Combined PIVKA II and Vimentin-Guided EMT Tracking in Pancreatic Adenocarcinoma Combined Biomarker-Guided EMT Tracking in PDAC.

"Background/Aim": the current inability to diagnose Pancreatic Cancer Adenocarcinoma (PDAC) at an early stage strongly influences therapeutic strategies. Protein Induced by Vitamin K Absence (PIVKA II) showed an accurate diagnostic performance for PDAC. Since circulating PIVKA II has been recently associated with pancreatic origin cells with Vimentin, an epithelial-to-mesenchymal transition (EMT) early activation marker, the aim of this study was to investigate in vivo the combination between the two proteins. "Materials and Methods": we assayed the presence of PIVKA II and Vimentin proteins by using different diagnostic methods. A total of 20 PDAC patients and 10 healthy donors were tested by Western Blot analysis; 74 PDAC patient and 46 healthy donors were assayed by ECLIA and Elisa. "Results": Western Blot analysis showed the concomitant expression of PIVKA II and Vimentin in PDAC patient sera. Immunometric assay performed on a larger cohort of patients demonstrated that 72% of PIVKA II-positive PDAC patients were Vimentin-positive. Additionally, in a group of PDAC patients with PIVKA II levels ≥2070 ng/mL, the percentage of Vimentin-positive subjects reached 84%. "Conclusion": the association between PIVKA II protein and the EMT suggests that this molecule could be considered a marker of the acquisition of an aggressive phenotype.

[Single-center retrospective observational study on predictors of residual mitral regurgitation 1 year after MitraClip® implantation]. / Studio osservazionale retrospettivo monocentrico sui predittori di insufficienza mitralica residua a 1 anno dall'impianto di MitraClip®.

BACKGROUND: The extent of residual mitral regurgitation (MR) (1+ vs ≥2+) has a notable impact on the outcome of MitraClip (MC) repair of significant functional MR. In this retrospective single-center study, we evaluated the predictors of MI ≥2+ at 1 year in one of our case series. METHODS: Overall, 58 patients with moderate severe functional MR underwent MC implantation; of these, 48 patients had instrumental clinical follow-up for 1 year. RESULTS: At 1 year, 10 patients died (mortality 17.2%). In the remaining 48 patients, the incidence of rehospitalization was 8.3%, and the incidence of MR grade 1+ and ≥2+ was 54.1% (n = 26) and 45.9% (n = 22), respectively. In patients with MR ≥2+, clinical and instrumental outcomes were worse than in patients with MR 1+. The height of the posterior leaflet and the extent of immediate postprocedural MR were independent predictors of MR ≥2+. CONCLUSIONS: Percutaneous repair with MC of moderate/severe functional MR has favorable 1-year outcomes in terms of mortality and rehospitalizations. The best results are achieved in patients with residual MR 1+. Echocardiographic parameters are independent predictors of residual MR ≥2+.

Analysis of age-dependent gene-expression in human tissues for studying diabetes comorbidities.

The study of the relationship between type 2 diabetes mellitus (T2DM) disease and other pathologies (comorbidities), together with patient age variation, poses a challenge for medical research. There is evidence that patients affected by T2DM are more likely to develop comorbidities as they grow older. Variation of gene expression can be correlated to changes in T2DM comorbidities insurgence and progression. Understanding gene expression changes requires the analysis of large heterogeneous data at different scales as well as the integration of different data sources into network medicine models. Hence, we designed a framework to shed light on uncertainties related to age effects and comorbidity by integrating existing data sources with novel algorithms. The framework is based on integrating and analysing existing data sources under the hypothesis that changes in the basal expression of genes may be responsible for the higher prevalence of comorbidities in older patients. Using the proposed framework, we selected genes related to comorbidities from existing databases, and then analysed their expression with age at the tissues level. We found a set of genes that changes significantly in certain specific tissues over time. We also reconstructed the associated protein interaction networks and the related pathways for each tissue. Using this mechanistic framework, we detected interesting pathways related to T2DM whose genes change their expression with age. We also found many pathways related to insulin regulation and brain activities, which can be used to develop specific therapies. To the best of our knowledge, this is the first study that analyses such genes at the tissue level together with age variations.

