ± 12.9, P P P = 0.04), mean glucose values (mg/dL, 160.2 ± 26.5 vs 175.5 ± 32.6, P = 0.001) and standard deviation (59.2 ± 13.1 vs 68.6 ± 17.7, P = 0.001) was observed in patients with COVID-19. No significant change of glycemic metrics was found in the NO COVID-19 group across the time. Conclusion Young home-isolated patients with type 1 diabetes and COVID-19 showed a worsening of glucose control during COVID-19, as compared with age-matched diabetic subjects without the infection.

Aim: To investigate the rate of antibiotic resistance and its main risk factors in a population of patients with diabetic foot infection (DFI) during the COVID-19 pandemic, in comparison with the population of 2019. Methods: Two hundred and twenty-five patients with DFI were admitted in a tertiary care center from January 2019 to December 2020. Antibiotic resistance was evaluated by microbiological examination of soft tissues’ or bone's biopsy. Results: Compared with 2019 group (n = 105), 2020 group (n = 120) had a significantly higher prevalence of antibiotic resistance [2019 vs 2020, 36% vs 63%, P

Cardiovascular disease (CVD) remains the leading cause of death in patients with type 2 diabetes (T2D). Older age, prior heart failure (HF) and CV events, peripheral artery disease, and kidney complications can identify a subgroup of patients with T2D at high risk of mortality who are likely to achieve the greatest benefit from newer glucose-lowering agents. Both glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors can reduce CV risk in patients with T2D, and both are recommended by the American Diabetes Association to reduce the risk of major cardiovascular events (MACE). The magnitude of the benefits of GLP-1RA and SGLT-2 inhibitors on MACE are similar, ranging from 12 to 14% reduction of risk, but only GLP-1RA may reduce the risk of stroke. The most striking difference between the two classes of drugs relates to the amelioration on hospitalization for HF, as the benefit of SGLT-2 inhibitors surpass by threefold that obtained with GLP-1RA. Despite this, GLP-1RA also exert a significant benefit on HF which suggest their use when SGLT-2 inhibitors are contraindicated or not tolerated. The difference between the two classes is less impressive for the kidney outcome. Overall, the results of CVOTs published so far seems to suggest that the gap between the cardiorenal benefits of SGLT-2 and GLP-1RA is narrowing.

Aims: This study aims at evaluating the metrics of glycemic control in people with type 1 diabetes using the hybrid closed loop (HCL) system during the COVID-19 lockdown. Methods: This is a retrospective study of thirty adults with type 1 diabetes using HCL and followed with telemedicine at an Italian University Hospital. Data on metrics of glucose control were collected at different times: two weeks before the lockdown (Time 0), first two weeks of lockdown (Time 1), last two weeks of lockdown (Time 2) and first two weeks after the lockdown (Time 3). The primary endpoint was the change in glucose management indicator (GMI) across the different time points. Results: GMI did not worsen over time (Time 1 vs Time 3, 7% vs 6.9%, P < 0.05), whereas a reduction of mean glucose (P = 0.004) and indices of glucose variability was observed. Time in range (TIR) significantly increased (68.5% vs 73.5%, P = 0.012), and time above range (TAR) level 2 (251–400 mg/dL) significantly decreased (P = 0.002). The improvement of TIR and glucose variability was mainly observed in participants < 35 years. Conclusions: Adults with type 1 diabetes using HCL showed a significant improvement of most of the metrics of glucose control during the COVID-19 lockdown.

The coronavirus disease 2019 (COVID-19) has been declared as pandemic by the World Health Organization and is causing substantial morbidity and mortality all over the world. Type 2 diabetes, hypertension, and cardiovascular disease significantly increase the risk for hospitalization and death in COVID-19 patients. Hypoglycemia and hyperglycemia are both predictors for adverse outcomes in hospitalized patients. An optimized glycemic control should be pursued in patients with diabetes and SARS-CoV-2 infection in order to reduce the risk of severe COVID-19 course. Both insulin and GLP-1RAs have shown optimal glucose-lowering and anti-inflammatory effects in type 2 diabetic patients and may represent a valid therapeutic option to treat asymptomatic and non-critically ill COVID-19 diabetic patients.

