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Direct oral anticoagulants (DOACs) are widely employed for antithrombotic prophylaxis in patients with atrial fibrillation (AF). However, there is still uncertainty about their risk-benefit profile in older patients. Here, we evaluated the efficacy, safety, and dose appropriateness of DOACs in a real-world population of outpatients with non-valvular AF, with a specific focus on subjects aged over 80 years and/or with reduced renal function.Single-center retrospective study including patients who had been prescribed a DOAC between May 2014 and May 2021 for long-term anticoagulation in non-valvular AF. Patients anticoagulated for4 weeks were excluded. The primary efficacy outcome was a composite of cardiovascular (CV) death, stroke, or systemic embolism. The primary safety outcome was major bleeding.A total of 1154 patients (median age 84 yrs., range 57-100 yrs.), among which 862 were 80 years and older, were included. In the subgroup of subjects ≥80 yrs., a subtherapeutic dose of DOAC was associated with an increased incidence of CV mortality, stroke, or systemic embolism (multivariable Cox regression, HR = 2.09, 95 % CI: 1.09-4.02), with no benefit in terms of prevalence of bleeding events (21.5 % vs. 18.6 %, p = 0.428), and the incidence of adverse safety and efficacy outcomes was not increased in patients with a reduced renal function (eGFR ≤30 mL/min). Plasma concentration of DOACs, assessed in a subset of 367 patients, did not increase with advanced age (≥ 80 yrs., two-way ANOVA, p = 0.656) nor with declining eGFR (≤30 mL/min, two-way ANOVA, p = 0.643) and was not associated with adverse safety and efficacy outcomes.Data from our study support the use of DOACs in populations of older adults and remark on the risks associated with inappropriate prescriptions in terms of CV mortality and adverse events.

to investigate heart failure (HF) hospitalizations, the following one-year follow-up, and any possible connection between rehospitalizations due to HF and patients' characteristics derived from administrative databases.retrospective longitudinal design.the study was conducted analyzing public hospital records of a district in Abruzzo Region (Central Italy), which counts more than 300,000 inhabitants. Patients hospitalized for HF from 01.01.2016 to 31.12.2017 (index event) were included in the study and followed-up for one year.frequency of repeated hospital admissions, time intervals from the index HF hospitalizations, and causes of readmissions were investigated.a total of 1,587 patients discharged alive after an index hospitalization for HF were included in the study. The mean age of the patients was 79.6 years and the majority of them were females (53.7%). The mean length of stay (LOS) for the index hospitalizations was 8.8 ±6.8 days. During the follow-up period, 336 (21.2%) patients underwent one to four repeated hospitalizations for HF. The first readmission due to HF occurred after a median time of 106.5 days from the index event discharge, and for 20.0% of all cases it occurred within 31 days; 453 patients (28.6%) were readmitted exclusively for other causes, and 67 (4.2%) died out of hospital without any previous HF re-hospitalization. When the outcome was considered as a composite endpoint (out-of-hospital death/HF re-hospitalization), age=75 (HR 1.737; 95%CI 1.330-2.267), LOS at the index hospitalization=8 days (HR 1.302; 95%CI 1.066-1.591), and repeated hospitalizations for other causes (HR 1.789; 95%IC 1.465-2.185) were associated with the risk of repeated hospitalizations for HF.this study shows that about one HF patient out of five experienced at least one re-hospitalization for HF within one year from index hospitalization. In addition to having a longer index hospitalization, these patients were older and frequently suffered from comorbidities which also led to hospitalizations. The results underline the need for a close and careful follow-up after the discharge of old HF patients with multiple pathologies in order to avoid further HF admissions in a short time.

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Specific microRNAs (miRs), including the "angio-miR-126" and the "inflamma-miR-146a-5p," have been proposed as biomarkers and even therapeutic targets of obesity-associated metabolic diseases. Physical activity, a key measure of prevention for obesity and its complications, is reported to influence the expression of these miRs. In this study, we investigate whether a physical activity program proven to improve metabolic parameters in obese patients can correct the circulating levels of these miRs. Plasma miR-126 and miR-146a-5p were measured in a cohort of obese patients (n = 31, 16F + 15M) before and after the 3-month physical activity program of the CURIAMO trial (registration number for clinical trials: ACTRN12611000255987) and in 37 lean controls (24F + 13M). miR-146a-5p, but not miR-126, was significantly increased in obese patients as compared with lean controls and decreased in approximately two-thirds of the participants post-intervention with a response that positively correlated with pre-intervention levels of this miR. Waist circumference, the inflammatory cytokine IL-8 and lipid parameters, principally total cholesterol, showed the strongest correlation with both the baseline levels and post-intervention correction of miR-146a-5p. Post-hoc analysis of experimental data supports the use of miR-146a-5p as a biomarker and predictor of the clinical response to physical activity in obese patients. Furthermore, miR-146a-5p expression was confirmed to increase together with that of the inflammatory genes TLR4, NF-κB, IL-6, and TNF-α in LPS-stimulated human mononuclear leukocytes. In conclusion, the inflamma-miR-146a-5p can serve as a personalized predictor of clinical outcome in obese patients entering physical activity weight-reduction programs. © 2018 IUBMB Life, 70(10):1012-1022, 2018.

