Prognostic value of soluble ST2, high-sensitivity cardiac troponin, and NT-proBNP in type 2 diabetes: a 15-year retrospective study

Background: Patients with type 2 diabetes (T2DM) present an increased risk of cardiovascular (CV) disease and excess CV-related mortality. Beyond the established role of brain natriuretic peptide (BNP) and cardiac troponins (cTn), other non-cardiac-specific biomarkers are emerging as predictors of CV outcomes in T2DM. Methods: Serum levels of soluble suppression of tumorigenesis 2 (sST2), high-sensitivity (hs)-cTnI, and N-terminal (NT)-proBNP were assessed in 568 patients with T2DM and 115 healthy controls (CTR). Their association with all-cause mortality and the development of diabetic complications was tested in T2DM patients over a median follow-up of 16.8 years using Cox models and logistic regressions. Results: sST2 followed an increasing trend from CTR to uncomplicated T2DM patients (T2DM-NC) to patients with at least one complication (T2DM-C), while hs-cTnI was significantly higher in T2DM-C compared to CTR but not to T2DM-NC. A graded association was found between sST2 (HR 2.76 [95% CI 1.20-6.33] for ≥ 32.0 ng/mL and 2.00 [1.02-3.94] for 16.5-32.0 ng/mL compared to < 16.5 ng/mL, C-statistic = 0.729), NT-proBNP (HR 2.04 [1.90-4.55] for ≥ 337 ng/L and 1.48 [1.05-2.10] for 89-337 ng/L compared to < 89 ng/L, C-statistic = 0.741), and 15-year mortality in T2DM, whereas increased mortality was observed in patients with hs-cTnI ≥ 7.8 ng/L (HR 1.63 [1.01-2.62]). A 'cardiac score' based on the combination of sST2, hs-cTnI, and NT-proBNP was significantly associated with all-cause mortality (HR 1.35 [1.19-1.53], C-statistic = 0.739) and development of CV events. Conclusions: sST2, hs-cTnI, and NT-proBNP are associated with 15-year mortality and onset of CV events in T2DM. The long-term prognostic value of sST2 and its ability to track variables related to insulin resistance and associated metabolic disorders support its implementation into routine clinical practice

Prevalenza della celiachia in una popolazione di donatori di sangue non anemici con carenza di ferro

La celiachia (CD) è un disordine infiammatorio cronico dell’intestino tenue scatenato dall’esposizione al glutine associato a cofattori ambientali in persone geneticamente predisposte. La presentazione clinica di questo disordine è molto variabile andando con forme asintomatiche o gravi quadri clinici chiaramente evidenti. La CD è un disordine multi sistemico che porta a differenti combinazioni nella presentazione clinica. Negli ultimi tempi sembra che ci sia un cambiamento nella presentazione clinica della CD virando dai quadri classici di malassorbimento ad una delle forme non classiche di presentazione con sintomi tenui, non specifici come stanchezza, alterazioni ematologiche, stipsi e/o distensione addominale. Ad oggi viene universalmente accettato che la CD è una condizione autoimmune in cui il fattore scatenante, il glutine e l’autoantigene, la transglutaminasi tissutale, sono entrambi conosciuti rendendo tale condizione l’unica di questo tipo. La CD è la più frequente forma di intolleranza alimentare nel mondo occidentale di grande importanza clinica. Nonostante c’è abbastanza consenso nelle comunità scientifiche internazionali nell’esaminare i pazienti con anemia da carenza di ferro, rimane da investigare l’utilità dello screening nella popolazione generale che presenta livelli di ferritina al di sotto dei valori normali in assenza di anemia e altri segni o sintomi suggestivi di CD. Nel sottogruppo di donatori con carenza di ferro subclinica presi in esame, la prevalenza di celiachia è maggiore di quella che si osserva nella popolazione presa come riferimento negli studi precedenti. Questo dato è importante perché giustificherebbe vista l’alta prevalenza, l’esecuzione di saggi per la celiachia in tutti i donatori non anemici che presentano carenza di ferro. La carenza di ferro in assenza di anemia è chiaramente un forte fattore predittivo di positività alle indagini sierologiche per celiachia. Il valore predittivo dei livelli bassi di ferritina sembrerebbe aumentare ulteriormente nei soggetti di sesso maschile, visto che sono in media nella popolazione generale proprio quelli che presentano valori di ferritina significativamente superiori rispetto alla femminile.Celiac disease (CD) is a chronic inflammatory disorder of the small intestine triggered by gluten exposure, in association with environmental cofactors, in genetically predisposed subjects. The clinical presentation of this disorder is very variable, going from the asymptomatic forms to the evident clinical manifestation. CD is a multi-system disorder that leads to different combinations in the clinical presentation. In recent times there seems to be a change in the clinical presentation of the CD from the classical malabsorption to one of the non-classical forms of presentation with mild, non-specific symptoms such as fatigue, hematological changes, constipation and/or abdominal distension. To date it is clear that CD is an autoimmune condition where the triggering factor (gluten) and the autoantigen (tissue transglutaminase) are both known, making it the only one of this type. CD is the most frequent form of food intolerance in the Western world with great clinical importance. Although there is sufficient consensus in the international scientific community in examining patients with IDA, it remains to investigate the usefulness of screening in the general population that has levels of ferritin below normal values in the absence of anemia and other signs or symptoms suggestive of CD. In the subgroup of donors with subclinical iron deficiency examined in the present thesis the prevalence of celiac disease is greater than that observed in the population taken as a reference in previous studies. This data is important because it justifies the execution of essays for celiac disease in all non-anemic donors with iron deficiency. Iron deficiency in the absence of anemia is clearly a strong predictor of positivity to serological investigations for celiac disease. The predictive value of the low levels of ferritin seems to further increase in the male subjects, given that usually they have significantly higher ferritin values than female