The outbreak of the Coronavirus Disease 2019 (COVID-19) started in December 2019 in Wuhan (China) and has since spread in more than 200 countries. The pandemic was brought about by a novel virus causing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Among the comorbidities of people suffering from COVID-19, the most prevalent are diabetes, cardiovascular disease, and hypertension, all of which are associated with worse outcomes (1). People with diabetes are at increased risk of severe viral respiratory tract infections, including the SARS-CoV, H1N1 influenza, and Middle East Respiratory Syndrome (MERS-CoV). The prevalence of diabetes in individuals with COVID-19 has been reported to range between nearly 10% and up to 30%, depending on the location of the study, population, age of participants in the studies, severity of illness, and method of testing (2). Moreover, diabetes has emerged as an important predictor of severity of the SARS-CoV-2, as the risk of fatal outcomes has been reported to be 50% higher in individuals with diabetes than in those without (3). Given the high transmission rate of SARS-CoV-2 and the global prevalence of diabetes, which affects nearly half a billion people worldwide, the coexistence of both COVID-19 and diabetes should be considered alarming, as it represents the combination of two pandemics.

Neck ultrasound (nUS) is the cornerstone of clinical management of thyroid nodules in pediatric patients, as well as adults. The current study was carried out to explore and compare the diagnostic performance of the main US-based risk stratification systems (RSSs) (i.e., the American College of Radiology (ACR), European (EU), Korean (K) TI-RADSs and ATA US RSS criteria) for detecting malignant thyroid lesions in pediatric patients. We conducted a retrospective analysis of consecutive children and adolescents who received a diagnosis of thyroid nodule. We included subjects with age &lt, 19 years having thyroid nodules with benign cytology/histology or final histological diagnosis. We excluded subjects with (a) a previous malignancy, (b) a history of radiation exposure, (c) cancer genetic susceptibility syndromes, (d) lymph nodes suspicious for metastases of thyroid cancer at nUS, (e) a family history of thyroid cancer, or (f) cytologically indeterminate nodules without histology and nodules with inadequate cytology. We included 41 nodules in 36 patients with median age 15 years (11–17 years). Of the 41 thyroid nodules, 29 (70.7%) were benign and 12 (29.3%) were malignant. For both ACR TI-RADS and EU-TIRADS, we found a sensitivity of 41.7%. Instead, for both K-TIRADS and ATA US RSS, we found a sensitivity of 50%. The missed malignancy rate for ACR-TIRADS and EU-TIRADS was 58.3%, while that for K-TIRADS and ATA US RSS was 50%. The unnecessary FNA prevalence for ACR TI-RADS and EU-TIRADS was 58.3%, while that for K-TIRADS and ATA US RSS was 76%. Our findings suggest that the four US-based RSSs (i.e., ACR-TIRADS, EU-TIRADS, K-TIRADS, and ATA US RSS) have suboptimal performance in managing pediatric patients with thyroid nodules, with one-half of cancers without indication for FNA according to their recommendations.

As a consequence of the coronavirus disease 2019 (COVID-19) pandemic, profound changes in daily lives have occurred. In Italy, the exponential spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection required extraordinary measures to limit viral transmission, leading to an almost complete lockdown of the country (1). The mandatory lockdown significantly affected patients with chronic diseases, including people with diabetes and diabetic foot ulceration (DFU), which represents a heavy burden for health care systems in terms of mortality and reduced quality of life (1,2). The interruption of preventive education, early treatment, and diagnosis may have led to increased hospitalization of patients with severe DFU at high amputation risk (3). The aim of this study was to evaluate clinical features and amputation risk of individuals with diabetes and DFU admitted to a tertiary care center during the COVID-19 lockdown compared with a population admitted in the first 5 months of 2019. Patients with diabetes and DFU admitted to the Division of Endocrinology and Metabolic Diseases at the Teaching Hospital of University of Campania “Luigi Vanvitelli” (Naples, Italy) from 9 March 2020 to 18 May 2020 were included in this study. This cohort was compared with a population of patients admitted …

