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Aims: Obesity-induced nephropathy is an established clinical entity arising from a 'maladaptive' response to lipid accumulation at the nephron level. Bariatric surgery positively affects renal function, reducing or increasing glomerular filtration rate (GFR) in subjects with hyperfiltration and renal impairment, respectively. The effect of this surgery in patients with normal estimated GFR (eGFR) is less clear. Methods: A complete clinical and biochemical assessment of 135 severely obese, otherwise healthy subjects, was obtained before Roux-en-Y gastric bypass (RYGB). All subjects underwent an OGTT with plasma glucose and insulin determinations. Follow-up data were recorded at 6, 12, 24 and 48 months after intervention. Results: Baseline eGFR was 98.2 ± 13.6 ml/min/1.73 m; hyperfiltration (>120 ml/min/1.73 m) was present in 7% of the cohort. No eGFR variation over the follow-up emerged, except at the last visit (−3.6 ± 1.4 ml/min/1.73 m at month 48, p = 0.01 vs baseline). In the univariate analysis, the renal performance at 48 months was inversely related to baseline eGFR ( r = −0.17, p = 0.04) and plasma triglycerides ( r = −0.04, p = 0.05). Fasting and OGTT-derived variables did not impact eGFR. By multiple regression analysis, eGFR time course was independently predicted only by baseline eGFR ( p = 0.03). Interestingly, patients having a baseline eGFR >100 ml/min/1.73 m (median value) showed, after 48 months, an average loss of −8.3 ± 2.2 ml/min/1.73 m, while those with eGFR <100 exhibited a slight increase (+1.8 ± 2.3 ml/min/1.73 m, p < 0.01). Conclusions: Long-term data confirm the safety of RYGB on renal function. Interestingly, a subtle hyperfiltration, i.e., occurring in high-normal range of eGFR, is attenuated by surgical procedure. Lastly, high serum triglycerides may track an unfavorable renal outcome. [ABSTRACT FROM AUTHOR]

Aims: The cost-effectiveness of screening for silent coronary heart disease (CHD) in type 2 diabetes (DM2) is still debated.Methods: We applied a diagnostic algorithm for silent CHD detection, in a cohort of 102 asymptomatic DM2 subjects (57±7years), attending 5 Italian outpatient clinics, to verify its predictive value. The risk of silent CHD was calculated considering classical risk factors, and presence of microangiopathy/macroangiopathy. Patients were divided in 3 groups, i.e. group 1: normal ECG and low silent CHD risk; group 2: abnormal ECG, irrespective of silent CHD risk; group 3: high silent CHD risk, irrespective of ECG. To group 2 and 3, a functional test was recommended and performed in 78% of patients.Results: Silent CHD prevalence was similar in group 2 and 3 (25 vs. 17% respectively; p=0.495). However, evaluating the entire cohort, a significant higher prevalence of silent CHD was observed in subjects with abnormal vs. normal ECG (23 vs. 4%; P=0.004), but not in subjects with high vs. low pre-test silent CHD risk (14 vs. 9%; p=0.472).Conclusions: An abnormal ECG was a strong, independent predictor of silent CHD (OR 8.9; CI 1.27-62.5; p=0.028) in DM2. Therefore, a functional stress testing should be considered in DM2 patients with ECG abnormalities. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: The P2X7 receptor‐NLRP3 inflammasome complex (P2X7R‐Infl) regulates inflammatory and immune responses. Physical exercise modulates heat‐shock proteins (Hsps), influencing cytokine levels and oxidative stress; Hsp72 triggers P2X7R‐Infl‐dependent responses. Subjects and Methods: We studied the effect of a single bout of maximal exercise on lymphomonocyte expression of P2X7R, NLRP3, caspase‐1, NF‐kB and Hsp72 and circulating levels of IL‐1β, IL‐18 and MCP‐1, all modulated by P2X7R‐Infl, in healthy sedentary (SED), trained (ATH), endurance (END) male individuals. Results: Baseline P2X7R, NLRP3 and Caspase‐1 expression progressively increased from SED to ATH and END; NF‐kβ showed the same trend. Hsp72 did not differ among