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Functional constipation (FC) is one of the most common disorders in childhood and has a neg-ative impact on the quality of life of children. Scientific evidence regarding a causal relation-ship between FC and cow’s milk allergy is controversial, as it is also reported by the latest European Society for Paediatric Gastroenterology, Hepatology and Nutrition-North American Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN–NASPGHAN) rec-ommendations. In the case of FC, routine allergometric tests are not recommended and the cows’ milk-free diet is only proposed in the case of laxative-resistant constipation and only following the advice of an expert. Instead, after a careful review of the literature and in view of the many clinical cases encountered in our clinical practice, we believe that it is useful to propose cows’ milk-free diet as first line for the treatment of FC at least in pre-school children and in children with a personal or family history of atopy or with a previous diagnosis of cow’s milk protein allergy.

Background: Whether concomitant administration of anticancer agents influences the efficacy and safety of oral anticoagulants in patients treated for cancer-associated venous thromboembolism (VTE) is undefined. The pharmacological interaction between anticancer agents and direct oral anticoagulants is perceived as a concern.Methods: We evaluated the effects of concomitant administration of anticancer agents on recurrent VTE, major bleeding and death in patients with cancer-associated VTE randomised to receive apixaban or dalteparin in the Caravaggio study.Results: Anticancer agents were concomitantly given to 336 patients (58.3%) treated with apixaban and to 332 patients (57.3%) treated with dalteparin. In patients treated with apixaban, recurrent VTE occurred in 20 (6.0%) and 12 (5.0%) among patients treated or not treated with anticancer agents, respectively (hazard ratio [HR] = 1.14; 0.55-2.38); major bleeding occurred in 12 (3.6%) and 10 (4.2%) patients , respectively (HR = 0.79; 0.34-1.82), and death occurred in 74 (22.0%) and 61 (25.4%) patients , respectively (HR = 0.71; 0.51-1. 00). In patients treated with dalteparin, recurrent VTE occurred in 24 (7.2%) and 22 (8.9%) among patients treated or not treated with anticancer agents, respectively (HR = 0.71; 0.40-1.28); major bleeding occurred in 16 (4.8%) and 7 (2.8%) patients, respectively (HR = 1.78; 0.66-4.79 ), and death occurred in 87 (26.2% ) and 66 (26.7 %) patients, respectively (HR = 0.85; 0.62-1.18). The comparative efficacy and safety of apixaban and dalteparin was not different in patients treated or not treated with anticancer agents. No effect on recurrent VTE, major bleeding or death was observed with inhibitors or inducers of P-glycoprotein and/or CYP3A4.Conclusion: In our study, concomitant administration of anticancer agents had no effect on the risk of VTE recurrence or major bleeding in patients treated with apixaban or dalteparin for cancer-associated VTE.(c) 2021 Elsevier Ltd. All rights reserved.

Background: Recent research highlighted the potential role of circulating cell-free DNA (cfDNA), resulted by apoptosis or cell necrosis, as a prognostic marker in the setting of different clinical conditions. Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Apoptosis of renal epithelial cells is proposed as a mechanism involved in CRS type 1. In this study, we investigated cfDNA levels in patients with acute heart failure (AHF) and CRS type 1 and the possible correlation between cfDNA levels and inflammatory and apoptotic parameters. Methods: We enrolled 17 AHF patients and 15 CRS type 1 who exhibited AKI at the time of admission (caused by AHF) or developed AKI during the first 48 h from admission. cfDNA was extracted from plasma and quantified by real-time polymerase chain reaction. Plasma levels of NGAL, tumor necrosis factor-α, interleukin (IL)-6, IL-18, and caspase-3 were measured. Results: We observed significantly higher levels of cfDNA in patients with CRS type 1 than patients with AHF. Caspase-3, IL-6, IL-18, and NGAL levels resulted significantly increased in patients with CRS type 1. Moreover, a positive correlation between cfDNA levels and caspase-3 levels was found, as well as between cfDNA levels and IL-6 and renal parameters. Conclusion: Our study explores the premise of cfDNA as a marker for apoptosis and inflammation in CRS type 1 patients. cfDNA could potentially serve as an index for noninvasive monitoring of tissue damage and apoptosis in patients with AKI induced by AHF.

The aim of this study was to examine the impact of two different post-match training interventions on the subsequent recovery of perceptual and biochemical parameters after the game. In a crossover design, eight sub-elite players underwent a soccer-specific training (SST) and an active recovery (AR) regimen on the second day after a match (+48 h). Muscle soreness as well as muscle damage (creatine kinase, CK), inflammatory (C-reactive protein and interleukin 6), immunological (e.g., lymphocytes, neutrophils, and monocytes), and endocrine (cortisol) markers were obtained at baseline (−72 h), immediately after (0 h), and 72 h post-match (+72 h). AR promoted a higher restoration of muscle soreness values (P = 0.004, η2p = 0.49) together with a better restoration of CK within 72 h post-match compared with SST (P = 0.04, η2p = 0.36). Conversely, no significant (P > 0.05, η2p < 0.91) differences were observed in the recovery timeframe of inflammatory, immunological, and endocrine responses between SST and AR. Overall, AR elicited a quicker muscle soreness and CK restoration compared to SST intervention at 72 h post-match. Such information provides novel evidence-based findings on the appropriateness of different recovery strategies and may aid to improve the practitioners’ decision-making process when two consecutive games are played within 3 days.

Background: Several instruments have been proposed to investigate restricted, repetitive behaviors (RRBs) in individuals with Autism Spectrum Disorder (ASD). Systematic video observations may overcome questionnaire and interview limitations to investigate RRBs. This study aimed to analyze stereotypic patterns through video recordings and to determine the correlation between the number and appearance of RRBs to ASD severity. Methods: Twenty health professionals wearing a body cam recorded 780 specific RRBs during everyday activities of 67 individuals with ASD (mean age: 14.2 ± 3.72 years) for three months. Each stereotypy was classified according to its complexity pattern (i.e., simple or complex) based on body parts and sensory channels involved. Results: The RRBs spectrum for each subject ranged from one to 33 different patterns (mean: 11.6 ± 6.82). Individuals with a lower number of stereotypies shown a lower ASD severity compared to subjects with a higher number of stereotypies (p = 0.044). No significant differences were observed between individuals exhibiting simple (n = 40) and complex patterns (n = 27) of stereotypies on ASD severity, age, sex, and the number of stereotypes. Conclusions: This study represents the first attempt to systematically document expression patterns of RRBs with a data-driven approach. This may provide a better understanding of the pathophysiology and management of RRBs.