Aim The aim of this study was to investigate the factors involved in healing failure in a population of patients with diabetic foot ulcers (DFU) after one year of follow-up. Methods One hundred and forty-four patients were treated for DFU in a tertiary-care center and had a regular follow-up for one year. Laboratory measurements and clinical assessments, including long-term diabetes complications and risk factors for DFU, were collected at baseline and patients were divided in two groups according to the outcome [Healed group (H, n = 91), and Not Healed group (NH, n = 53)]. Results Compared with H group, NH group had significant higher levels of urinary albumin excretion [H vs NH, median (IQR), 23.5 (10.1, 41.1) vs 26.4 (20.8, 141.1), P = 0.032] and significantly increased prevalence of diabetic kidney disease (DKD) (22% vs 40%, P = 0.038) and Charcot Arthropathy (3% vs 16%, P = 0.025). No differences among the other long-term complications of diabetes, risk factors for DFU or clinical features were found. The multiple logistic regression analysis identified DKD and Charcot Arthropathy as negative predictors of healing. Conclusions In a population of people with type 2 diabetes with DFU treated in a tertiary-care center, DKD and Charcot Arthropathy were related to poor healing within one year-follow-up.

Background & aims: Neurotensin (NTS), a 13-aminoacid peptide localized in central nervous system and gastrointestinal tract, is involved in lipid metabolism and promotes various cancers onset mainly by binding to neurotensin receptor 1 (NTSR1). Increased plasma levels of pro-NTS, the stable NTS precursor, have been associated with type 2 diabetes (T2D), cardiovascular diseases and metabolic associated fatty liver disease (MAFLD). We aimed to evaluate 1) the impact of NTS rs1800832 and NTSR1 rs6090453 genetic variants on liver damage in 1166 MAFLD European individuals, 2) the relation between NTS variant and circulating pro-NTS and 3) the hepatic NTS expression by RNAseq transcriptomic analysis in 125 bariatric patients. Results: The NTS rs1800832 G allele was associated with hepatic fibrosis (OR 1.27, 95% confidence interval (CI). 1.02–1.58; p = 0.03), even more in carriers of both NTS and NTSR1 G risk alleles (OR 1.17, 95% CI. 1.03–1.34; p = 0.01), with cirrhosis (OR 1.58, 95% CI. 1.07–2.34; p = 0.02) and HCC (OR 1.98, 95% CI. 1.24–3.2; p = 0.004). Pro-NTS circulating levels were correlated with T2D (p = 0.005), BMI, (p = 0.04), age (p = 0.0016), lobular inflammation (p = 0.0025), fibrosis>2 (p < 0.0001), cirrhosis (p = 0.0009) and HCC (p < 0.0001) and more so after stratification for the NTS G allele. Transcriptomic data showed that hepatic NTS expression correlated with that of fibrogenic genes (p < 0.05). Conclusions: NTS rs1800832 variant is associated with advanced fibrosis and HCC in MAFLD patients likely affecting NTS protein activity. The rs6090453 NTSR1 gene variant synergizes with NTS rs1800832 mutation to promote liver damage. Prospective studies are necessary to confirm NTS role in liver disease progression.