Diabetic status is characterized by chronic low-grade inflammation and an increased burden of senescent cells. Recently, the senescence-associated secretory phenotype (SASP) has been suggested as a possible source of inflammatory factors in obesity-induced type 2 diabetes. However, while senescence is a known consequence of hyperglycaemia, evidences of SASP as a result of the glycaemic insult are missing. In addition, few data are available regarding which cell types are the main SASP-spreading cells in vivo. Adopting a four-pronged approach we demonstrated that: i) an archetypal SASP response that was at least partly attributable to endothelial cells and macrophages is induced in mouse kidney after in vivo exposure to sustained hyperglycaemia; ii) reproducing a similar condition in vitro in endothelial cells and macrophages, hyperglycaemic stimulus largely phenocopies the SASP acquired during replicative senescence; iii) in endothelial cells, hyperglycaemia-induced senescence and SASP could be prevented by SOD-1 overexpression; and iiii) ex vivo circulating angiogenic cells derived from peripheral blood mononuclear cells from diabetic patients displayed features consistent with the SASP. Overall, the present findings document a direct link between hyperglycaemia and the SASP in endothelial cells and macrophages, making the SASP a highly likely contributor to the fuelling of low-grade inflammation in diabetes., Highlights • Hyperglycaemia induces senescence and the SASP in endothelial cells and macrophages in vivo. • Hyperglycaemia-induced senescence phenocopies replicativesenescence in endothelial cells. • Overexpression of SOD-1 blunts hyperglycaemia-induced endothelial senescence and SASP. • Macrophages exposed to hyperglycaemia develop senescence and SASP markers. • Circulating angiogenic cells from T2DM patients show increased senescence and SASP mRNAs.

Type 2 diabetes mellitus (T2DM) is characterised by chronic low-grade inflammation, recently referred to as 'metaflammation', a relevant factor contributing to the development of both diabetes and its complications. Nonetheless, 'canonical' anti-inflammatory drugs do not yield satisfactory results in terms of prevention of diabetes progression and of cardiovascular events, suggesting that the causal mechanisms fostering metaflammation deserve further research to identify new druggable targets. Metaflammation resembles ageing-induced low-grade inflammation, previously referred to as inflammageing, in terms of clinical presentation and the molecular profile, pointing to a common aetiology for both conditions. Along with the mechanisms proposed to fuel inflammageing, here we dissect a plethora of pathological cascades triggered by gluco- and lipotoxicity, converging on candidate phenomena possibly explaining the enduring pro-inflammatory program observed in diabetic tissues, i.e. persistent immune-system stimulation, accumulation of senescent cells, epigenetic rearrangements, and alterations in microbiota composition. We discuss the possibility of harnessing these recent discoveries in future therapies for T2DM. Moreover, we review recent evidence regarding the ability of diets and physical exercise to modulate selected inflammatory pathways relevant for the diabetic pathology. Finally, we examine the latest findings showing putative anti-inflammatory mechanisms of anti-hyperglycaemic agents with proven efficacy against T2DM-induced cardiovascular complications, in order to gain insights into quickly translatable therapeutic approaches.

Uno stretto controllo della glicemia rappresenta nel paziente diabetico un elemento cruciale per la prevenzione delle complicanze cardiovascolari. E dimostrato che le complicanze microvascolari e macrovascolari non sono correlate solo all’iperglicemia a digiuno e a quella di lungo termine, ma anche alle oscillazioni glicemiche, quali i picchi iperglicemici postprandiali. L’emoglobina glicata (HbA1C), esame gold standard nel monitoraggio glicemico, rappresentando un marcatore dell’iperglicemia dei 2–3 mesi precedenti l’esame, non fornisce indicazioni sulla glicemia di breve termine e sulle oscillazioni glicemiche. Inoltre, considerando l’elevata variabilita preanalitica di questo esame, da alcuni anni vengono studiati possibili marcatori alternativi o da affiancare all’HbA1C nel monitoraggio della glicemia: tra questi l’1,5-anidroglucitolo, in grado di fornire, con un solo esame, una specifica misura dell’iperglicemia nelle 2 settimane precedenti il prelievo.

La diminuzione del glucosio nelle provette e tempo-dipendente dopo il prelievo e puo causare artificialmente bassi valori di glicemia se la glicolisi non e appropriatamente inibita dall’ uso corretto dell’anticoagulante. In questo lavoro abbiamo fatto una accurata revisione della letteratura sul possibile uso del citrato assieme al sodio EDTA e al sodio fluoruro. Noi concludiamo che, per lo screening e la diagnosi del diabete mellito, incluso il diabete gestazionale, il glucosio dovrebbe essere determinato nel plasma usando la sopra menzionata mistura sia allo stato solido che allo stato liquido (in questo caso deve essere applicato il corretto fattore di conversione numerico). Per la misura del glucosio in pazienti con diabete gia diagnosticato per il monitoraggio in follow up, provette con litio eparina possono essere usate ma la separazione del plasma delle essere rapidamente condotta. In alternativa possono essere usate provette per siero con acceleratore della coagulazione e gel separatore.

Type-2 Diabetes (T2D), diabetic complications, and their clinical risk factors harbor a substantial genetic component but the genetic factors contributing to overall diabetes mortality remain unknown. Here, we examined the association between genetic variants at 21 T2D-susceptibility loci and all-cause mortality in an elderly cohort of 542 Italian diabetic patients who were followed for an average of 12.08 years. Univariate Cox regression analyses detected age, waist-to-hip ratio (WHR), glycosylated haemoglobin (HbA1c), diabetes duration, retinopathy, nephropathy, chronic kidney disease (CKD), and anaemia as predictors of all-cause mortality. When Cox proportional hazards multivariate models adjusted for these factors were run, three erythropoietin (EPO) genetic variants in linkage disequilibrium (LD) with each other (rs1617640-T/G, rs507392-T/C and rs551238-A/C) were significantly (False Discovery Rate EPO gene is an independent predictor of mortality in patients with T2D. Thus, understanding the mechanisms by which the genetic variability of EPO affects the mortality of T2D patients may provide potential targets for therapeutic interventions to improve the survival of these patients.

