ACTION-FRANCE: Insights into Perceptions, Attitudes, and Barriers to Obesity Management in France.

Background/Objectives: ACTION-FRANCE (Awareness, Care, and Treatment In Obesity maNagement in France) aims to identify the perceptions, attitudes, behaviors, and potential barriers to effective obesity management in France and guide collaborative actions. Methods: ACTION-FRANCE is a cross-sectional survey of people with obesity (PwO) and healthcare professionals (HCPs) in France. The PwO and HCP survey questionnaire periods ran from 27 September 2022 to 1 February 2023 and from 19 December 2022 to 31 March 2023, respectively. Results: The study, encompassing 1226 PwO and 166 HCPs, reveals a shared recognition of obesity as a chronic condition. However, despite being requested by most PwO, weight-related discussions are surprisingly infrequent, leading to delayed diagnosis and care. PwO and HCPs held different views as to why: HCPs often attributed it to PwO's lack of motivation or disinterest, whereas PwO avoided them because they felt weight management was their own responsibility and were uncomfortable discussing it. When weight was discussed, primarily with general practitioners (GPs), discussions mostly focused on physical activity and diet. However, results identified the strong psychosocial impact of obesity: 42% of respondents reported anxiety/depressive symptoms, and many more hesitated to engage in certain social activities because of their weight. Psychotherapy was only discussed by 55% of HCPs. Pharmaceutical options were also rarely discussed (19.5% of HCPs), though 56.1% of PwO reported they would want to. Conclusions: HCPs' and PwO's perceptions differed significantly and need to converge through enhanced communication. A holistic approach, integrating comprehensive training for GPs and recognizing psychological comorbidities, would help to bridge perceptual gaps effectively and foster more empathetic and effective patient care.

Microvesicle-associated and circulating microRNAs in diabetic dyslipidemia: miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 have biomarker potential.

BACKGROUND: Circulating MicroRNAs (miRNAs) carried by microvesicles (MVs) have various physiological and pathological functions by post-transcriptional regulation of gene expression being considered markers for many diseases including diabetes and dyslipidemia. We aimed to identify new common miRNAs both in MVs and plasma that could be predictive biomarkers for diabetic dyslipidemia evolution. METHODS: For this purpose, plasma from 63 participants in the study (17 type 2 diabetic patients, 17 patients with type 2 diabetes and dyslipidemia, 14 patients with dyslipidemia alone and 15 clinically healthy persons without diabetes or dyslipidemia) was used for the analysis of circulating cytokines, MVs, miRNAs and MV-associated miRNAs. RESULTS: The results uncovered three miRNAs, miR-218, miR-132 and miR-143, whose expression was found to be significantly up-regulated in both circulating MVs and plasma from diabetic patients with dyslipidemia. These miRNAs showed significant correlations with important plasma markers, representative of this pathology. Thus, MV/plasma miR-218 was negatively correlated with the levels of erythrocyte MVs, plasma miR-132 was positively connected with MV miR-132 and negatively with uric acid and erythrocyte plasma levels, and plasma miR-143 was negatively related with creatinine levels and diastolic blood pressure. Also, three miRNAs common to MV and plasma, namely miR-21, miR-122, and miR-155, were identified to be down-regulated and up-regulated, respectively, in diabetic dyslipidemia. In addition, MV miR-21 was positively linked with cholesterol plasma levels and plasma miR-21 with TNFα plasma levels, MV miR-122 was negatively correlated with LDL-c levels and plasma miR-122 with creatinine and diastolic blood pressure and positively with MV miR-126 levels, MV miR-155 was positively associated with cholesterol and total MV levels and negatively with HDL-c levels, whereas plasma miR-155 was positively correlated with Il-1ß plasma levels and total MV levels and negatively with MV miR-223 levels. CONCLUSIONS: In conclusion, miR-218, miR-132, miR-143, and miR-21, miR-122, miR-155 show potential as biomarkers for diabetic dyslipidemia, but there is a need for more in-depth studies. These findings bring new information regarding the molecular biomarkers specific to diabetic dyslipidemia and could have important implications for the treatment of patients affected by this pathology.

Stem cell-derived extracellular vesicles reduce the expression of molecules involved in cardiac hypertrophy-In a model of human-induced pluripotent stem cell-derived cardiomyocytes.