Miriam Longo,1,2 Lorenzo Scappaticcio,1 Giuseppe Bellastella,1,2 Vlenia Pernice,1 Paolo Cirillo,1 Antonietta Maio,1 Filomena Castaldo,1,2 Dario Giugliano,1,2 Katherine Esposito,1,3 Maria Ida Maiorino1,2 On Behalf of the METRO Study Group1Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy; 2Unit of Endocrinology and Metabolic Diseases, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy; 3Unit of Diabetes, University of Campania “Luigi Vanvitelli”, Naples 80138, ItalyCorrespondence: Maria Ida MaiorinoUnit of Endocrinology and Metabolic Diseases, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Piazza Miraglia 2, Naples 80138, ItalyTel +39 0815665289Fax +39 0815665032Email mariaida.maiorino@unicampania.itPurpose: Type 1 diabetes is associated with high risk of cardiovascular disease (CVD). Reduced levels of circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) have been indicated as a risk factor for adverse cardiovascular outcomes and death in people at high cardiovascular risk. The aim of the present study was to evaluate the change in CPCs and EPCs levels in a population of young type 1 diabetic patients treated with intensive insulin regimen over a period of 2 years.Patients and Methods: A total of 204 type 1 diabetic patients, of whom 84 treated with insulin pump (CSII) and 120 with multiple daily insulin injections (MDI), completed a 2-year follow-up. Clinical measurements, including the indices of glycemic control and glucose variability, were collected at baseline and after 2 years. Both CPC and EPC cell count were assessed by flow cytometry.Results: Mean age of participants was 24.5 years and mean diabetes duration was 13.6 years. After 2 years, we found a significant reduction of HbA1c (− 0.3% versus baseline, P < 0.001), associated with decrease in mean amplitude of glucose excursion (MAGE) (− 0.5 mmol/L versus baseline, P< 0.001), continuous overall net glycemic action (CONGA) (− 0.2 mmol/L versus baseline, P=0.006), and blood glucose standard deviation (BGSD) (− 0.2 mmol/L versus baseline, P< 0.001). The number of all EPCs phenotypes, but not CPC cell count, significantly raised up in the entire population, with higher increase in CSII group. MAGE resulted as an independent predictor for increased levels of both CD34+ (P = 0.020) and CD34+KDR+ (P = 0.004) cell count in the whole population.Conclusion: Over a 2-year follow-up, young type 1 diabetic patients showed an increase in circulating EPCs levels, which was higher in patients with CSII. Glucose variability resulted as an independent predictor of the raised levels of EPCs in this selected population.Keywords: endothelial progenitor cells, circulating progenitor cells, glucose variability, type 1 diabetes, CSII, MDI

Growth hormone (GH), mostly through its peripheral mediator, the insulin-like growth factor 1(IGF1), in addition to carrying out its fundamental action to promote linear bone growth, plays an important role throughout life in the regulation of intermediate metabolism, trophism and function of various organs, especially the cardiovascular, muscular and skeletal systems. Therefore, if a prepubertal GH secretory deficiency (GHD) is responsible for short stature, then a deficiency in adulthood identifies a nosographic picture classified as adult GHD syndrome, which is characterized by heart, muscle, bone, metabolic and psychic abnormalities. A GHD may occur in patients with pituitary autoimmunity; moreover, GHD may also be one of the features of some genetic syndromes in association with other neurological, somatic and immune alterations. This review will discuss the impact of pituitary autoimmunity on GHD and the occurrence of GHD in the context of some genetic disorders. Moreover, we will discuss some genetic alterations that cause GH and IGF-1 insensitivity and the arguments in favor and against the influence of GH/IGF-1 on longevity and cancer in the light of the papers on these issues that so far appear in the literature.

Critical limb ischemia is the most serious form of peripheral artery disease, characterized by severe functional consequences, difficult clinical management and reduced life expectancy. The goal of this study was to investigate the miR-210 role in the neo-angiogenic response after acute limb ischemia. Complementary approaches were used in a mouse model of hindlimb ischemia: miR-210 loss-of-function was obtained by administration of LNA-oligonucleotides anti-miR-210, for miR-210 gain-of-function, a doxycycline-inducible miR-210 transgenic mouse was used. We tested miR-210 ability to stimulate vascular regeneration following ischemia. We found that miR-210 was necessary and sufficient to stimulate blood perfusion recovery, as well as arteriolar and capillary density increase, in the ischemic muscle. To clarify the molecular events underpinning miR-210 pro-angiogenic action, the transcriptomic changes in ischemic muscles upon miR-210 blocking were analyzed. We found that miR-210 impacted the transcriptome significantly, regulating pathways and functions linked to vascular regeneration. In agreement with a pro-angiogenic role, miR-210 also improved cardiac function and left ventricular remodeling after myocardial infarction. Moreover, miR-210 blocking decreased capillary density in a Matrigel plug assay, indicating that miR-210 is necessary for angiogenesis independently of ischemia. Collectively, these data indicate that miR-210 plays a pivotal role in promoting vascular regeneration.