Essentials Currently, DOACs are given at fixed doses and do not require laboratory monitoring. Direct oral anticoagulant-specific measurements were performed at trough and peak. Patients who developed bleeding events showed higher DOAC plasma levels at peak. This study suggests the need of a more accurate DOAC dose assessment. Background: Direct oral anticoagulants (DOACs) are administered at fixed dose. The aim of the study was to evaluate the relationship between DOAC C-trough or C-peak plasma levels and bleeding complications in patients with non-valvular atrial fibrillation (NVAF). Methods: Five hundred sixty five consecutive naive NVAF patients were enrolled. The DOAC measurements at C-trough and at C-peak (available in 411 patients) were performed at steady state, within the first month of treatment. Major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and minor bleeding (MinB), occurring during 1year of follow-up after blood sampling, were recorded. For each DOAC, interval of C-trough and C-peak levels was subdivided into four equal classes and results were attributed to these classes; the median values of results were also calculated. Results: Two hundred eight patients were on apixaban, 185 on dabigatran, and 172 on rivaroxaban. For 1-[qqqdeletezzz]year follow up for all patients, we observed: 19 MB (3.36%), 6 CRNMB (1.06%), and 47 MinB (8.31%). The prevalence of bleeding patients with anticoagulant levels in the upper classes of C-peak activity (II + III + IV) was higher than that in the lowest class. Normalized results of C-peak levels were higher in patients with bleeding than in those without bleeding. Conclusions: Bleeding complications during DOAC treatment were more frequent among atrial fibrillation (AF) patients with higher C-peak anticoagulant levels. In addition to a previous study that showed an increased risk of thrombotic complications in the patients with low C-trough levels, this study seems to indicate that patients with NVAF on DOACs would need a more accurate definition of their optimal therapeutic window.

Background and aims Literature data suggest an association between Helicobacter pylori infection and glucose homeostasis. However, a causative link between them has not been demonstrated yet. The aim of this study is to investigate the effect of H. pylori eradication on glucose homeostasis in patients with type 2 diabetes. Methods and results A randomized, double-blind, placebo-controlled trial was conducted to investigate the effect of H. pylori eradication on glucose homeostasis in 154 patients with type 2 diabetes and who tested positive for H. pylori infection (mean age (SD), 63.1 (8.1) years). Subjects were assigned to H. pylori eradication treatment or placebo. Metabolic and inflammatory parameters were measured in all subjects at baseline and 4 weeks after the treatment. H. pylori eradication led to an improvement in glucose homeostasis, measured by HOMA-IR (p ITT (0 = 0.041), due to the decrease in fasting insulin levels (p = 0.004). The results also showed that lower levels of inflammatory parameters were present after eradication. Conclusion To our knowledge this is the first randomized, double blind, controlled study where the effect of H. pylori eradication on glucose homeostasis in subjects with type 2 diabetes has been investigated. Our findings demonstrate that H. pylori eradication improves glucose homeostasis in patients with type 2 diabetes through a decrease in pro-inflammatory factors. Trial registration number: ACTRN12609000255280 ( https://www.anzctr.org.au/ ).

Dipeptidyl peptidase-4 inhibitors are widely used in type 2 diabetes. Endothelium plays a crucial role maintaining vascular integrity and function. Chronic exposure to high glucose drives to endothelial dysfunction generating oxidative stress. Teneligliptin is a novel dipeptidyl peptidase-4 inhibitor with antioxidant properties. This study is aimed to verify a potential protective action of teneligliptin in endothelial cells exposed to high glucose. Human umbilical vein endothelial cells were cultured under normal (5 mmol/L) or high glucose (25 mmol/L) during 21 days, or at high glucose during 14 days followed by 7 days at normal glucose, to reproduce the high-metabolic memory state. During this period, different concentrations of teneligliptin (0.1, 1.0 and 3.0 µmol/L) or sitagliptin (0.5 µmol/L) were added to cells. Ribonucleic acid and protein expression were assessed for antioxidant response, proliferation, apoptosis and endoplasmic reticulum stress markers. Teneligliptin promotes the antioxidant response in human umbilical vein endothelial cells, reducing ROS levels and inducing Nrf2-target genes messenger ribonucleic acid expression. Teneligliptin, but not sitagliptin, reduces the expression of the nicotine amide adenine dinucleotide phosphate oxidase regulatory subunit P22 −phox, however, both blunt the high glucose-induced increase of TXNIP. Teneligliptin improves proliferation rates in human umbilical vein endothelial cells exposed to high glucose, regulating the expression of cell-cycle inhibitors markers (P53, P21 and P27), and reducing proapoptotic genes (BAX and CASP3), while promotes BCL2 expression. Teneligliptin ameliorates high glucose-induced endoplasmic reticulum stress reducing the expression of several markers (BIP, PERK, ATF4, CHOP, IRE1a and ATF6). Teneligliptin has antioxidant properties, ameliorates oxidative stress and apoptotic phenotype and it can overcome the metabolic memory effect, induced by chronic exposure to high glucose in human endothelial cells.

Il tumore del colon retto (CCR) rappresenta ancora oggi una delle neoplasie piu importanti, con indici di mortalita e progressione metastatica della malattia legati alle caratteristiche biologiche e strutturali del tumore primario. A fronte di un aumento complessivo dell’incidenza si e registrata una riduzione della mortalita di quasi il 35% negli ultimi due decenni. Al calo della mortalita hanno dato un contributo notevole gli interventi di medicina predittiva e preventiva che si avvalgono di una serie di strumenti diagnostici e device chirurgici esplorativi (endoscopia) che consentono diagnosi molto precoce e interventi ambulatoriali sulle lesioni displasiche e poliposiche, evitando la trasformazione neoplastica e l’invasivita della massa tumorale. La presente review descrive i progressi ottenuti soprattutto negli interventi di screening di massa sulla popolazione, per i quali riveste notevole importanza la ricerca del sangue occulto fecale (SOF) che permette l’individuazione di zone di microsanguinamento nell’alveo colico, possibile sentinella di un processo neoplastico. Il SOF ha riscosso un notevole successo negli ultimi tempi e, nelle Regioni in cui il processo di screening e ormai collaudato e consolidato, ha permesso di abbattere notevolmente il rischio di malattia metastatica e l’indice di mortalita associato. Un altro passo avanti molto importante e rappresentato dall’utilizzo di moderne tecniche di indagine molecolare che consentono di analizzare mutazioni e lesioni epigenetiche a carico di geni coinvolti nel meccanismo patogenetico di induzione tumorale (analisi del DNA fecale) come strumento ad alta sensibilita e specificita per il riconoscimento delle microlesioni neoplastiche. Nel presente lavoro viene infine dato spazio al ruolo che vari marcatori sierologici come il CEA e il Ca 19.9 rivestono quali fattori predittivi e prognostici nel follow-up e nel monitoraggio del successo terapeutico, secondo i termini della medicina di evidenza.