Over the centuries, iconographic representations of St Anthony of Padua, one of the most revered saints in the Catholic world, have been inspired by literary sources, which described the Saint as either naturally corpulent or with a swollen abdomen due to dropsy (i.e. fluid accumulation in the body cavities). Even recent attempts to reconstruct the face of the Saint have yielded discordant results regarding his outward appearance. To address questions about the real appearance of St Anthony, we applied body mass estimation equations to the osteometric measurements taken in 1981, during the public recognition of the Saint’s skeletal remains. Both the biomechanical and the morphometric approach were employed to solve some intrinsic limitations in the equations for body mass estimation from skeletal remains. The estimated body mass was used to assess the physique of the Saint with the body mass index. The outcomes of this investigation reveal interesting information about the body type of the Saint throughout his lifetime.

A careful angiographic assessment of a chronic total occlusion (CTO) is essential for optimal procedural planning. In the classic Hybrid Approach, the insertion of two guiding catheters at the beginning of the intervention is recommended. This is fundamental to perform simultaneous double injection, to achieve complete visualization of the coronary circulation and to choose the best starting strategy between antegrade wire escalation (AWE), antegrade dissection and re-entry (ADR) and the retrograde techniques (retrograde wire escalation [RWE] and retrograde dissection and re-entry [RDR]). In the Hybrid Algorithm the set-up is the same, regardless of the chosen first strategy, and therefore routinely uses double access. Because revascularizations of CTOs commonly require large bore catheters (7-8 French) to ensure high back up support, the femoral arterial access is preferred by most of the operators. However, the use of a double access, large introducer sheaths and femoral approach are associated with a greater risk of access-related complications and even the occurrence of major adverse cardiovascular events. We have previously proposed an algorithm, called "Minimalistic Hybrid Approach", which aims to limit the routine use of dual injection, and to favour the use of trans-radial access and smaller (6-7 French) guiding catheters. In this algorithm the chosen starting strategy depends on the complexity of the lesion assessed by J-CTO score and on the presence of favourable contralateral interventional collateral circulation. However, this novel algorithm proved to have some limitations, such as the non-specific evaluation of CTOs with ipsilateral collateral circulation and the too arbitrary choice of the starting strategy based on a J-CTO score cut-off. These considerations led to the development of an "updated" Minimalistic Hybrid Approach algorithm that takes into account the type of collaterals (ipsilateral or contralateral) and the "a priori" choice of the hybrid technique, with the highest chance of success in that specific CTO lesion (independently from the J-CTO score). One important aspect that makes this algorithm unique is its "dynamicity": not only for the technique to be used, as in the classic hybrid algorithm (shifting between AWE, ADR, RWE and RDR), but also for the set-up, with access site and French size to be adapted during the PCI to the technique adopted. We believe that this novel approach could further improve the safety of CTO-PCI without losing its current efficacy.

Primary ventricular fibrillation (PVF) may occur in the early phase of ST-elevation myocardial infarction (STEMI) prior to primary percutaneous coronary intervention (PCI). Multiple electrocardiographic STEMI patterns are associated with PVF and short-term mortality including the tombstone, Lambda, and triangular QRS-ST-T waveform (TW). We aimed to compare the predictive value of different electrocardiographic STEMI patterns for PVF and 30-day mortality. We included a consecutive cohort of 407 STEMI patients (75% males, median age 66 years) presenting within 12 h of symptoms onset. At first medical contact, 14 (3%) showed the TW or Lambda ECG patterns, which were combined in a single group (TW-Lambda pattern) characterized by giant R-wave and downsloping ST-segment. PVF prior to primary PCI occurred in 39 (10%) patients, significantly more often in patients with the TW-Lambda pattern than those without (50% vs. 8%, p < 0.001). For the multivariable analysis, Killip class ≥3 (OR 6.19, 95% CI 2.37–16.1, p < 0.001) and TW-Lambda pattern (OR 9.64, 95% CI 2.99–31.0, p < 0.001) remained as independent predictors of PVF. Thirty-day mortality was also higher in patients with the TW-Lambda pattern than in those without (43% vs. 6%, p < 0.001). However, only LVEF (OR 0.86, 95% CI 0.82–0.90, p < 0.001) and PVF (OR 4.61, 95% CI 1.49–14.3, p = 0.042) remained independent predictors of mortality. A mediation analysis showed that the effect of TW-Lambda pattern on mortality was mediated mainly via the reduced LVEF. In conclusion, among patients presenting with STEMI, the electrocardiographic TW-Lambda pattern was associated with both PVF before PCI and 30-day mortality. Therefore, this ECG pattern may be useful for early risk stratification of STEMI.

The data reported in this article are related to the paper entitle “Stem cells transplantation positively modulates the heart-kidney cross talk in Cardiorenal Syndrome Type II” (Vescovo et al., 2019), which analyzed the impact of stem cells injection in cardiorenal syndrome type II. The dataset contains detailed information on apoptosis and cytokines milieu modification after injection of c-Kit–selected human amniotic fluid stem cells (hAFS) or rats vascular progenitor cells (rSVC-GFP group) in an experimental model of CRSII. The data can be useful for clarifying the paracrine effects exerted by the injected cells.