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients.

Neutral lipid storage disease type M (NLSD-M) is an ultra-rare, autosomal recessive disorder that causes severe skeletal and cardiac muscle damage and lipid accumulation in all body tissues. In this hereditary pathology, the defective action of the adipose triglyceride lipase (ATGL) enzyme induces the enlargement of cytoplasmic lipid droplets and reduction in the detachment of mono- (MG) and diglycerides (DG). Although the pathogenesis of muscle fiber necrosis is unknown, some studies have shown alterations in cellular energy production, probably because MG and DG, the substrates of Krebs cycle, are less available. No tests have been tried with medium-chain fatty acid molecules to evaluate the anaplerotic effect in NLSD cells. In this study, we evaluated the in vitro effect of triheptanoin (Dojolvi®), a highly purified chemical triglyceride with seven carbon atoms, in fibroblasts obtained from five NLSD-M patients. Glycolytic and mitochondrial functions were determined by Seahorse XF Agylent Technology, and cellular viability and triglyceride content were measured through colorimetric assays. After the addition of triheptanoin, we observed an increase in glycolysis and mitochondrial respiration in all patients compared with healthy controls. These preliminary results show that triheptanoin is able to induce an anaplerotic effect in NLSD-M fibroblasts, paving the way towards new therapeutic strategies.

The Prognostic Role of ST2L and sST2 in Patients Who Underwent Carotid Plaque Endarterectomy: A Five-Year Follow-Up Study.

Soluble suppressor of tumorigenicity (sST)-2 plasma concentration is related to atherosclerosis. The aim of this study was to assess the prognostic impact of sST2 and its membrane-associated form (ST2L) in patients with carotid atherosclerotic plaque who underwent endarterectomy (CEA). Eighty-two consecutive patients (age range: 48−86 years) who underwent CEA were enrolled. Anthropometric, clinical, instrumental, and laboratory evaluations were gathered. Thirty-seven (45%) patients were symptomatic of cerebrovascular diseases. Patients underwent a five-year follow-up. Phone calls and the analysis of national and regional databases were performed in order to evaluate the occurrence of the primary outcome (all-cause mortality). The population was divided according to survival status. Statins were administered in 81% and 87.5% of survivors and non-survivors, respectively. sST2 levels were higher in non-survivors than in survivors (117.0 ± 103.9 vs. 38.0 ± 30.0 ng/mL, p < 0.001) and in symptomatic individuals, compared with asymptomatic (80.3 ± 92.1 ng/mL vs. 45.4 ± 41.4 ng/mL, p = 0.02). ROC curve analysis identified sST2 cut-off: >98.44 ng/mL as the best predictor for mortality. At the one-year follow-up, the survival rate decreased up to 20% in patients with sST2 higher than the cut-off value. A multivariate regression analysis revealed that only sST2 (HR: 1.012, 95% CI: 1.008−1.016, p < 0.0001) and triglycerides plasma levels (HR: 1.008, 95% CI: 1.002−1.015, p = 0.0135) remained significantly associated with all-cause mortality. ST2L was not associated with all-cause mortality risk. sST2 may act as an independent prognostic determinant of all-cause mortality and symptomatic cerebrovascular diseases in patients with carotid atherosclerotic plaque who underwent CEA.

Vitamin D and cardiovascular disease risk. A literature overview.

BACKGROUND: Atherosclerosis and cerebro and cardiovascular disease associated represent the major cause of morbidity and mortality worldwide. Recently, vitamin D deficiency has been considered a new potential risk factor of these conditions. METHODS AND RESULTS: In this reviw we briefly describe the biological role of vitamin D, analyze the pathophysiological associations between cardiovascular disease and vitamin D, summarize and synthesize the evidence from literature about the association between vitamin D and cardiovascular disease. RESULTS: Vit D is an essential vitamin for bone metabolism and homeostasis. The maintenance of optimal blood levels contributes to the correct homeostasis by influencing different metabolic processes, including those underlying cardiovascular diseases. However, the evidence does not support vitamin D routine administration for the prevention and treatment of cardiovascular disease and intake to achieve specific cardiovascular effects. Evidence shows that maintaining optimal levels of vitamin D, ensures cardiovascular protection.