Background To test the effect of normoglycemia and glucagon-like peptide-1 (GLP-1), alone or in combination, on the possible normalization of endothelial function in type 1 diabetes. Methods Fifteen people with type 1 diabetes participated in three experiments: reaching and maintaining normoglycemia for 4 h; reaching and maintaining hyperglycemia plus GLP-1 infusion for 4 h; and reaching and maintaining normoglycemia for 4 h with simultaneous infusion of GLP-1. Results Both normoglycemia and GLP-1 infusion restored endothelial function and decreased and plasma 8-iso prostaglandin F2α levels. However, only the combination of normoglycemia and GLP-1 was able to normalize endothelial function. Conclusions This study confirms that long-lasting hyperglycemia in type 1 diabetes induces a permanent alteration which contributes to maintaining endothelial dysfunction even when glycemia is normalized, and that in the presence of normoglycemia, GLP-1 can contribute to normalizing endothelial function.

The prevalence of type 2 diabetes mellitus, one of the major causes of morbility and mortality in Europe, is increasing in all European countries. Diabetes is not distributed equally among all population groups, as higher incidence, appearance of complications, and different mortality rates have been observed among migrants and the native population. These differences may be due to genetic profiles, lifestyle, and utilization of the health care system in different ways. Taking into account that the quantity of migrants is nowadays increasing, mainly in the southern part of Europe, the knowledge of diabetes in migrants through a better collection of data is necessary, considering that few limited epidemiological studies have evaluated the importance of this problem in EU countries. A special effort in developing a comprehensive management for native and immigrant populations in order to prevent and cure diabetes should be mandatory. This activity could be helpful to limit the incidence of future diabetes complications and to avoid the consequent burden of the health care system along with a control on its costs. It is clear that diabetes complication prevention is essential for long-term sustainability of the health care system.

Recently, it has been demonstrated that Glucagon-like peptide-1 (GLP-1) has a protective effect on endothelial cells. Our hypothesis is that this GLP-1 protective effect is partly lost when the cells are exposed to sustained high glucose concentrations. Human umbilical vein endothelial cells (HUVECs) were cultured for 21 days in normal glucose (5 mmol/L, NG) or high glucose (25 mmol/L glucose, HG). GLP-1 (7-37) and Ruboxistaurin were added at 50 and 500 nM, respectively, alone or in combination, 1 h before cell harvesting. Analysis of GLP-1 receptor protein levels, as well as of the gene expression of different ER stress-related genes, proliferation markers, antioxidant cell response-related genes, and PKA subunits, was performed. ROS production was also measured in HUVECs exposed to mentioned treatments. GLP-1 receptor expression was reduced in HUVECs exposed to chronic high glucose concentrations but was partially restored by a chemical PKCβ-specific inhibitor. GLP-1, added as an acute treatment in endothelial cells, had the capacity to induce the expression of Nrf2-detoxifying enzyme targets, to increase transcription levels of scavenger genes, to attenuate the expression of high glucose-induced PKA subunits, ER stress and also the apoptotic phenotype of HUVECs; these effects occured only when high glucose-induced PKCβ overexpression was reduced by Ruboxistaurin. In a similar manner, ROS production induced by high glucose was reduced by GLP-1 in the presence of PKCβ inhibitor. This study suggests that an increase in PKCβ, induced by high glucose, could have a role in endothelial GLP-1 resistance, reducing GLP-1 receptor levels and disrupting the GLP-1 canonical pathway.

Aims ZnT8 Arg325Trp polymorphism has been associated with type 2 diabetes (T2DM) susceptibility. The Arg-325 risk variant shows accelerated zinc (Zn) transport kinetic and reduced glucose-stimulated insulin secretion in pancreatic cells. However, it remains unexplored the role of Znt8 polymorphism in the regulation of Zn homeostasis and inflammatory response in peripheral blood mononuclear cells (PBMCs) from T2DM patients. Methods and results A total of 556 healthy controls and 413 T2DM patients were genotyped for ZnT8 Arg325Trp polymorphism confirming the association of Arg-325 variant with an increased T2DM risk (OR = 1.35 95% C.I: 1.10–1.66; p = 0.0044). Moreover, PBMCs from Arg/Arg T2DM subjects showed increased intracellular free Zn, higher gene expression of Metallothioneins, Znt1, Znt8, Zip2 genes, and reduced Znt4 and Znt7. Higher release of IL-1α, IL-1β, IFN-γ, IL-12p70 and TNF-α and a reduced IL-10 secretion after lipopolysaccharide (LPS) stimulation were observed in PBMCs from Arg/Arg T2DM carriers as compared to subjects with the Trp variant. Conclusions Our data provide evidence of a substantial different Zn homeostasis regulation between Znt8 Arg-325 and Trp-325 carriers in PBMCs from T2DM patients. Moreover, Znt8 Arg-325 risk variant shows an enhanced inflammatory response upon LPS stimulation that might aggravate insulin resistance and the progression of diabetes cardiovascular complications.