Aims Despite the increasing use of early invasive strategies in non-ST-elevation acute coronary syndromes (NSTE-ACS), optimal initial antithrombotic therapy (ATT) based on the safety/efficacy profile of all guideline-recommended combinations remains crucial for the early management of both medically and invasively treated NSTE-ACS patients. Methods and results Randomized controlled trials on ATT in NSTE-ACS/unstable angina reporting early (within 14 days) major adverse cardiovascular events (MACE) and major bleeding were selected. Overall, 3799 studies were screened, 117 clinical trials were assessed as potentially eligible, 20 trials were included in the study. According to treatment and type of intervention, nine different meta-analyses were performed including a total of 88 748 patients. A significant reduction of trial-defined MACE was found for aspirin vs. placebo [odds ratio (OR), 0.57; 95% confidence interval (CI), 0.34–0.96], heparin vs. placebo (OR, 0.38; 95% CI, 0.15–0.97), aspirin + heparin vs. placebo (OR, 0.32; 95% CI, 0.18–0.59), aspirin + heparin vs. aspirin (OR, 0.57; 95% CI, 0.42–0.79), aspirin + low molecular weight heparin (LMWH) vs. aspirin + unfractionated heparin (UFH; OR, 0.81; 95% CI, 0.69–0.95) and aspirin + ticagrelor/prasugrel + heparins vs. aspirin + clopidogrel + heparins (OR, 0.76; 95% CI, 0.62–0.94). A significant decrease in major bleeding was found only for fondaparinux vs. LMWH on the background of aspirin + clopidogrel (OR, 0.52; 95% CI, 0.44–0.62) despite a clear trend towards increased bleeding for heparin compared to aspirin, aspirin + heparin compared to placebo, aspirin + heparin compared to aspirin, aspirin + P2Y12inhibitors + UFH/LMWH compared to aspirin + UFH/LMWH, and aspirin + ticagrelor/prasugrel + heparins compared to aspirin + clopidogrel + heparins. Conclusion To our knowledge, these findings are the first to report the safety and efficacy of all the various combinations of currently recommended ATT for the early management of NSTE-ACS, providing a comprehensive evidence-base to guide decisions depending on the patients’ bleeding risk and treatment strategy.

Amyloidosis is a group of progressive and devastating disorders resulting from misfolded proteins extracellular deposition into tissues. When deposition of fibrils occurs in cardiac tissues, this systemic disease can lead to a very poor prognosis. In this review, we focused on the most common types of cardiac amyloidosis and their treatments. Early diagnosis remains critically important, and here we reviewed the diagnostic methods adopted starting from the non-invasive imaging techniques to more invasive approaches, and the typing of precursor proteins. Typing the different misfolding proteins is mandatory since therapy differs accordingly and thus guiding therapy. We highlighted the most updated and recent treatment strategies to cure amyloidosis.

Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury. In this study, we evaluate the role of lipopolysaccharide (LPS) and various inflammatory markers in the developing acute kidney injury (AKI) in acute heart failure (AHF) patients. We enrolled 31 AHF patients and 20 CRS type 1 (the cause of AKI was presumed to be related to cardiac dysfunction) and 17 healthy volunteers without AHF, AKI or CKD, as control group (CTR). We assessed levels of LPS, proinflammatory cytokines (TNF-α, IL-6, IL-18), and oxidative stress marker (myeloperoxidase, MPO). We observed a significant increase in LPS, TNF-α, IL-6, IL-18 and MPO levels in CRS type 1 and AHF group compared to CTR. LPS levels resulted significantly higher in CRS type 1 patients compared with AHF (118.2 pg/mL, IQR 77.8–217.6 versus 13.5 pg/mL, IQR 12.0–17.0, p = 0.008). We found a cytokines and oxidative stress dysregulation in CRS type 1 patients compared with AHF. Furthermore, we observed a strong positive significant correlation between LPS levels and IL-6 (Spearman’s rho = 0.79, p

BACKGROUND Composite endpoints are pivotal when assessing rare outcomes over relatively short follow-ups. Most randomized controlled trials (RCTs) comparing percutaneous coronary intervention (PCI) with stent implantation to optimal medical therapy (OMT) in chronic coronary syndromes (CCS) patients included both hard and soft outcomes in their primary endpoint, with periprocedural myocardial infarctions (MIs) systematically allocated to the PCI arm. We metaanalysed the above RCTs for composite hard endpoints, with and without periprocedural MIs. METHODS This study is registered in PROSPERO CRD42020166754 and follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Cochrane Collaboration reporting. Patients had inducible ischemia, no left main disease nor severe left ventricular dysfunction. RESULTS Six RCTs involving 10,751 patients followed for a mean of 4.4 years were included. PCI+OMT versus OMT alone was associated with no difference in the two co-primary composite endpoints of all-cause death/MI/stroke and cardiovascular death/MI including all-MIs (IRR 0.99; 95% CI 0.90-1.08 and IRR 0.95; 95% CI 0.83-1.08 respectively). After inclusion of spontaneous rather than all-MIs (i.e., excluding periprocedural MIs), the odds showed benefit of PCI+OMT for both co-primary endpoints (IRR 0.88; 95% CI 0.80-0.97, P

The prevalence of angina despite optimal medical therapy is high among patients with coronary chronic total occlusions. Despite advancements in techniques and operator’s experience, percutaneous revascularization of coronary chronic total occlusions is still associated with a not negligible risk of failures and complications. The Coronary Sinus Reducer, a new device developed to improve angina, has shown promising results in terms of efficacy and safety in patients with refractory symptoms. The aim of this review is to summarize the evidence so far available and to guide clinicians in the selection of patients with chronic total occlusions that could benefit more from Coronary Sinus Reducer implantation. A recently published study suggests a clear value of this device in patients with chronic total occlusions. This is likely to be related to the presence of a well-developed collateral circulation. A careful evaluation of risks and benefits of both myocardial revascularization and Coronary Sinus Reducer implantation should be done in all the cases in order to better define the optimal strategy for the patient. The Coronary Sinus Reducer implantation has a rationale in patients with chronic total occlusion as an alternative or additional therapy to myocardial revascularization.