Aims GIOIA is an ongoing prospective multicentre study aiming to assess the vascular and metabolic effects of SGLT-2 inhibitors (gliflozins) and DPP-4 inhibitors (gliptins) in the routine clinical practice of patients with type 2 diabetes (T2D). Herein we describe the preliminary effectiveness data at 6 months. Methods SGLT-2i and DPP-4i-naive adult patients with T2D (N = 301 and 260, respectively), with glycated haemoglobin A1c (A1C) >7%, an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2, on background therapy with metformin, insulin or both, are being followed to evaluate markers of vascular (carotid intima-media thickness), myocardial (myocardial diastolic function) and renal (urinary albumin/creatinine ratio) damage during treatment with SGLT-2i or DPP-4i for a period of 24 months. Result At baseline, patients initiated on SGLT-2i are younger (about 6 years) and more heavy (about 7.5 kg), have higher A1C level (0.5% more), a longer diabetes duration and more CV events (20% more) than patients initiated on DPP‐4i. At 6 months, patients on SGLT-2i (N = 298) and DPP-4i (N = 258) exhibit significant ameliorations in A1C (−1.% and −0.7%, respectively), which were greater (−1.2% and −0.81%) in those on a background metformin treatment only. The composite endpoint (A1C ≤ 7.0% + weight loss ≥ 3 kg) was achieved by 24% and 16% of patients receiving SGLT-2i or DPP-4i, respectively. No unexpected adverse events were reported. Conclusions Both SGLT-2i and DPP-4i provide substantial improvements in metabolic parameters in the usual clinical practice of T2D, especially when used as second-line treatment.

We provided an updated systematic review with meta-analysis of randomized controlled trials (RCTs) assessing the metabolic effects of combination therapy of insulin and GLP-1RA (combo) in comparison with other injectable therapy. We searched PubMed, Cochrane Register of Controlled Trials, Scholar, and ClinicalTrials.gov for RCTs evaluating changes in HbA1c (primary outcome), proportion of patients at HbA1c target

The combination of rapid-acting plus long-acting insulins has been the cornerstone of therapy of patients with type 1 diabetes mellitus (T1DM) and has also become the gold standard of insulin therapy in type 2 diabetes (T2DM). A significant proportion of T2DM patients are overtreated, with potential harms of insulin therapy exceeding its benefits. Treatment simplification aims to decrease the complexity of insulin regimens, including, but not limited to fewer administration times and fewer blood glucose checks. Few small studies in T2DM patients with good glycemic control have shown that glucagon-like peptide-1 receptor agonists (GLP-1RA) or sodium-glucose cotrasporter-2 (SGLT-2) inhibitors can be a safe and effective alternative to bolus insulin, if basal insulin administration is continued. Two larger and controlled trials have thrown some light about simplification of complex insulin regimens in patients with T2DM and poor glycemic control. Although different in their design (randomized controlled trial versus pragmatic trial), their results provide evidence that it is possible to switch from a basal bolus insulin regimen to a combination of basal insulin plus either a GLP-1RA or a daily gliflozin pill, with same or better glycemic control, less injections, less insulin doses, less hypoglycemia and increased satisfaction of therapy. The dogma about the untouchability of basal bolus insulin regimen has been confuted.