Type 2 Diabetes (T2D) is a chronic disease associated with a number of micro- and macrovascular complications that increase the morbidity and mortality of patients. The risk of diabetic complications has a strong genetic component. To this end, we sought to evaluate the association of 40 single nucleotide polymorphisms (SNPs) in 21 candidate genes with T2D and its vascular complications in 503 T2D patients and 580 healthy controls. The genes were chosen because previously reported to be associated with T2D complications and/or with the aging process. We replicated the association of T2D risk with IGF2BP rs4402960 and detected novel associations with TERT rs2735940 and rs2736098. The addition of these SNPs to a model including traditional risk factors slightly improved risk prediction. After stratification of patients according to the presence/absence of vascular complications, we found significant associations of variants in the CAT, FTO, and UCP1 genes with diabetic retinopathy and nephropathy. Additionally, a variant in the ADIPOQ gene was found associated with macrovascular complications. Notably, these genes are involved in some way in mitochondrial biology and reactive oxygen species regulation. Hence, our findings strongly suggest a potential link between mitochondrial oxidative homeostasis and individual predisposition to diabetic vascular complications.

Adipocytokines are bioactive molecules that are deeply involved in the occurrence of atherosclerosis, obesity, and autoimmune inflammatory diseases.This study was conducted to evaluate the effects of tumor necrosis factor-α (TNF-α) inhibitors on serum levels of adipocytokines in patients with chronic plaque psoriasis.Serum levels of adiponectin, resistin, visfatin, leptin, TNF-α, and interleukin-6 (IL-6) were evaluated in sera obtained from 47 patients with psoriasis, both at baseline and after they had received TNF-α inhibitors for 24 weeks. Equivalent data were obtained for 39 control subjects matched by age, sex, body mass index, waist : hip ratio, geographical origin, Mediterranean dietary habits, and smoking habits.At baseline, mean serum levels of TNF-α, IL-6, leptin, resistin, and visfatin were higher in the psoriasis group than in healthy controls; these differences were statistically significant (P0.05). Conversely, mean serum levels of adiponectin were significantly lower in patients with psoriasis than in controls (P0.0001). Serum levels of adipocytokines did not linearly correlate with anthropometric indices in psoriasis patients (P0.05), except in the case of leptin, for which serum levels were related to waist : hip ratio in both men and women (P0.05). After 24 weeks of treatment, although serum levels of proinflammatory adipocytokines were decreased, only that of leptin showed a statistically significant reduction (P = 0.0003). Serum levels of adiponectin, an anti-inflammatory adipocytokine, were only mildly increased and persisted at a significantly lower level than in healthy controls (P0.005).Patients with psoriasis show an imbalance between pro- and anti-inflammatory adipocytokines, which is reduced but not normalized after administration of TNF-α inhibitors for 24 weeks. This partial rebalancing seems to be mainly related to a reduction in proinflammatory adipocytokines, rather than an increase in anti-inflammatory adipocytokines.

Summary Objective In the SMILE-4 study, zofenopril + acetyl salicylic acid (ASA) was more effective than ramipril + ASA on 1-year prevention of major cardiovascular events (MACE) in patients with acute myocardial infarction complicated by left ventricular dysfunction. In this retrospective analysis, we evaluated drug efficacy in subgroups of patients, according to a history of diabetes mellitus. Methods The primary study endpoint was 1-year combined occurrence of death or hospitalization for cardiovascular causes. Diabetes was defined according to medical history (previous known diagnosis). Results A total of 562 of 693 (81.0%) patients were classified as nondiabetics and 131 (18.9%) as diabetics. The adjusted rate of MACE was lower under zofenopril than under ramipril in both nondiabetics [27.9% vs. 34.9% ramipril; odds ratio, OR and 95% confidence interval: 0.55 (0.35, 0.86)] and diabetics [30.9% vs. 41.3%; 0.56 (0.18, 1.73)], although the difference was statistically significant only for the nondiabetic group (P = 0.013). Zofenopril was superior to ramipril as regards to the primary study endpoint in the subgroup of 157 patients with uncontrolled blood glucose (≥126 mg/dL), regardless of a previous diagnosis of diabetes [0.31 (0.10, 0.90), P = 0.030]. Zofenopril significantly reduced the risk of hospitalization for cardiovascular causes in both nondiabetics [0.64 (0.43, 0.96), P = 0.030] and diabetics [0.38 (0.15, 0.95), P = 0.038], whereas it was not better than ramipril in terms of prevention of cardiovascular deaths. Conclusions This retrospective analysis of the SMILE-4 study confirmed the good efficacy of zofenopril plus ASA in the prevention of long-term MACE also in the subgroup of patients with diabetes mellitus.

Essentials Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently. DOAC specific measurements were performed at trough in patients with atrial fibrillation. Patients who developed thromboembolic events showed lower DOAC plasma levels. This study supports the concept of measuring DOAC levels at steady state. Summary: Background Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C-trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry. Methods DOAC-specific measurements (diluted thrombin time or anti-activated factor II calibrated for dabigatran; anti-activated FX calibrated for rivaroxaban or apixaban) at C-trough were performed locally at steady state within 15–25 days after the start of treatment. For each DOAC, the interval of C-trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow-up were recorded. Results Thromboembolic events (1.8%) occurred in 10 patients who had baseline C-trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C-trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA2DS2-VASc score than that of the total patient population: 5.3 (95% confidence interval [CI] 4.3–6.3 versus 3.0 (95% CI 2.9–3.1). Conclusion In this study cohort, thrombotic complications occurred only in DOAC-treated AF patients who had very low C-trough levels, with a relatively high CHA2DS2-VASc score. Larger studies are warranted to confirm these preliminary observations. © 2018 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Several epidemiological and prospective studies suggest that an early intensive control of hyperglycaemia is able to decrease the risk of diabetic micro- and macro-vascular complications. A growing body of experimental evidence supports the concept that the risk for diabetes complications may be linked to oxidative stress, non-enzymatic glycation of proteins, epigenetic changes, and chronic inflammation, laying the foundation for the “metabolic memory” theory. From a clinical point of view, this theory supports the need for a very early aggressive treatment, with the goal of normalizing metabolic control as soon as possible. It may also prove beneficial to introduce therapeutic agents that are able to reduce reactive species and glycation, in addition to presenting better control of glucose levels in patients with diabetes, in order to minimize long-term diabetes complications. In this review, we evaluate the effect of glucose intake and metabolism in the light of this theory.