Cardiac pathological hypertrophy is the major risk factor that usually progresses to heart failure. We hypothesized that extracellular vesicles (EVs), known to act as important mediators in regulating physiological and pathological functions, could have the potential to reduce the cardiac hypertrophy and the ensuing cardiovascular diseases. Herein, the effects of mesenchymal stem cell-derived extracellular vesicles (EV-MSCs) on cardiac hypertrophy were investigated. EVs were isolated from the secretome of human adipose tissue-derived stem cells (EV-ADSCs) or bone marrow-derived stem cells (EV-BMMSCs). Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were stimulated with AngII and TGF-ß1, in absence or presence of EVs. The results showed that exposure of hiPSC-CMs to AngII and TGF-ß1 generated in vitro model of hypertrophic cardiomyocytes characterized by increases in surface area, reactive oxygen species production, protein expression of cardiac-specific biomarkers atrial natriuretic factor, migration inhibitory factor, cTnI, COL1A1, Cx43, α-SMA and signalling molecules SMAD2 and NF-kBp50. The presence of EV-ADSCs or EV-BMMSCs in the hiPSC-CM culture along with hypertrophic stimuli reduced the protein expressions of hypertrophic specific markers (ANF, MIF, cTnI, COL1A1) and the gene expressions of IL-6 molecule involved in inflammatory process associated with cardiac hypertrophy and transcription factors SMAD2, SMAD3, cJUN, cFOS with role in cardiomyocyte hypertrophic response induced by AngII and TGF-ß1. The EV-ADSCs were more effective in reducing the protein expressions of hypertrophic and inflammatory markers, while EV-BMMSCs in reducing the gene expressions of transcription factors. Notably, neither EV-ADSCs nor EV-BMMSCs induced significant changes in cardiac biomarkers Cx43, α-SMA and fibronectin. These different effects of stem cell-derived EVs could be attributed to their miRNA content: some miRNAs (miR-126-3p, miR-222-3p, miR-30e-5p, miR-181b-5p, miR-124-3p, miR-155-5p, miR-210-3p hsa-miR-221-3p) were expressed in both types of EVs and others only in EV-ADSCs (miR-181a-5p, miR-185-5p, miR-21-5p) or in EV-BMMSCs (miR-143-3p, miR-146a-5p, miR-93-5p), some of these attenuating the cardiac hypertrophy while others enhance it. In conclusion, in hiPSC-CMs the stem cell-derived EVs through their cargo reduced the expression of hypertrophic specific markers and molecules involved in inflammatory process associated with cardiac hypertrophy. The data suggest the EV potential to act as therapeutic mediators to reduce cardiac hypertrophy and possibly the subsequent cardiovascular events.

Quantitative contrast-enhanced endoscopic ultrasound in pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumors: can we predict survival using perfusion parameters? A pilot study.

AIM: Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) parameters may be used to predict prognosis of pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumors (pNET). The aim of this study was to investigate the association between several perfusion parameters on CEH-EUS performed before treatment and survival outcome in patients with PDAC or pNET. MATERIAL AND METHODS: Thirty patients with PDAC or pNET who underwent CEH-EUS and EUS-guided fine needle aspiration (EUS-FNA) were included. Quantitative analysis of tumor vascularity was performed using time-intensity curve (TIC) analysis-derived parameters, obtained from processing CEH-EUS recordings with a commercially available software (VueBox). Cox proportional hazards models were used to determine associations with survival outcome. RESULTS: Median overall survival (OS) for PDAC patients was 9.61 months (95% CI: 0.1-38.7) while the median OS for pNET patients was 15.81 months (95% CI: 5.8-24.75. In a multivariate model for OS, a lower peak enhancement (HR=1.76, p=0.02) and a lower wash-in area under the curve (HR=1.06, p=0.001) were associated with worse survival outcome for patients with PDAC. CONCLUSIONS: CEH-EUS parameters may be used as a surrogate to predict PDAC aggressiveness and survival before treatment. After validation by large-scale studies, CEH-EUS perfusion parameters have the potential to be used in pretreatment risk stratification of patients with PDAC and in evidence-based clinical decision support.

Efficacy and Safety of Deep Sedation and Anaesthesia for Complex Endoscopic Procedures-A Narrative Review.

Propofol sedation for advanced endoscopic procedures is a widespread technique at present, which generates controversy worldwide when anaesthetic or non-anaesthetic personnel administer this form of sedation. There is some evidence for safe administered propofol sedation by non-anaesthetic personnel in patients undergoing endoscopy procedures, but there are only few randomised trials addressing the safety and efficacy of propofol in patients undergoing advanced procedures. A serious possible consequence of propofol sedation is the rapid and unpredictable progression from deep sedation to general anaesthesia mostly when elderly and frail patients are involved in the diagnosis or treatment of various neoplasia. This situation requires rescue measures with skilled airway management. The aim of this paper is to review the safety and efficacy aspects of sedation techniques, with special reference to propofol administration covering the whole patient journey, including preassessment, sedation options and discharge when advanced endoscopic procedures are performed.

Technical Performance, Overall Accuracy and Complications of EUS-Guided Interventional Procedures: A Dynamic Landscape.