(1) Although guidelines about the use of MRI sequences for Multiple Sclerosis (MS) diagnosis and follow-up are available, variability in acquisition protocols is not uncommon in everyday clinical practice. The aim of this study was to evaluate the real-world application of MS imaging guidelines in different settings to clarify the level of adherence to these guidelines. (2) Via an on-line anonymous survey, neuroradiologists (NR) were asked about MRI protocols and parameters routinely acquired when MS patients are evaluated in their center, both at diagnosis and follow-up. Furthermore, data about report content and personal opinions about emerging neuroimaging markers were also retrieved. (3) A total of 46 participants were included, mostly working in a hospital or university hospital (80.4%) and with more than 10 years of experience (47.9%). We found a relatively good adherence to the suggested MRI protocols regarding the use of T2-weighted sequences, although almost 10% of the participants routinely acquired 2D sequences with a slice thickness superior to 3 mm. On the other hand, a wider degree of heterogeneity was found regarding gadolinium administration, almost routinely performed at follow-up examination (87.0% of cases) in contrast with the current guidelines, as well as a low use of a standardized reporting system (17.4% of cases). (4) Although the MS community is getting closer to a standardization of MRI protocols, there is still a relatively wide heterogeneity among NR, with particular reference to contrast administration, which must be overcome to guarantee an adequate quality of patients’ care in MS.

Background Obesity is a major worldwide threat to human health. Increasing evidence indicates that epigenetic modifications have a major impact on the natural history of this disorder. Ankyrin Repeat Domain 26 (Ankrd26) is involved in the development of both obesity and diabetes in mice and is modulated by environmentally induced epigenetic modifications. This study aims at investigating whether impaired ANKRD26 gene expression and methylation occur in human obesity and whether they correlate to the phenotype of these subjects. Results We found that downregulation of ANKRD26 mRNA and hyper-methylation of a specific region of the ANKRD26 promoter, embedding the CpG dinucleotides − 689, − 659, and − 651 bp, occur in peripheral blood leukocytes from obese compared with the lean subjects. ANKRD26 gene expression correlates inversely to the percentage of DNA methylation at these 3 CpG sites. Luciferase assays reveal a cause-effect relationship between DNA methylation at the 3 CpG sites and ANKRD26 gene expression. Finally, both ANKRD26 mRNA levels and CpG methylation correlate to body mass index and to the pro-inflammatory status and the increased cardio-metabolic risk factors of these same subjects. Conclusion Downregulation of the ANKRD26 gene and hyper-methylation at specific CpGs of its promoter are common abnormalities in obese patients. These changes correlate to the pro-inflammatory profile and the cardio-metabolic risk factors of the obese individuals, indicating that, in humans, they mark adverse health outcomes.

Dyslipidemia and altered iron metabolism are typical features of nonalcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7) gene variation has been associated with circulating lipids and liver damage during iron overload. The aim of this study was to examine the impact of the PCSK7 rs236918 variant on NAFLDrelated traits in 1,801 individuals from the Liver Biopsy Cohort (LBC), 500,000 from the UK Biobank Cohort (UKBBC), and 4,580 from the Dallas Heart Study (DHS). The minor PCSK7 rs236918 C allele was associated with higher triglycerides, aminotransferases, and hepatic inflammation in the LBC (P < 0.05) and with hypercholesterolemia and liver disease in the UKBBC. In the DHS, PCSK7 missense variants were associated with circulating lipids. PCSK7 was expressed in hepatocytes and its hepatic expression correlated with that of lipogenic genes (P < 0.05). The rs236918 C allele was associated with upregulation of a new gintra-PCSK7 h long noncoding RNA predicted to interact with the protein, higher hepatic and circulating PCSK7 protein (P < 0.01), which correlated with triglycerides (P = 0.04). In HepG2 cells, PCSK7 deletion reduced lipogenesis, fat accumulation, inflammation, transforming growth factor β pathway activation, and fibrogenesis. In conclusion, PCSK7 gene variation is associated with dyslipidemia and more severe liver disease in high risk individuals, likely by modulating PCSK7 expression/ activity.