Background The use of glycated albumin (GA) has been proposed as an additional glycemic control marker particularly useful in intermediate-term monitoring and in situation when HbA 1c test is not reliable. Methods We have performed the first multicenter evaluation of the analytical performance of the enzymatic method quantILab Glycated Albumin assay implemented on the most widely used clinical chemistry analyzers (i.e. Abbott Architect C8000, Beckman Coulter AU 480 and 680, Roche Cobas C6000, Siemens ADVIA 2400 and 2400 XPT). Results The repeatability of the GA measurement (expressed as CV, %) implemented in the participating centers ranged between 0.9% and 1.2%. The within-laboratory CVs ranged between 1.2% and 1.6%. A good alignment between laboratories was found, with correlation coefficients from 0.996 to 0.998. Linearity was confirmed in the range from 7.6 to 84.7%. Conclusion The new enzymatic method for glycated albumin evaluated by our investigation is suitable for clinical use.

// Liana Spazzafumo 1,* , Emanuela Mensa 2,* , Giulia Matacchione 2,* , Tiziana Galeazzi 3 , Lucia Zampini 3 , Rina Recchioni 4 , Fiorella Marcheselli 4 , Francesco Prattichizzo 5 , Roberto Testa 6 , Roberto Antonicelli 7 , Paolo Garagnani 8,9 , Massimo Boemi 10 , Massimiliano Bonafe 8 , Anna Rita Bonfigli 11 , Antonio Domenico Procopio 2,4 and Fabiola Olivieri 2,4 1 Center of Biostatics, INRCA-IRCCS National Institute, Ancona, Italy 2 Department of Clinical and Molecular Sciences, DISCLIMO, Universita Politecnica delle Marche, Ancona, Italy 3 Pediatric Division, Department of Clinical Sciences, Universita Politecnica delle Marche, Ospedali Riuniti, Presidio Salesi, Ancona, Italy 4 Center of Clinical Pathology and Innovative Therapy, INRCA-IRCCS National Institute, Ancona, Italy 5 Department of Cardiovascular and Metabolic Diseases, IRCCS Multimedica, Sesto San Giovanni, Italy 6 Clinical Laboratory and Molecular Diagnostics, INRCA-IRCCS National Institute, Ancona, Italy 7 UTIC-Cardiology INRCA-IRCCS, National Institute, Ancona, Italy 8 Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna, Bologna, Italy 9 Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden 10 Diabetology Unit, INRCA-IRCCS, National Institute, Ancona, Italy 11 Scientific Direction, INRCA-IRCCS, National Institute, Ancona, Italy * The authors contributed equally to this work Correspondence to: Anna Rita Bonfigli, email: // Keywords : cellular senescence; beta galactosidase activity; type 2 diabetes; aging; inflammaging; Gerotarget Received : August 02, 2017 Accepted : October 04, 2017 Published : October 16, 2017 Abstract β-Galactosidase (β-Gal) activity has been the most extensively utilized biomarker for the detection of cellular senescence. It can be measured also in plasma, and few recent evidence showed an altered plasmatic β-Gal activity in patients affected by some age-related diseases (ARDs). Since T2DM is one of the most common ARDs, we aimed to investigate if plasmatic β-Gal activity is modulated in T2DM patients and if “age” could affect such modulation. To gain mechanistic insights we paralleled this investigation with the evaluation of β-Gal activity in young and senescent endothelial cells (HUVECs) cultured in normo- and hyper-glycaemic environment. A significant age-related increase of plasmatic β-Gal activity was observed in healthy subjects (n. 230; 55-87 years), whereas the enzymatic activity was significantly reduced in T2DM patients (n. 230; 55-96 years) compared to healthy subjects. β-Gal activity detectable both in cells and in the culture medium was significantly increased in senescent cells compared to the younger ones, both under normo- and hyper-glycaemic condition. However, the hyper-glycaemic condition was not associated with an increased β-Gal activity in milieu compared to normo-glycaemic condition. Overall our data reinforce the notion that plasmatic β-Gal activity could be a systemic biomarker of aging, whereas T2DM patients are characterized by a different age-releated trend.

Purpose of review Quality of nutrition plays a central role in illnesses such as diabetes and its complications. Dietary and lifestyle habits may have a strong impact, either worsening or improving the evolution of diabetes mellitus. Some factors, such as obesity, worsen the illness, causing chronic inflammation, lipid metabolic disorder, accelerated atherosclerosis, increased risk for thrombosis, hypertension, hyperinsulinemia, insulin resistance, and cellular senescence. Some other nutritional components, however, have an opposite effect, probably increasing antioxidant defense. Recent findings The effects of nutritional factors on cellular senescence in diabetic patients are described in this review. In particular, we discuss some of the nutritional causes of cellular senescence in diabetes mellitus and focus on different nutraceutical compounds that can affect cellular senescence. Furthermore, relevant mechanisms of action are also described. Summary Diet and nutraceutical factors have important effects on diabetes mellitus. Some molecules, which improve antioxidant defense, may counteract cellular senescence. A good lifestyle with physical activity and good weight control can improve the quality of life in diabetic people; on the contrary, obesity and vitamin deficiencies may worsen the evolution of this illness, even inducing cellular senescence.