groups. Acute exercise strongly reduced P2X7R in all participants, irrespective of their degree of physical training. Inflammasome responses differed across groups: in SED, NLRP3 and Caspase‐1 increased; in ATH, NLRP3 reduced and caspase‐1 did not vary; in END, NLRP3 and Caspase‐1 declined. Baseline IL‐1β, higher in END, was unmodified after exercise; IL‐18 decreased; MCP‐1 doubled in SED, did not vary in ATH, declined in END. In the whole study population, significant direct relationships emerged between P2X7R expression and IL‐1β, IL‐18, MCP‐1 levels, all P < .001; also Caspase‐1 related with these markers. A multivariate analysis showed age, BMI and P2X7R as determinants of postexercise IL‐1β levels. Conclusion: Endurance show higher P2X7R‐Infl expression and function vs SED and ATH; however, maximal exercise determines prevailing pro‐inflammatory vs anti‐inflammatory responses in untrained and trained participants, respectively, highlighting a likely cause‐effect relationship between degree of physical activity and P2X7R‐Infl‐mediated responses. [ABSTRACT FROM AUTHOR]

Background: Sodium-glucose cotransporter-2 inhibitors reduce blood pressure (BP) and renal and cardiovascular events in patients with type 2 diabetes through not fully elucidated mechanisms. Aim of this study was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms. Methods: Neuro-hormonal and vascular variables, together with 24 h diuresis, urinary sodium, glucose, isoprostanes and free-water clearance were assessed before and after a 2-day treatment with dapagliflozin 10 mg QD in sixteen type 2 diabetic patients; data were compared with those obtained in ten patients treated with hydrochlorothiazide 12.5 mg QD. Brachial artery endothelium-dependent and independent vasodilation (by flow-mediated dilation) and pulse wave velocity were assessed. Renal resistive index was obtained at rest and after glyceryl trinitrate administration. Differences were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor; Bonferroni post hoc comparison test was also used. Results: Dapagliflozin decreased systolic BP and induced an increase in 24 h diuresis to a similar extent of hydrochlorothiazide; 24 h urinary glucose and serum magnesium were also increased. 24 h urinary sodium and fasting blood glucose were unchanged. Oxidative stress was reduced, as by a decline in urinary isoprostanes. Flow-mediated dilation was significantly increased (2.8 ± 2.2 to 4.0 ± 2.1%, p < 0.05), and pulse-wave-velocity was reduced (10.1 ± 1.6 to 8.9 ± 1.6 m/s, p < 0.05), even after correction for mean BP. Renal resistive index was reduced (0.62 ± 0.04 to 0.59 ± 0.05, p < 0.05). These vascular modifications were not observed in hydrochlorothiazide-treated individuals. Conclusions: An acute treatment with dapagliflozin significantly improves systemic endothelial function, arterial stiffness and renal resistive index; this effect is independent of changes in BP and occurs in the presence of stable natriuresis, suggesting a fast, direct beneficial effect on the vasculature, possibly mediated by oxidative stress reduction. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is one of the most frequent cause of hospitalization in elderly and often coexists with concurrent geriatric syndromes, like cognitive disturbances; various pathophysiological mechanisms are shared by HF and cognitive decline, notably a substrate of low-grade inflammation. We investigated whether SNPs in the purinergic receptor (P2X7R) and apolipoprotein (APO) E genes, both involved in a series of inflammatory responses, are associated to HF or cognitive impairment and are able to predict post-discharge mortality in the elderly. We prospectively analyzed 198 patients (age 85 ± 8 years, predominantly females) admitted to a Geriatric unit for acute HF, whose diagnosis was based on clinical signs, brain natriuretic peptide (BNP) values and ecocardiography in uncertain diagnosis (BNP values between 100 and 400 pg/mL); cognitive