Twenty expert caregivers wearing a body cam recorded 1868 videoclips in 67 autistic subjects along a 3 months close follow-up. A team consisting of a senior child neuro-psychiatrist and a senior psychologist selected 780 of them as expressing repetitive behaviors (RB) and made an empirical classification according to components, complexity, body parts and sensory channels involved, with the aim to understand better the pattern complexity and correlate with autism severity. The RB spectrum for each subject ranged from 1 to 33 different patterns (average= 11.6; S.D.= 6.82). Forty subjects expressed prevalent simple pattern and 27 prevalent complex patterns. No significant differences are found between the two groups according to ADOS score severity. This study represents a first attempt to systematically document expression patterns of RB with a data driven approach. This may provide a better understanding of the pathophysiology, diagnosis, and treatment of RB.

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice with implications on long-term outcomes. Metabolic disorders including diabetes mellitus and obesity are independent predictors of atrial fibrillation and present therapeutic targets to reduce both the incidence and duration burden of atrial fibrillation. The presence of pericardial fat in direct contact with cardiac structures, as well the subsequent release of proinflammatory cytokines, may play an important role in this connection. Atrial fibrillation is an independent predictor of cognitive impairment and dementia. While clinical stroke is a major contributor, other factors such as cerebral hypoperfusion and microbleeds play important roles. New evidence suggests that atrial fibrillation and cognitive impairment may be downstream events of atrial cardiomyopathy, which may be caused by several factors including metabolic syndrome, obesity, and obstructive sleep apnea. The mechanisms linking these comorbidities to cognitive impairment are not yet fully elucidated. A clearer understanding of the association of AF with dementia and cognitive impairment is imperative. Future studies should focus on the predictors of cognitive impairment among those with AF and aim to understand the potential mechanisms underlying these associations. This would inform strategies for the management of AF aiming to prevent continued cognitive impairment.

Coronary sinus Reducer (CSR) implantation is currently recommended to relieve angina in patients with refractory symptoms despite optimal medical therapy and maximally achievable revascularization. The impact of diabetes mellitus on outcome after CSR implantation is at present unknown. We aimed to explore the impact of CSR in refractory angina patients with diabetes mellitus. Data from consecutive patients undergoing CSR implantation at four different centres between 2014 and 2018 were included. Patients were divided according to the presence or absence of diabetes mellitus. Primary objective of this analysis was to evaluate the clinical response to CSR implantation defined as an improvement of ≥ 1 classes of the Canadian Cardiovascular Society (CCS) Classification. A total of 219 patients were included, 116 (53%) of whom had diabetes mellitus. The median age of the population was 69 years and 167 patients (76%) were male. There were no significant differences between groups of patients with and without diabetes mellitus with respect to CCS class at baseline (p value = 0.32) and at follow-up (p = 0.75). Over a median follow-up of 393 [224–1004] days, 84 (72%) of the patients with diabetes mellitus met the primary outcome, similarly to those without diabetes mellitus (p = 0.28). Fifty-three patients (24%) did not have an improvement in CCS class and no one experienced worsening of angina. CSR implantation was equally effective in improving angina symptoms among patients with refractory angina and diabetes mellitus compared to patients without diabetes mellitus.

Epithelial-to-mesenchymal transition (EMT) is involved in prostate cancer (PCa) metastatic progression, and its plasticity suggests epigenetic implications. Deregulation of DNA methyltransferases (DNMTs) and several microRNAs (miRNAs) plays a relevant role in EMT, but their interplay has not been clarified yet. In this study, we provide evidence that DNMT3A interaction with several miRNAs has a central role in an ex vivo EMT PCa model obtained via exposure of PC3 cells to conditioned media from cancer-associated fibroblasts. The analysis of the alterations of the miRNA profile shows that miR-200 family (miR-200a/200b/429, miR-200c/141), miR-205 and miR-203, known to modulate key EMT factors, are down-regulated and hyper-methylated at their promoters. DNMT3A (mainly isoform a) is recruited onto these miRNA promoters, coupled with the increase of H3K27me3/H3K9me3 and/or the decrease of H3K4me3/H3K36me3. Most interestingly, our results reveal the differential expression of two DNMT3A isoforms (a and b) during ex vivo EMT and a regulatory feedback loop between miR-429 and DNMT3A that can promote and sustain the transition towards a more mesenchymal phenotype. We demonstrate the ability of miR-429 to target DNMT3A 3′UTR and modulate the expression of EMT factors, in particular ZEB1. Survey of the PRAD-TCGA dataset shows that patients expressing an EMT-like signature are indeed characterized by down-regulation of the same miRNAs with a diffused hyper-methylation at miR-200c/141 and miR-200a/200b/429 promoters. Finally, we show that miR-1260a also targets DNMT3A, although it does not seem to be involved in EMT in PCa.

Oropharyngeal squamous cell carcinoma (OPSCC) is an increasing world health problem with a more favorable prognosis for patients with human papillomavirus (HPV)-positive tumors compared to those with HPV-negative OPSCC. How HPV confers a less aggressive phenotype, however, remains undefined. We demonstrated that HPV-positive OPSCC cells display reduced macroautophagy/autophagy activity, mediated by the ability of HPV-E7 to interact with AMBRA1, to compete with its binding to BECN1 and to trigger its calpain-dependent degradation. Moreover, we have shown that AMBRA1 downregulation and pharmacological inhibition of autophagy sensitized HPV-negative OPSCC cells to the cytotoxic effects of cisplatin. Importantly, semi-quantitative immunohistochemical analysis in primary OPSCCs confirmed that AMBRA1 expression is reduced in HPV-positive compared to HPV-negative tumors. Collectively, these data identify AMBRA1 as a key target of HPV to impair autophagy and propose the targeting of autophagy as a viable therapeutic strategy to improve treatment response of HPV-negative OPSCC. Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; CDDP: cisplatin (CDDP); FFPE: formalin-fixed paraffin-embedded (FFPE); HNC: head and neck cancers (HNC); HPV: human papillomavirus (HPV); hrHPV: high risk human papillomavirus (hrHPV); OCSCC: oral cavity squamous carcinomas (OCSSC); OPSCC: oropharyngeal squamous cell carcinoma (OPSCC); OS: overall survival (OS); qPCR: quantitative polymerase chain reaction; RB1: RB transcriptional corepressor 1; ROC: receiver operating characteristic curve (ROC).