OBJECTIVE To test the hypothesis that the simultaneous administration of GLP-1 and insulin may increase their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes. RESEARCH DESIGN AND METHODS In two groups of persons with type 2 diabetes, two sets of experiments were performed. The first group had two normoglycemic-normoinsulinemic clamps with or without GLP-1 and two normoglycemic-hyperinsulinemic clamps with or without GLP-1. The second group had two hyperglycemic-normoinsulinemic clamps and two hyperglycemic-hyperinsulinemic clamps with or without GLP-1. RESULTS During the normoglycemic-hyperinsulinemic clamp, flow-mediated dilatation (FMD) increased, while soluble intercellular adhesion molecule (sICAM-1), plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), nitrotyrosine, and interleukin (IL)-6 decreased compared with normoglycemic-normoinsulinemic clamp. Similar results were obtained with the infusion of GLP-1 during the normoglycemic-normoinsulinemic clamp. The combination of hyperinsulinemia and GLP-1 in normoglycemia was accompanied by a further FMD increase and sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 decrease. During the hyperglycemic-normoinsulinemic clamp, FMD significantly decreased, while sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 significantly increased. When hyperglycemia was accompanied by hyperinsulinemia or by the simultaneous infusion of GLP-1, these phenomena were attenuated. The simultaneous presence of hyperinsulinemia and GLP-1 had an increased beneficial effect. CONCLUSIONS Our results show that the combination of insulin and GLP-1 is more effective than insulin or GLP-1 alone in improving endothelial dysfunction, inflammation, and oxidative stress in type 2 diabetes.

Tumor suppressor protein p53 has been demonstrated to regulate genes involved in energy generating metabolic pathways and apoptosis. To date, a new field of research is the involvement of TP53 codon 72 (Arg72Pro) polymorphism in the diabetic disease. The aim of this study was to evaluate whether the genotype and the related genetic models of Arg72Pro polymorphism of TP53 (rs1042522) are associated with insulin resistance and its metabolic parameters in diabetic and non-diabetic subjects. We examined 335 type 2 diabetic patients (65.5 ± 8.4 years) and 367 non-diabetic subjects (60.5 ± 11.7 years). The results were validated in a validation sample consisting of 199 type 2 diabetic (66.2 ± 8.5 years) and 224 non-diabetic subjects (61.2 ± 12.7 years). In the study sample, the analysis of covariance, adjusted for the effects of age, gender and BMI, showed a significant genotype-diabetes effect on insulin resistance evaluated by HOMA-IR (p = 0.038). This result was mediated by variations in fasting plasma insulin (p = 0.027), as no TP53 genotype-diabetes effects were detected for fasting plasma glucose. In particular, in the diabetic subjects, Pro/Pro genotype was associated with lower values of HOMA-IR with respect to Arg/Arg (p = 0.013) and Arg/Pro (p = 0.006) carriers. No difference in HOMA-IR between diabetic and non-diabetic Pro/Pro carriers was found. Significant recessive model-diabetes interaction effects on fasting insulin and HOMA-IR adjusted for age, sex and BMI were found (p = 0.007 and p = 0.029, respectively). Linear regression analyses, based on the assumption of an additive genetic model adjusted for age, sex and BMI, highlight p53 gene-diabetes interaction effects on fasting insulin (β = -1.27; p = 0.001) and HOMA-IR (β = -0.22; p = 0.006). The results of statistical analyses on fasting insulin and HOMA-IR were all confirmed in the validation sample. Furthermore, the logistic regression models confirmed that the effect of HOMA-IR levels on diabetes was moderated by Pro/Pro genotype in both study and validation samples (OR = 0.29, p = 0.034, 95 % CI = 0.09-0.91, OR = 0.37, p = 0.035, 95 % CI = 0.15-0.93, respectively). Our findings suggest that p53 codon 72 (Arg72Pro) polymorphism influences insulin resistance in type 2 diabetic patients independently of body mass.

Background Intracellular antioxidant response to high glucose is mediated by Cu/Mn-superoxide dismutases (SOD-1/SOD-2), catalase (CAT) and glutathione peroxidases (GPx), particularly glutathione peroxidase-1 (GPx-1). Although oscillating glucose can induce a more deleterious effect than high glucose on endothelial cells, the mechanism by which oscillating glucose exerts its dangerous effects is incompletely understood; however, the involvement of oxidative damage has been generally accepted. In this study we sought to determine whether oscillating glucose differentially modulates antioxidant response, and to elucidate the potential regulatory mechanisms exerted by the microRNA-185 (miR-185). Methods Human endothelial cells were exposed for 1 week to constant and oscillating high glucose. SOD-1, SOD-2, CAT and GPx-1, as well as two markers of oxidative stress [8-hydroxy-2′-deoxyguanosine (8-OHdG) and the phosphorylated form of H2AX (γ-H2AX)] were measured at the end of the experiment. Intracellular miR-185 was measured and loss-of function assays were performed in HUVEC. Bioinformatic tool was used to predict the link between miR-185 on 3′UTR of GPx-1 gene. Luciferase assay was performed to confirm the binding on HUVEC. Results After exposure to constant high glucose SOD-1 and GPx-1 increased, while in oscillating glucose SOD-1 increased and GPx-1 did not. SOD-2 and CAT remained unchanged under both conditions. A critical involvement of oscillating glucose-induced miR-185 in the dysregulation of endogenous GPx-1 was found. Computational analyses predict GPx-1 as miR-185′s target. HUVEC cultures were used to confirm glucose’s causal role on the expression of miR-185, its target mRNA and protein and finally the activation of antioxidant response. In vitro luciferase assays confirmed computational predictions targeting of miR-185 on 3′-UTR of GPx-1 mRNA. Knockdown of miR-185, using anti-miR-185 inhibitor, was accompanied by a significant upregulation of GPx-1 in oscillating glucose. 8-OHdG and γ-H2AX increased more in oscillating glucose than in constant high glucose. Conclusions Glucose oscillations may exert more deleterious effects on the endothelium than high glucose, likely due to an impaired response of GPx-1, coupled by the upregulation of miR-185. Electronic supplementary material The online version of this article (doi:10.1186/s12933-016-0390-9) contains supplementary material, which is available to authorized users.