Background: Osteomyelitis is a progressive infection of bone and bone marrow by microorganisms, resulting in inflammatory destruction of bone, bone necrosis, and new bone formation. Skull involvement is a rare occurrence which mainly affects children with chronic inflammatory diseases of paranasal sinusitis, or malignant otitis. In adults, cranial vault osteomyelitis can occur after cranial surgery or head trauma. Case Description: We describe an unusual case of chronic cranial osteomyelitis occurred 3 months following a mild traumatic brain injury. The causative mechanisms along with the diagnostic modalities are discussed. Conclusion: Focal cranial vault osteomyelitis, in the absence of severe trauma, can be challenging to diagnose. Imaging findings and patient history should be carefully investigated to make a correct diagnosis.

Aims: Sodium–glucose cotransporter-2 inhibitors (gliflozins) and statins are oral drugs that may have beneficial cardiovascular effects in patients with type 2 diabetes, especially in those with known cardiovascular disease. We planned a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) that evaluated the effect of gliflozins on MACE risk in patients with T2D stratified by age and by statin use. Methods: The electronic search was carried out until 20 January 2020. RCTs were included if they were CVOTs performed in adults with T2D, compared add-on therapy with any gliflozin versus placebo, and had major cardiovascular events (MACE) as primary outcome. We limited the evaluation to MACE in order to minimize the statistical impact of post-hoc analyses. We used a random-effect model to calculate hazard ratio (HR) and 95% CI. Results: The hazard ratio for MACE was 0.95 (95% CI, 0.86–1.05) in people

Background An understanding of the natural history of unruptured intracranial aneurysms (IAs) has always played a critical role in presurgical or endovascular planning, to avoid possibly fatal events. Size, shape, morphology, and location are known risk factors for rupture of an aneurysm, but morphologic parameters alone may not be sufficient to perform proper rupture risk stratification. Methods We performed a systematic PubMed search and focused on hemodynamics forces that may influence aneurysmal initiation, growth, and rupture. Results We included 223 studies describing several hemodynamic parameters related to aneurysm natural history. In these studies, different modalities of aneurysm model creation have been used to evaluate flow and to comprehensively analyze the evolution of IAs. Controversy exists about the correlation between these parameters and initiation, growth, rupture risk, or stabilization of the aneurysmal sac. Recent findings have also shown the importance of flow patterns in this process and the relationship between unruptured IA geometry and hemodynamic parameters. Conclusions The role of hemodynamic forces in evaluation of the natural history of unruptured IAs presents is inherently complex and is still not completely understood. In this complex scenario, although several attempts have been described in the literature, a proper risk rupture stratification and treatment strategy selection based on hemodynamic forces has not yet been created. Further efforts should be made to accomplish this important goal. © 2017 Elsevier Inc.

Background: Eagle syndrome (ES) is a rare symptomatic condition generally caused by an elongated styloid process (SP) or calcification of the stylohyoid complex. On the diagnosis is made, its treatment remains subjective since the indications for surgical intervention are still not standardized. Although styloidectomy is the surgical treatment of choice, no consensus exists regarding the transcervical or/and transoral route. Here, we report our experience in a patient with bilateral internal carotid artery (ICA) dissection caused by ES, who underwent innovative surgical technique. Case Description: A 53-year-old man, with the right-sided middle cerebral artery acute stroke, underwent computed tomography angiography 3 days after a successful endovascular treatment. The study showed a bilateral ICA dissection with bilateral hypertrophic SPs and a close relationship of ICAs with both SPs anteriorly and C1 transverse process posteriorly. Considering the occurrence of ICA compression by a styloid/C1 transverse process juxtaposition, the patient underwent the left partial C1 transversectomy by an extraoral approach. A temporary paresis of the ipsilateral lower lip lasted 1 month, with a partial remission after 3 months. The patient reported significant improvement of symptoms with a good esthetics and functional outcome. Conclusion: A styloid/C1 transverse process juxtaposition should be considered as an alternative pathogenetic mechanism in vascular ES. When a posterior ICA compression by C1 transverse process is present, a bone reshaping of C1 rather than a conventional styloidectomy can be considered an efficacious treatment which allows a good preservation of the styloid muscles and ligaments.