Vascular and Myocardial Function in Young People with Type 1 Diabetes Mellitus: Insulin Pump Therapy Versus Multiple Daily Injections Insulin Regimen.

INTRODUCTION: Multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII) are two modalities of treating type 1 diabetes mellitus (T1DM). The benefits of CSII on long-term metabolic control and outcomes compared to those of MDI are still debated. We investigated both vascular function and myocardial performance in T1DM adolescents on MDI or CSII treatment. METHODS: One hundred twenty-three T1DM subjects (mean age 14.16±2.55 years), 63 on MDI regimen, 60 on CSII, and 57 controls were enrolled. Anthropometric and biochemical characteristics were evaluated. Ultrasound assessments of carotid intima-media thickness (cIMT), flow-mediated dilatation of brachial artery, anteroposterior diameter of the infrarenal abdominal aorta (APAO), and transthoracic echocardiography were performed. RESULTS: T1DM subjects on the CSII regimen showed better glycemic control than those on MDI, expressed as glycated haemoglobin (HbA1c). c-IMT and APAO were higher in MDI than CSII patients (0.61±0.11 mm vs. 0.56±0.07 mm, p=0.04; 13.61±3.29 mm vs. 11.65±1.84 mm, p=0.01, respectively). Left and right Tei index and left E/e' ratio were higher in MDI than CSII subjects (0.82±0.40 vs. 0.52±0.19, p=0.002; 0.86±0.41 vs. 0.64±0.1, p=0.02; 5.89±2.0 vs. 4.73±1.59, p=0.02, respectively). Multiple regression analyses showed that glucose level, HbA1c and diabetes onset were significantly related to vascular and echocardiographic parameters in MDI and CSII patients. CONCLUSIONS: CSII regimen in T1DM adolescents improves glycemic control and seems to ameliorate endothelial function and global myocardial performance as compared to MDI therapy.

Anodal Transcranial Direct Current Stimulation over the Cerebellum Enhances Sadness Recognition in Parkinson's Disease Patients: a Pilot Study.

Emotional processing impairments, resulting in a difficulty to decode emotions from faces especially for negative emotions, are characteristic non-motor features of Parkinson's disease (PD). There is limited evidence about the specific contribution of the cerebellum to the recognition of emotional contents in facial expressions even though patients with cerebellar dysfunction often lose this ability. In this study, we aimed to evaluate whether the recognition of facial expressions can be modulated by cerebellar transcranial direct current stimulation (tDCS) in PD patients. Nine PD patients were enrolled and received anodal and sham tDCS (2 mA, 20 min), for 5 consecutive days, in two separate cycles at intervals of at least 1 month. The facial emotion recognition task was administered at baseline (T0) and after cerebellar tDCS on day 5 (T1). Our preliminary study showed that anodal cerebellar tDCS significantly enhanced emotional recognition in response to sad facial expressions by about 16%, but left recognition of anger, happiness, and neutral facial expressions unchanged. Despite the small sample size, our preliminary results show that anodal tDCS applied for five consecutive days over the cerebellum modulates the way PD patients recognize specific facial expressions, thus suggesting that the cerebellum plays a crucial role in recognition of negative emotions and corroborating previous knowledge on the link between social cognition and the cerebellum.

Continuous flow left ventricular assist devices do not worsen endothelial function in subjects with chronic heart failure: a pilot study.