Patients with HCV who achieve a sustained virological response (SVR) on direct-acting antiviral (DAA) therapy still need to be monitored for signs of liver disease progression. To this end, the identification of both disease biomarkers and therapeutic targets is necessary.Extracellular vesicles (EVs) purified from plasma of 15 healthy donors (HDs), and 16 HCV-infected patients before (T0) and after (T6) DAA treatment were utilized for functional and miRNA cargo analysis. EVs purified from plasma of 17 HDs and 23 HCV-infected patients (T0 and T6) were employed for proteomic and western blot analyses. Functional analysis in LX2 cells measured fibrotic markers (mRNAs and proteins) in response to EVs. Structural analysis was performed by qPCR, label-free liquid chromatography-mass spectrometry and western blot.On the basis of observations indicating functional differences (i.e. modulation of FN-1, ACTA2, Smad2/3 phosphorylation, collagen deposition) of plasma-derived EVs from HDs, T0 and T6, we performed structural analysis of EVs. We found consistent differences in terms of both miRNA and protein cargos: (i) antifibrogenic miR204-5p, miR181a-5p, miR143-3p, miR93-5p and miR122-5p were statistically underrepresented in T0 EVs compared to HD EVs, while miR204-5p and miR143-3p were statistically underrepresented in T6 EVs compared to HD EVs (p0.05); (ii) proteomic analysis highlighted, in both T0 and T6, the modulation of several proteins with respect to HDs; among them, the fibrogenic protein DIAPH1 was upregulated (LogTaken together, these results highlight structural EV modifications that are conceivably causal for long-term liver disease progression in patients with HCV despite DAA-mediated SVR.Direct-acting antivirals lead to virological cure in the majority of patients with chronic hepatitis C virus infection. However, the risk of liver disease progression or complications in patients with fibrosis and cirrhosis remains in some patients even after virological cure. Herein, we show that extracellular vesicle modifications could be linked to long-term liver disease progression in patients who have achieved virological cure; these modifications could potentially be used as biomarkers or treatment targets in such patients.

Background Diagnosis of latent autoimmune diabetes in adults (LADA) is usually based on the adult age, anti-pancreatic islet cell antibodies detection, and insulin independence. This study investigates the diagnostic value of antibodies against human glutamic acid decarboxylase (hGAD) peptides in LADA and type 1 diabetes mellitus (T1DM) patients, and their cross-reactivity with an Enterovirus Coxsackie B4 (CVB4) shared epitope. Methods Sera from 27 LADA patients, 23 T1DM patients, and 24 controls were tested in ELISA for antibodies against hGAD peptides and a selected sequence of P2C protein of CVB4 (CVB4P2C). Diagnostic power of peptides was analyzed by ROC-curve analysis and cross-reactivity among peptides evaluated. Results IgM and IgG antibodies showed significant differences between LADA and T1DM versus controls for all peptides. Antibody responses present high agreement among peptides for IgM and IgG-isotypes in T1DM, which is not reproduced in LADA. IgM antibodies showed high predicting diagnostic power particularly in LADA (sensitivity > 85%, specificity 95.8%). Conclusions Our study highlights the usefulness of peptides as diagnostic antigens in T1DM and LADA, and extends previous findings by comparing IgM and IgG-isotype antibodies in the same population. Additionally, results highlight the role of the entourage in the shared sequon PEVKXK in GAD and CVB4P2C particularly in IgMs identification.

Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy, with a prevalence that has increased significantly in the last decade, coming to affect 12–18% of all pregnancies. GDM is believed to be the result of a combination of genetic, epigenetic and environmental factors. Following the identification of susceptibility genes for type 2 diabetes by means of genome-wide association studies, an association has also been demonstrated between some type 2 diabetes susceptibility genes and GDM, suggesting a partial similarity of the genetic architecture behind the two forms of diabetes. More recent genome-wide association studies, focusing on maternal metabolism during pregnancy, have demonstrated an overlap in the genes associated with metabolic traits in gravid and non-gravid populations, as well as in genes apparently unique to pregnancy. Epigenetic changes—such as DNA methylation, histone modifications and microRNA gene silencing—have also been identified in GDM patients. Metabolomics has been used to profile the metabolic state of women during pregnancy, based on the measurement of numerous low-molecular-weight metabolites. Measuring amino acids and conventional metabolites has revealed changes in pregnant women with a higher insulin resistance and high blood glucose levels that resemble the changes seen in non-gravid, insulin-resistant populations. This would suggest similarities in the metabolic profiles typical of insulin resistance and hyperglycemia whether individuals are pregnant or not. Future studies combining data obtained using multiple technologies will enable an integrated systems biology approach to maternal metabolism during a pregnancy complicated by GDM. This review highlights the recent knowledge on the impact of genetics and epigenetics in the pathophysiology of GDM and the maternal and fetal complications associated with this pathology condition.

Treatment of coronary chronic total occlusions represents one of the major challenges in the field of interventional cardiology. This is due to the complexity of these procedures and to the relatively higher risk of complications. In recent years, the development of innovative techniques and the evolution of materials have produced significant progress in this field. Better procedural outcomes have been achieved, with fewer complications. This article highlights the most recent scientific evidence and techniques, with the intention to guide interventional cardiologists in optimal patient selection and procedure choice.