A 42-year-old woman presented with progressive blurred vision, vertigo, and headache. MRI showed bilateral intraocular protrusion of the optic nerve head and right transverse sinus thrombosis . Low-molecular-weight heparin was administered without symptom relief. Additional MRI showed left frontoparietal arachnoid space obliteration by pathological tissue, and infiltration of the sagittal and right transverse sinuses. After Gd administration, we observed diffuse enhancement of the dura in the left cerebral hemisphere and subdural and epicranial soft-tissue infiltration . A biopsy of the extra-axial tissue was performed. Histological examination showed a neoplasm composed of large cells with ovoid nuclei associated with non-neoplastic lymphocytes. Frequent mitotic figures were observed in the large cells. The large neoplastic cells were positive for CD20, bcl-2, bcl-6, and MUM1 and negative for CD10 and CD30. Accordingly, a diffuse infiltrative form of Bing-Neel syndrome was diagnosed. The patient was treated with 3 cycles of rituximab, dexamethasone, methotrexate HD, and cytarabine. Osmotic and steroid therapies were undertaken.

Background: Intramedullary spinal ependymoma is a tumor, hardly characterizable with conventional magnetic resonance (MR) imaging only. MR diffusion tensor imaging (DTI) with three dimensional fiber tracking reconstructions allows the evaluation of the relationship between neoplasm and white matter fiber tracts, being a powerful tool in presurgical planning. We present DTI findings in a case of a young female with an extensive cervicothoracic spinal ependymoma. Case Description: The patient complained of a 2 month history of acute urinary retention, weakness and numbness on the lower limbs and the upper left limb. She underwent MR imaging that showed an extensive cervicothoracic spinal mass, difficult to characterize with conventional MR sequences. DTI showed peripherally displacement of fibers, without involvement of the spinal cord, findings consistent with an ependymoma. The patient underwent surgery with a complete resection "en bloc" of the lesion, which showed clear cleavage planes, as detected by DTI. Histopathological findings confirmed the diagnosis of ependymoma. Conclusions: DTI is a useful tool in presurgical planning, helping in differentiating not infiltrating neoplasms, such as spinal ependymomas, from other infiltrative and more aggressive neoplasms, which are considered not resectable. © 2017 Surgical Neurology International | Published by Wolters Kluwer - Medknow.

Methylglyoxal (MGO) is a reactive dicarbonyl produced as by-product of glycolysis, and its formation is heightened in hyperglycaemia. MGO plasma levels are two-fold to five-fold increased in diabetics and its accumulation promotes the progression of vascular complications. Impairment of endothelium-derived nitric oxide represents a common feature of endothelial dysfunction in diabetics. We previously demonstrated that MGO induces endothelial insulin resistance. Increasing evidence shows that high glucose and MGO modify vascular expression of several microRNAs (miRNAs), suggesting their potential role in the impairment of endothelial insulin sensitivity. The aim of the study is to investigate whether miRNAs may be involved in MGO-induced endothelial insulin resistance in endothelial cells. MGO reduces the expression of miR-190a both in mouse aortic endothelial cells (MAECs) and in aortae from mice knocked-down for glyoxalase-1. miR-190a inhibition impairs insulin sensitivity, whereas its overexpression prevents the MGO-induced insulin resistance in MAECs. miR-190a levels are not affected by the inhibition of ERK1/2 phosphorylation. Conversely, ERK1/2 activation is sustained by miR-190a inhibitor and the MGO-induced ERK1/2 hyper-activation is reduced by miR-190a mimic transfection. Similarly, protein levels of the upstream KRAS are increased by both MGO and miR-190a inhibitor, and these levels are reduced by miR-190a mimic transfection. Interestingly, silencing of KRAS is able to rescue the MGO-impaired activation of IRS1/Akt/eNOS pathway in response to insulin. In conclusion, miR-190a down-regulation plays a role in MGO-induced endothelial insulin resistance by increasing KRAS. This study highlights miR-190a as new candidate for the identification of strategies aiming at ameliorating vascular function in diabetes.