DNA damage response (DDR) and senescence: shuttled inflamma-miRNAs on the stage of inflamm-aging

A major issue in aging research is how cellular phenomena affect aging at the systemic level. Emerging evidence suggests that DNA damage response (DDR) signaling is a key mechanism linking DNA damage accumulation, cell senescence, and organism aging. DDR activation in senescent cells promotes acquisition of a proinflammatory secretory phenotype (SASP), which in turn elicits DDR and SASP activation in neighboring cells, thereby creating a proinflammatory environment extending at the local and eventually the systemic level. DDR activation is triggered by genomic lesions as well as emerging bacterial and viral metagenomes. Therefore, the buildup of cells with an activated DDR probably fuels inflamm-aging and predisposes to the development of the major age-related diseases (ARDs). Micro (mi)-RNAs - non-coding RNAs involved in gene expression modulation - are released locally and systemically by a variety of shuttles (exosomes, lipoproteins, proteins) that likely affect the efficiency of their biological effects. Here we suggest that some miRNAs, previously found to be associated with inflammation and senescence - miR-146, miR-155, and miR-21 - play a central role in the interplay among DDR, cell senescence and inflamm-aging. The identification of the functions of shuttled senescence-associated miRNAs is expected to shed light on the aging process and on how to delay ARD development

Epigenetic mechanisms of endothelial dysfunction in type 2 diabetes

The development of type-2 diabetes mellitus (T2DM) and its complications is largely due to the complex interaction between genetic factors and environmental influences, mainly dietary habits and lifestyle, which can either accelerate or slow down disease progression. Recent findings suggest the potential involvement of epigenetic mechanisms as a crucial interface between the effects of genetic predisposition and environmental factors. The common denominator of environmental factors promoting T2DM development and progression is that they trigger an inflammatory response, promoting inflammation-mediated insulin resistance and endothelial dysfunction. Proinflammatory stimuli, including hyperglycemia, oxidative stress, and other inflammatory mediators, can affect epigenetic mechanisms, altering the expression of specific genes in target cells without changes in underlying DNA sequences. DNA methylation and post-translational histone modifications (PTHMs) are the most extensively investigated epigenetic mechanisms. Over the past few years, non-coding RNA, including microRNAs (miRNAs), have also emerged as key players in gene expression modulation. MiRNAs can be actively released or shed by cells in the bloodstream and taken up in active form by receiving cells, acting as efficient systemic communication tools. The miRNAs involved in modulation of inflammatory pathways (inflammamiRs), such as miR-146a, and those highly expressed in endothelial lineages and hematopoietic progenitor cells (angiomiRs), such as miR-126, are the most extensively studied circulating miRNAs in T2DM. However, data on circulating miRNA signatures associated with specific diabetic complications are still lacking. Since immune cells and endothelial cells are primarily involved in the vascular complications of T2DM, their relative contribution to circulating miRNA signatures needs to be elucidated. An integrated approach encompassing different epigenetic mechanisms would have the potential to provide new mechanistic insights into the genesis of diabetes and its severe vascular complications and identify a panel of epigenetic markers with diagnostic/prognostic and therapeutic relevance