Omega-3 fatty acid (O3FA) supplementation has shown conflicting evidence regarding its benefit in cardiovascular events. We performed a pairwise and network meta-analysis to elucidate the benefit of different doses of O3FA supplementation in cardiovascular prevention.Fourteen studies were identified providing data on 125,763 patients. A prespecified cut-off value of 1 g per day was set for low-dose (LD) O3FA and 1 g per day for high-dose (HD) O3FA. The efficacy outcomes of interest were total death, cardiac death, sudden cardiac death, myocardial infarction, stroke, coronary revascularization, unstable angina, and major vascular events. Safety outcomes of interest were bleeding, gastrointestinal disturbances, and atrial fibrillation events. HD treatment was associated with a lower risk of cardiac death (IRR 0.79, 95% CI [0.65-0.96], p = 0.03 versus control), myocardial infarction (0.71 [0.62-0.82], p 0.0001 versus control and 0.79 [0.67-0.92], p = 0.003 versus LD), coronary revascularization (0.74 [0.66-0.83], p 0.0001 versus control and 0.74 [0.66-0.84], p 0.0001 versus LD), unstable angina (0.73 [0.62-0.86], p = 0.0001 versus control and 0.74 [0.62-0.89], p = 0.002 versus LD), and major vascular events (0.78 [0.71-0.85], p 0.0001 versus control and 0.79 [0.72-0.88], p 0.0001 versus LD). HD treatment was associated with increased risk for bleeding events (1.49 [1.2-1.84], p = 0.0002 versus control and 1.63 [1.16-2.3], p = 0.005 versus LD) and increased atrial fibrillation events compared to control (1.35 [1.1-1.66], p = 0.004). HD O3FA treatment was associated with lower cardiovascular events compared to LD and to control, but increased risk for bleeding and atrial fibrillation events.

The aim of this study was to examine attendance for early postpartum follow-up among women with gestational diabetes mellitus (GDM), and to identify factors that influenced their likelihood of attending. One thousand eight hundred and nineteen women with GDM were retrospectively analyzed. During pregnancy, the following data were collected: age, family history of diabetes, ethnicity, prepregnancy BMI, fasting plasma glucose, glycated hemoglobin, gestational week of GDM diagnosis, timing and mode of delivery, newborn’s birth weight and length. Glycemia and insulinemia during OGTT, lipid profile and postpartum BMI were assessed at follow-up. Based on the OGTT, women were classified as having normal glucose tolerance (NGT) or abnormal glucose tolerance (AGT), which included impaired fasting glucose (IFG), impaired glucose tolerance (IGT), IFG + IGT, and DM2. Factors predicting postpartum attendance for follow-up and onset of AGT were considered. Of the 889 (48.9%) who attended the scheduled postpartum OGTT, 741 (83.4%) had NGT, while 148 (16.6%) had AGT (IFG 6.7%, IGT 7.7%, IFG + IGT 0.8%, DM2 1.5%). The predictors of adherence to follow-up were: not belonging to an immigrant group; family history of DM2; and insulin therapy in pregnancy. The same factors were also predictive of AGT. Our data suggest a role of ethnicity in both attendance for postpartum follow-up and its outcome. Despite efforts to provide care for women with GDM, postpartum screening rates are still low among Italian women, and especially among immigrants. Hence, the need to improve these patients’ awareness of the severe risk of developing diabetes after pregnancy, concentrating efforts especially on women belonging to the most at risk ethnic groups.

BACKGROUND: Recent guidelines recommend consideration of the use of oral edoxaban or rivaroxaban for the treatment of venous thromboembolism in patients with cancer. However, the benefit of these oral agents is limited by the increased risk of bleeding associated with their use. METHODS: This was a multinational, randomized, investigator-initiated, open-label, noninferiority trial with blinded central outcome adjudication. We randomly assigned consecutive patients with cancer who had symptomatic or incidental acute proximal deep-vein thrombosis or pulmonary embolism to receive oral apixaban (at a dose of 10 mg twice daily for the first 7 days, followed by 5 mg twice daily) or subcutaneous dalteparin (at a dose of 200 IU per kilogram of body weight once daily for the first month, followed by 150 IU per kilogram once daily). The treatments were administered for 6 months. The primary outcome was objectively confirmed recurrent venous thromboembolism during the trial period. The principal safety outcome was major bleeding. RESULTS: Recurrent venous thromboembolism occurred in 32 of 576 patients (5.6%) in the apixaban group and in 46 of 579 patients (7.9%) in the dalteparin group (hazard ratio, 0.63; 95% confidence interval [CI], 0.37 to 1.07; P

Introduction The impact of omega-3 fatty acids (O3FA) supplementation on cardiovascular risk is still in debate, largely due to the heterogeneity of population enrolled and variable dose and composition of the formulations used in the previous studies. Yet, O3FA may favorably impact on cardiovascular risk by reducing major cardiovascular events (including cardiac death and ischemic events). Evidence acquisition We aim to perform a comprehensive review of the topic of O3FA for cardiovascular prevention, stemming from a systematic review, to pairwise meta-analysis and network meta-analysis, limiting our inclusion only to randomized clinical trials comparing low dose (LD) ( 1 g per day) O3FA versus placebo. The efficacy outcomes of interest are total death, cardiac death, sudden cardiac death, myocardial infarction, stroke, coronary revascularization, unstable angina and major vascular events. Safety outcomes of interest are bleeding, gastrointestinal disturbances and atrial fibrillation events. Evidence synthesis This meta-analysis is expected to include several important studies on cardiovascular primary and secondary prevention and detail on important cardiovascular outcomes. Furthermore, we intend to highlight safety outcomes related to O3FA supplementation. Conclusions The present network meta-analysis results will aid physicians in the decision to prescribe O3FA in patients with or at risk of cardiovascular events. In particular, it will be able to solve controversies emerged from previous randomized clinical trials and meta-analyses regarding the benefit of different doses of O3FA supplementation in the cardiovascular prevention.

In the last years, proteomics has represented a valuable approach to elucidate key aspects in the regulation of type I/III interferons (IFNs) and autophagy, two main processes involved in the response to viral infection, to unveil the molecular strategies that viruses have evolved to counteract these processes. Besides their main metabolic roles, mitochondria are well recognized as pivotal organelles in controlling signaling pathways essential to restrain viral infections. In particular, a major role in antiviral defense is played by mitochondrial antiviral signaling (MAVS) protein, an adaptor protein that coordinates the activation of IFN inducing pathways and autophagy at the mitochondrial level. Here, we provide an overview of how mass spectrometry-based studies of protein-protein interactions and post-translational modifications (PTMs) have fostered our understanding of the molecular mechanisms that control the mitochondria-mediated antiviral immunity.