AIMS: To evaluate endothelial function in subjects with left ventricular assist devices (LVADs), comparing them with subjects with chronic heart failure with reduced ejection fraction on the list for heart transplant (HT) and with HT patients with a normal systolic cardiac function to identify any differences. METHODS: We enrolled 28 subjects with LVAD, 55 subjects with HT, and 42 subjects with heart failure on the transplant list. The subjects underwent a general physical examination, assessment of laboratory blood parameters, and assessment of endothelial function through flow-mediated dilation (FMD) of brachial artery. RESULTS: The three groups were homogeneous as regards age, gender, smoke abuse, C-reactive protein (CRP) and FMD parameters (P = ns). In LVAD group percentage of FMD change showed an inverse correlation with CRP (rho: -0.5, P: 0.003), a well-known marker of inflammation and tissue damage. CONCLUSIONS: Continuous flow related to LVAD seems to not worsen endothelial function. Endothelial function was not affected by cardiovascular risk factors (hypertension, hypercholesterolaemia, diabetes, obesity, and tobacco habit), by the functional status expressed by New York Heart Association class, by the left ventricular systolic function and by the presence or absence of ischaemic heart disease in all the populations analysed. CRP was the only factor able to influence percentage of FMD change in patient with LVAD, reinforcing the hypothesis that inflammation is the main determinant of endothelial function.

Current Clinical Psychopharmacology in Borderline Personality Disorder.

BACKGROUND: Patients with Borderline Personality Disorder (BPD) manifest affective and behavioral symptoms causing personal distress, relationship difficulties, and reduced quality of life with global functioning impairment, mainly when the disease takes an unfavorable course. A substantial amount of healthcare costs is dedicated to addressing these issues. Many BPD patients receive medications, mostly those who do not respond to psychological interventions. OBJECTIVE: Our aim was to assess the efficacy of the most used strategies of pharmacological interventions in BPD with a comprehensive overview of the field. METHODS: We searched the PubMed database for papers focused on the most used psychotropic drugs for BPD. We included randomized controlled trials and open studies in adult patients with BPD, focusing on the efficacy and tolerability of single classes of drugs with respect to specific clinical presentations that may occur during the course of BPD. RESULTS: Specific second-generation antipsychotics (SGAs) or serotonergic antidepressants can be effective for different core symptoms of BPD, mainly including mood symptoms, anxiety, and impulse dyscontrol. Some atypical antipsychotics can also be effective for psychotic and dissociative symptoms. Specific antiepileptics can be useful in some cases in treating different BPD symptoms, mainly including mood instability, impulsiveness, and anger. CONCLUSION: No medication is currently approved for BPD, and clinicians should carefully assess the benefits and risks of drug treatment. Further studies are needed to identify specific personalized treatment strategies, also considering the clinical heterogeneity and possible comorbidities of BPD.

The Impairment in Kidney Function in the Oral Anticoagulation Era. A Pathophysiological Insight.

The need for anticoagulation in patients with atrial fibrillation (AF) is fundamental to prevent thromboembolic events. Direct oral anticoagulants (DOACs) recently demonstrated to be superior, or at least equal, to Warfarin in reducing the risk for stroke/systemic embolism and preventing major bleeding and intracranial hemorrhages. The AF population often suffers from chronic kidney disease (CKD). Indeed, the relationship between AF and renal function is bidirectional: AF can trigger kidney failure, while kidney impairment can promote alterations able to enhance AF. Therefore, there are concerns regarding prescriptions of anticoagulants to patients with AF and CKD. The worsening in kidney function can be effectively due to anticoagulants administration. Warfarin has been recognized to promote acute kidney injury in case of excessive anticoagulation levels. Nevertheless, further mechanisms can induce the chronic worsening of renal function, thus leading to terminal kidney failure as observed in post-hoc analysis from registration trials and dedicated observational studies. By contrast, DOACs seem to protect kidneys from injuries more efficiently than Warfarin, although they still continue to play a role in promoting some kidney lesions. However, the exact mechanisms remain unknown. This narrative review aimed to discuss the influence of oral anticoagulants on renal impairment as well as to overview potential pathophysiological mechanisms related to this clinical complication.