Extracellular microRNAs and endothelial hyperglycemic memory: a therapeutic opportunity?

Type 2 diabetes mellitus (T2DM) is a major cause of cardiovascular disease. Several large clinical trials have shown that the risk by diabetic patients of developing cardiovascular complications is only partially reduced by early, intensive glycemic control and lifestyle interventions, and that such complications result from changes in complex, not fully explored networks that contribute to the maintenance of endothelial function. The accumulation of senescent cells and the low-grade, systemic, inflammatory status that accompanies aging (inflammaging) are involved in the development of endothelial dysfunction. Such phenomena are modulated by epigenetic mechanisms, including microRNAs (miRNAs). MiRNAs can modulate virtually all gene transcripts. They can be secreted by living cells and taken up in active form by recipient cells, providing a new communication tool between tissues and organs. MiRNA deregulation has been associated with the development and progression of a number of age-related diseases, including the enduring gene expression changes seen in diabetic patients. We review recent evidence on miRNA changes in T2DM, focusing on the ability of diabetes-associated miRNAs to modulate endothelial function, inflammaging, and cellular senescence. We also discuss the hypothesis that miRNA-containing extracellular vesicles, i.e. exosomes and microvesicles, could be harnessed to restore a "physiological" signature capable of preventing or delaying the harmful systemic effects of T2DM

Quantification of Carbonic Anhydrase Inhibitors and Metabolites in Urine and Hair of Patients and Their Relatives

Carbonic anhydrase inhibitors (CAIs) are prescription drugs also used in doping to dilute urine samples and tamper with urinalyses. Dorzolamide, brinzolamide, and acetazolamide are prohibited by the World Anti-Doping Agency. Detecting CAIs and their metabolites in biological samples is crucial to documenting misuse in doping. We quantified dorzolamide, brinzolamide, acetazolamide, and their metabolites in the urine and hair of 88 patients under treatment for ocular hypertension or glaucoma. Samples of the patients’ relatives were analyzed to assess potential for accidental exposure. After washing, 25 mg hair was incubated with an acidic buffer at 100 °C for 1 h. After cooling and centrifugation, the supernatant was analyzed by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urine (100 μL) was diluted and centrifuged before UHPLC-MS/MS analysis. Run time was 8 min through a reverse-phase column with a mobile phase gradient. MS/MS analysis was performed in a multiple-reaction monitoring mode after positive electrospray ionization. Median urinary concentration was 245 ng/mL (IQR: 116.2–501 ng/mL) for dorzolamide, 81.1 ng/mL (IQR: 35.9–125.3 ng/mL) for N-deethyl-dorzolamide, 0.77 ng/mL (IQR: 0.64 ng/mL–0.84 ng/mL) for N-acetyl-dorzolamide, 38.9 ng/mL (IQR: 20.4–79.2 ng/mL) for brinzolamide, and 72.8 ng/mL (IQR: 20.7–437.3 ng/mL) for acetazolamide. Median hair concentration was 0.48 ng/mg (IQR: 0.1–0.98 ng/mg) for dorzolamide, 0.07 ng/mg (IQR: 0.06–0.08 ng/mg) for N-deethyl-dorzolamide, 0.40 ng/mL (IQR: 0.13–1.95 ng/mL) for brinzolamide. Acetazolamide was detected in only one hair sample. Dorzolamide and brinzolamide were detected in the urine of three and one relatives, respectively. Cutoff concentrations of urinary dorzolamide and brinzolamide are necessary to preclude false positives due to contamination or passive exposure. We reported the first concentrations of brinzolamide in hair