Peer review is the process of subjecting an author’s scholarly work, research or ideas to the scrutiny of others who are experts in the same field. The peer review of scientific manuscripts is a cornerstone of modern science and medicine. Some journals have difficulty in finding appropriate reviewers who are able to complete reviews on time avoiding publication delay. We discuss some of the main issues involved during the peer review process. The reviewer has a direct and important impact on the quality of a scientific medical Journal. Editors select reviewers on the basis of their expertise. Reviewers are more likely to accept to review a manuscript when it is relevant to their area of interest. They should respond to ethical principles, excluding any conflict of interest condition. The reviewer has to be professional, constructive, tactful, empathetic and respectful. Structured approaches, quality indicators and step-by-step process check list formats could be useful in obtaining a good review.

Background Muscle injuries are common in professional sports, especially in football. Recent epidemiological studies showed that muscle injuries account for more than 30% of professional football injuries (1.8-2.2/1000 h exposure); however, even though there are significant differences within a European comparison, a single professional football team diagnosed on average 12 muscle injuries per season, corresponding to more than 300 availability days lost. Objective The aim of this work is to present the diagnosis, general treatment and comprehensive management of muscle injuries in professional football. Material and methods The present work is based on current scientific findings, experiences of the authors and examples from routine practice in the management of muscle injuries in a professional sports environment. Results and conclusion The authors present a model of gradual progression for the treatment of muscular injuries and their rehabilitation. Due to the time-pressured nature of the professional sports environment, often promoted by coaches and media, this model could help lead players to recover as quickly as possible and return to competitive sports without relapse or sequel injury. This model integrates the player into the treatment plan. The progression sequences in the rehabilitation should be made clear to players and other parties involved, which are crucial for optimal healing. Even if absolute certainty cannot be achieved, i.e. the occurrence of re-injury or secondary injury, this model attempts to minimize the level of risk involved for the returning athlete. Since it is hardly possible to act strictly in line with more conservative guidelines due to the particular circumstances of the professional sport environment, the experiences of the authors are presented in the sense of best practice in order to support future decision-making processes.

// Gustavo J. S. Pereira 1 , Manuela Antonioli 2, 3 , Hanako Hirata 1 , Rodrigo P. Ureshino 1 , Aline R. Nascimento 1 , Claudia Bincoletto 1 , Tiziana Vescovo 3 , Mauro Piacentini 2, 3 , Gian Maria Fimia 3, 4 , Soraya S. Smaili 1 1 Department of Pharmacology, Federal University of Sao Paulo, (UNIFESP), Sao Paulo, Brazil 2 Department of Biology, University of Rome “Tor Vergata”, Rome, Italy 3 Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS 'Lazzaro Spallanzani', Rome, Italy 4 Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy Correspondence to: Soraya S. Smaili, email: ssmaili@unifesp.br Gian Maria Fimia, email: gianmaria.fimia@inmi.it Keywords: autophagy, glutamate, NAADP, two-pore channels, AMPK Received: August 20, 2016 Accepted: December 27, 2016 Published: December 31, 2016 ABSTRACT NAADP (nicotinic acid adenine dinucleotide phosphate) has been proposed as a second messenger for glutamate in neuronal and glial cells via the activation of the lysosomal Ca 2+ channels TPC1 and TPC2. However, the activities of glutamate that are mediated by NAADP remain unclear. In this study, we evaluated the effect of glutamate on autophagy in astrocytes at physiological, non-toxic concentration. We found that glutamate induces autophagy at similar extent as NAADP. By contrast, the NAADP antagonist NED-19 or SiRNA-mediated inhibition of TPC1/2 decreases autophagy induced by glutamate, confirming a role for NAADP in this pathway. The involvement of TPC1/2 in glutamate-induced autophagy was also confirmed in SHSY5Y neuroblastoma cells. Finally, we show that glutamate leads to a NAADP-dependent activation of AMPK, which is required for autophagy induction, while mTOR activity is not affected by this treatment. Taken together, our results indicate that glutamate stimulates autophagy via NAADP/TPC/AMPK axis, providing new insights of how Ca 2+ signalling glutamate-mediated can control the cell metabolism in the central nervous system.

Background: Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Its pathophysiology is complex and not completely understood. In this study, we examined the role of apoptosis and the caspase pathways involved. Material and Methods: We enrolled 40 acute heart failure (AHF) patients, 11 of whom developed AKI characterizing CRS type 1. We exposed the human cell line U937 to plasma from the CRS type 1 and AHF groups and then we evaluated apoptotic activity by annexin-V evaluation, determination of caspase-3, -8 and -9 levels, and BAX, BAD, and FAS gene expression. Results: We observed significant upregulation of apoptosis in monocytes exposed to CRS type 1 plasma compared to AHF, with increased levels of caspase-3 (p < 0.01), caspase-9 (p < 0.01), and caspase-8 (p < 0.03) showing activation of both intrinsic and extrinsic pathways. Furthermore, monocytes exposed to CRS type 1 plasma had increased gene expression of BAX and BAD (intrinsic pathways) (p = 0.010 for both). Furthermore, strong significant correlations between the caspase-9 levels and BAD and BAX gene expression were observed (Spearman ρ = – 0.76, p = 0.011, and ρ = – 0.72, p = 0.011). Conclusion: CRS type 1 induces dual apoptotic pathway activation in monocytes; the two pathways converged on caspase-3. Many factors may induce activation of both intrinsic and extrinsic apoptotic pathways in CRS type 1 patients, such as upregulation of proinflammatory cytokines and hypoxia/ischemia. Further investigations are necessary to corroborate the present findings, and to better understand the pathophysiological mechanism and consequent therapeutic and prognostic implications for CRS type 1.