performance was assesed by Short Portable Mental Status Questionnaire (SPMSQ). In all the participants, SNPs rs208294 and rs3751143 for P2X7R gene and rs429558 and rs7412 for APOE gene were assessed. Information on all-cause mortality was adjudicated by medical records review 36 months after discharge. We found no relationship between P2X7R and APOE polymorphisms and 36-month post-discharge mortality; a better outcome for overall survival was observed in patients with BNP values below the median (281 pg/mL) (p=0.002) persisting after adjustment for renal function and age, and in those with cognitive impairment (p<0.001). Patients harboring APOE-ε4 genotype showed higher BNP concentrations than noncarriers (1289.9 ± 226.9 vs 580.5 ± 90.2 pg/mL respectively, p=0.004), whereas none of the studied SNPs were associated to impairment in cognitive performance. In conclusion, neither P2X7R or APOE genotype seem to predict long-term mortality in elderly patients. Interestingly, APOE-ε4 genotype was associated to higher BNP values, suggesting a putative interaction between genetic and biochemical markers in identifying people at risk for HF. [ABSTRACT FROM AUTHOR]

Although larger trinucleotide expansions give rise to a neurodevelopmental disorder called fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a "premutation" (55–200 CGG repeats) in the FMR1 gene. FXTAS is one of the more common single-gene forms of late-onset ataxia and tremor that may have a more complex development in women, with atypical presentations. After a brief presentation of the atypical case of an Italian woman with FXTAS, who had several paroxysmal episodes suggestive of acute cerebellar and/or brainstem dysfunction, this article will revise the phenotype of FXTAS in women. Especially in females, FXTAS has a broad spectrum of symptoms, ranging from relatively severe diseases in mid-adulthood to mild cases beginning in later life. Female FXTAS and male FXTAS have a different symptomatic spectrum, and studies on the fragile X premutation should be conducted separately on women or men. Hopefully, a better understanding of the molecular processes involved in the polymorphic features of FXTAS will lead to more specific and effective therapies for this complex disorder. [ABSTRACT FROM AUTHOR]

Objective Smoking is a recognized cardiovascular risk factor. Perivascular visceral adipose tissue ( PVAT) is a source of inflammatory molecules, thus contributing to atherosclerosis progression. The P2 X7 receptor ( P2 X7 R)-inflammasome complex, crucial in determining IL-1β and IL-18 release, participates in this scenario. We evaluated whether smoking might affect the PVAT inflammatory phenotype and explored the putative role of the axis P2 X7 R-inflammasome in this picture. Subjects and Methods TNFα, IL-6, RBP4, MCP-1, as well as P2 X7 R and inflammasome components NLRP3, ASC, caspase-1 and IL-1β and IL-18 expression was determined in adipocytes isolated by PVAT of healthy smokers ( Smok) and nonsmokers ( No- Smok) subjects. Plasma and culture medium levels of these cytokines were also determined. Results Perivascular adipose tissue of Smok had a higher expression of P2 X7 R and inflammasome components; via P2 X7 R activation, it released more IL-1β and IL-18, whose serum levels were also higher in Smok than in No- Smok. Linear correlations of NLRP3 with P2 X7 R and IL-18 expression and release emerged. Smok also had a higher PVAT expression of the chemotactic factor MCP-1. However, no difference was observed in the PVAT expression of genes more strictly related to insulin resistance, like TNFα, RBP4, IL-6; this was coupled with similar plasma levels of TNFα and RBP4 in the two groups. Conclusion Smoking contributes to the pro-inflammatory status of the PVAT by enhancing expression and activity of the P2 X7 R-inflammasome complex; the effect on adipocytokines more related to insulin resistance and metabolic abnormalities appears trivial. [ABSTRACT FROM AUTHOR]