Background Short to intermediate integrated glycemic control is best determined by glycated albumin (GA). This assay is appropriate when interpretation of glycated hemoglobin (HbA1c) is critical because of hemoglobinopathies, severe anemias, or other factors that affect red blood lifespan as hemodialysis. We evaluated a new assay based on the enzymatic quantification of GA by ketoamine oxidase and an albumin-specific protease. Methods Limits of blank, detection, and quantification; precision; linearity; accuracy; interferences; correlation with HbA1c; and serum vs plasma study have been evaluated on ILab® systems. Results Limit of blank, detection, and quantification for GA (g/L) were, respectively, 0.26, 0.36, and 1.15. Repeatability and within-device precision CVs were lower than 2.11%, 1.61%, and 1.56% for GA (g/L), albumin (g/L), and GA%, respectively. Linearity for GA (g/L) and GA% was 1.2–36.8 and 5.5–92.2, respectively. Highest deviation from linearity was Conclusions GA enzymatic assay is a reliable, fully automated method allowing accurate and precise determination of GA in a routine laboratory.

Introduction: Glycolysis affects glucose determination in vitro. The placement of sample tubes in ice-water slurry with plasma separation within 30 minutes is recommended, or alternatively the use of a glycolysis inhibitor. The aim of our two-steps study was to evaluate which Terumo tube is best for glucose determination in routine clinical setting. Materials and methods: In the first study, blood from 100 volunteers was collected into lithium heparin (LH), NaF/Na heparin (FH) and NaF/citrate buffer/Na2EDTA (FC-Mixture) tubes. LH sample was treated as recommended and considered as reference, while FH and FC-Mixture samples were aliquoted, maintained at room temperature (RT) for 1, 2 and 4 hours; centrifuged and plasma analysed in triplicate. In the second study, samples from 375 volunteers were collected in LH, FH and FC-Mixture tubes and held at RT before centrifugation from 10 to 340 minutes, depending on each laboratory practice. Samples were analysed in one analytical run. Results: In the first study, FH glucose concentrations were 5.15 ± 0.66 mmol/L, 5.05 ± 0.65 mmol/L and 5.00 ± 0.65 mmol/L (P < 0.001) in tubes stored at RT for 1, 2 and 4 hours, respectively. Mean biases in all time points exceeded the analytical goal for desirable bias based on biological variation criteria. FC-Mixture glucose concentrations were 5.48 ± 0.65 mmol/L, 5.46 ± 0.6 mmol/L and 5.46 ± 0.64 mmol/L in tubes stored at RT for 1, 2 and 4 hours, respectively. Mean biases for FC-Mixture glucose in all time points reached optimal analytical goals. In the second study, the biases for LH and FH glucose compared to reference FC-Mixture glucose exceeded the preset analytical goals, regardless of the blood collection to centrifugation time interval. Conclusions: FC-mixture tubes glucose concentrations were preserved up to 4h storage at RT. We confirmed that NaF alone does not allow immediate glycolysis inhibition in real life pre-centrifugation storage conditions (up to 340 minutes). FC-Mixture should be used exclusively for glucose determination in laboratories unable to implement the recommended blood samples’ treatment.

Currently there is debate on whether hypoglycemia is an independent risk factor for atherosclerosis, but little attention has been paid to the effects of recovery from hypoglycemia. In normal control individuals and in people with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normoglycemia or hyperglycemia for another 2 h and then maintaining normal glycemia for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. Recovery with normoglycemia is accompanied by a significant improvement in endothelial dysfunction, oxidative stress, and inflammation, which are affected by hypoglycemia; however, a period of hyperglycemia after hypoglycemia worsens all of these parameters, an effect that persists even after the additional 6 h of normoglycemia. This effect is partially counterbalanced when hyperglycemia after hypoglycemia is accompanied by the simultaneous infusion of vitamin C, suggesting that when hyperglycemia follows hypoglycemia, an ischemia–reperfusion-like effect is produced. This study shows that the way in which recovery from hypoglycemia takes place in people with type 1 diabetes could play an important role in favoring the appearance of endothelial dysfunction, oxidative stress, and inflammation, widely recognized cardiovascular risk factors.

L’albumina e una proteina di notevole importanza nella fisiologia dell’organismo e alterazioni nella sua struttura e funzione possono avere rilevanti ripercussioni fisiopatologiche. e quanto accade in seguito a processi di glicossidazione che portano alla formazione dell’albumina glicata in concentrazioni elevate in caso di iperglicemia cronica o di picchi iperglicemici rilevanti. L’albumina glicata si presenta quindi non solo come un indice di controllo della malattia diabetica, ma anche come un vero e proprio fattore patogenetico. E in non poche e non poco importanti condizioni il suo utilizzo puo risultare piu vantaggioso della stessa emoglobina glicata. Tuttavia, a causa dei limiti iniziali di specificita delle tecniche impiegate per misurare genericamente le fruttosamine (l’insieme delle proteine glicate circolanti), e a causa del persistere di una certa confusione tra fruttosamina e albumina glicata, la determinazione di quest’ultima non ha goduto dello stesso successo dell’emoglobina glicata. In verita, con le metodiche piu recenti la misurazione dell’albumina glicata nel plasma umano e divenuta sufficientemente precisa e accurata, nonche semplice ed economica da eseguire. I risultati che stanno emergendo negli ultimi anni in merito ai progressi analitici e alle applicazioni cliniche dell’albumina glicata porteranno probabilmente nel prossimo futuro a una richiesta sempre maggiore, nell’ottica della crescente attenzione all’appropriatezza in laboratorio.