We investigated the effects of human amniotic fluid stem cells (hAFS) and rat adipose tissue stromal vascular fraction GFP-positive cells (rSVC-GFP) in a model of cardio-renal syndrome type II (CRSII).RHF was induced by monocrotaline (MCT) in 28 Sprague-Dawley rats. Three weeks later, four million hAFS or rSVC-GFP cells were injected via tail vein. BNP, sCreatinine, kidney and heart NGAL and MMP9, sCytokines, kidney and heart apoptosis and cells (Cs) engraftment were evaluated. Cell-treated rats showed a significant reduction of serum NGAL and Creatinine compared to CRSII. In both hAFS and rSVC-GFP group, kidney protein expression of NGAL was significantly lower than in CRSII (hAFS p = 0.036 and rSVC-GFP p 0.0001) and similar to that of controls. In both hAFS and rSVC-GFP treated rats, we observed cell engraftment in the medulla and differentiation into tubular, endothelial and SMCs cells. Apoptosis was significantly decreased in cell-treated rats (hAFS 14.07 ± 1.38 and rSVC-GFP 12.67 ± 2.96 cells/mmCell therapy produced improvement in kidney function in rats with CRSII. This was the result of interstitial, vessel and tubular cell engraftment leading to tubular and vessel regeneration, decreased tubular cells apoptosis and mitigated pro-inflammatory milieu. Reduction of NGLA-MMP9 complexes mainly due to decrease MMPs activity prevented further negative heart remodeling.

Purpose we investigated the effects of human amniotic fluid stem cells (hAFS) and rat adipose tissue stromal vascular fraction GFP-positive cells (rSVC-GFP) in a model of cardio-renal syndrome type II (CRSII). Methods RHF was induced by monocrotaline (MCT) in 28 Sprague-Dawley rats. Three weeks later, four million hAFS or rSVC-GFP cells were injected via tail vein. BNP, sCreatinine, kidney and heart NGAL and MMP9, sCytokines, kidney and heart apoptosis and cells (Cs) engraftment were evaluated. Results Cell-treated rats showed a significant reduction of serum NGAL and Creatinine compared to CRSII. In both hAFS and rSVC-GFP group, kidney protein expression of NGAL was significantly lower than in CRSII (hAFS p=0.036 and rSVC-GFP p Conclusion Cell therapy produced improvement in kidney function in rats with CRSII. This was the result of interstitial, vessel and tubular cell engraftment leading to tubular and vessel regeneration, decreased tubular cells apoptosis and mitigated pro-inflammatory milieu. Reduction of NGLA-MMP9 complexes mainly due to decrease MMPs activity prevented further negative heart remodelling.

Aims Although loop diuretics are the most commonly used drugs in acute heart failure (AHF) treatment, their short-term and long-term effects are relatively unknown. The significance of worsening renal function occurrence during intravenous treatment is not clear enough. This trial aims to clarify all these features and contemplate whether continuous infusion is better than an intermittent strategy in terms of decongestion efficacy, diuretic efficiency, renal function, and long-term prognosis. Methods and results This is a prospective, multicentre, randomized study that compares continuous infusion to intermittent infusion and a low vs. high diuretic dose of furosemide in patients with a diagnosis of acute heart failure, BNP ≥ 100 pg/mL, and specific chest X-ray signs. Randomization criteria have been established at a 1:1 ratio using a computer-generated scheme of either twice-daily bolus injection or continuous infusion for a time period ranging from 72 to 120 h. The initial dose will be 80 mg/day of intravenous furosemide and, in the case of poor response, will be doubled using an escalation algorithm. A high diuretic dose is defined as a furosemide daily amount >120 mg/day respectively. Conclusions Continuous and high dose groups could reveal a more intensive diuresis and a greater decongestion with respect to intermittent and low dose groups; high dose and poor loop diuretic efficiency should be related to increased diuretic resistance, renal dysfunction occurrence, and greater congestion status. Poor diuretic response will be associated with less decongestion and an adverse prognosis.

Introduction and aim Muscle injuries are frequent in the world of sport, especially in football. The most recent epidemiological studies show that muscle injuries represent more than 30% of all injuries (1.8–2.2/1000 h of exposure), which means that a professional football team suffers an average of 12 muscle injuries per season, equivalent to more than 300 lost sporting days. The objective of this article is to provide a working document that is clear, practical and comprehensive about diagnosis, general treatment and overall management of muscle injuries.

In a single-center study, 66 healthy volunteers aged between 18 and 50years were randomized to be immunized against rabies with three different injection routes: intradermal with DebioJect™ (IDJ), standard intradermal with classical needle (IDS), also called Mantoux method, and intramuscular with classical needle (IM). "Vaccin rabique Pasteur®" and saline solution (NaCl 0.9%) were administered at D0, D7 and D28. Antigen doses for both intradermal routes were 1/5 of the dose for IM. Tolerability, safety and induced immunogenicity of IDJ were compared to IDS and IM routes. Pain was evaluated at needle insertion and at product injection for all vaccination visits. Solicited Adverse Event (SolAE) and local reactogenicity symptoms including pain, redness and pruritus were recorded daily following each vaccination visit. Adverse events (AE) were recorded over the whole duration of the study. Humoral immune response was measured by assessing the rabies virus neutralizing antibody (VNA) titers using Rapid Fluorescent Focus Inhibition Test (RFFIT). Results demonstrated that the DebioJect™ is a safe, reliable and efficient device. Significant decreases of pain at needle insertion and at vaccine injection were reported with IDJ compared to IDS and IM. All local reactogenicity symptoms (pain, redness and pruritus) after injection with either vaccine or saline solution, were similar for IDJ and IDS, except that IDJ injection induced more redness 30min after saline solution. No systemic SolAE was deemed related to DebioJect™ and classical needles. No AE was deemed related to DebioJect™. No Serious Adverse Event (SAE) was reported during the study. At the end of the study all participants were considered immunized against rabies and no significant difference in humoral response was observed between the 3 studied routes.