Endoscopic ultrasound (EUS) gained wide acceptance as the diagnostic and minimally invasive therapeutic approach for intra-luminal and extraluminal gastrointestinal, as well as various non-gastrointestinal lesions. Since its introduction, EUS has undergone substantial technological advances. This multi-centric study is a retrospective analysis of a prospectively maintained database of patients who underwent EUS for the evaluation of lesions located within the gastrointestinal tract and the proximal organs. It aimed to extensively assess in dynamic the dual-center EUS experience over the course of the past 20 years. Hence, we performed a population study and an overall assessment of the EUS procedures. The performance of EUS-FNA/FNB in diagnosing pancreatic neoplasms was evaluated. We also investigated the contribution of associating contrast-enhanced ultrasound imaging (CE-EUS) with EUS-FNA/FNB for differentiating solid pancreatic lesions or cystic pancreatic lesions. A total of 2935 patients undergoing EUS between 2002-2021 were included, out of which 1880 were diagnostic EUS and 1052 EUS-FNA/FNB (80% FNA and 20% FNB). Therapeutic procedures performed included endoscopic transmural drainage of pancreatic fluid collections, celiac plexus block and neurolysis, while diagnostic EUS-like CE-EUS (20%) and real-time elastography (12%) were also conducted. Most complications occurred during the first 7 days after EUS-FNA/FNB or pseudocyst drainage. EUS and the additional tools have high technical success rates and low rates of complications. The EUS methods are safe, cost effective and indispensable for the diagnostic or therapeutic management in gastroenterological everyday practice.

VLA4-Enhanced Allogeneic Endothelial Progenitor Cell-Based Therapy Preserves the Aortic Valve Function in a Mouse Model of Dyslipidemia and Diabetes.

The number and function of endothelial progenitor cells (EPCs) are reduced in diabetes, contributing to deteriorated vascular repair and the occurrence of cardiovascular complications. Here, we present the results of treating early diabetic dyslipidemic mice or dyslipidemic with disease-matched EPCs modified to overexpress VLA4 (VLA4-EPCs) as compared with the treatment of EPCs transfected with GFP (GFP-EPCs) as well as EPCs from healthy animals. Organ imaging of injected PKH26-stained cells showed little pulmonary first-pass effects and distribution in highly vascularized organs, with splenic removal from circulation, mostly in non-diabetic animals. Plasma measurements showed pronounced dyslipidemia in all animals and glycaemia indicative of diabetes in streptozotocin-injected animals. Echocardiographic measurements performed 3 days after the treatment showed significantly improved aortic valve function in animals treated with VLA4-overexpressing EPCs compared with GFP-EPCs, and similar results in the groups treated with healthy EPCs and VLA4-EPCs. Immunohistochemical analyses revealed active inflammation and remodelling in all groups but different profiles, with higher MMP9 and lower P-selectin levels in GFP-EPCs, treated animals. In conclusion, our experiments show that genetically modified allogeneic EPCs might be a safe treatment option, with bioavailability in the desired target compartments and the ability to preserve aortic valve function in dyslipidemia and diabetes.

Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles on Atherosclerosis-Induced Vascular Dysfunction and Its Key Molecular Players.

Atherosclerosis is a progressive, chronic inflammatory disease of the large arteries caused by the constant accumulation of cholesterol, followed by endothelial dysfunction and vascular inflammation. We hypothesized that delivery of extracellular vesicles (EVs), recognized for their potential as therapeutic targets and tools, could restore vascular function in atherosclerosis. We explored by comparison the potential beneficial effects of EVs from subcutaneous adipose tissue stem cells (EVs (ADSCs)) or bone marrow mesenchymal stem cells (EVs (MSCs)) on the consequences of atherogenic diet on vascular health. Also, the influences of siRNA-targeting Smad2/3 (Smad2/3siRNA) on endothelial dysfunction and its key molecular players were analyzed. For this study, an animal model of atherosclerosis (HH) was transplanted with EVs (ADSCs) or EVs (MSCs) transfected or not with Smad2/3siRNA. For controls, healthy or HH animals were used. The results indicated that by comparison with the HH group, the treatment with EVs(ADSCs) or EVs(MSCs) alone or in combination with Smad2/3siRNA of HH animals induced a significant decrease in the main plasma parameters and a noticeable improvement in the structure and function of the thoracic aorta and carotid artery along with a decrease in the selected molecular and cellular targets mediating their changes in atherosclerosis: 1) a decrease in expression of structural and inflammatory markers COL1A1, α-SMA, Cx43, VCAM-1, and MMP-2; 2) a slight infiltration of total/M1 macrophages and T-cells; 3) a reduced level of cytosolic ROS production; 4) a significant diminution in plasma concentrations of TGF-ß1 and Ang II proteins; 5) significant structural and functional improvements (thinning of the arterial wall, increase of the inner diameter, enhanced distensibility, diminished VTI and Vel, and augmented contractile and relaxation responses); 6) a reduced protein expression profile of Smad2/3, ATF-2, and NF-kBp50/p65 and a significant decrease in the expression levels of miR-21, miR-29a, miR-192, miR-200b, miR-210, and miR-146a. We can conclude that 1) stem cell-derived EV therapies, especially the EVs (ADSCs) led to regression of structural and functional changes in the vascular wall and of key orchestrator expression in the atherosclerosis-induced endothelial dysfunction; 2) transfection of EVs with Smad2/3siRNA amplified the ability of EVs(ADSCs) or EVs(MSCs) to regress the inflammation-mediated atherosclerotic process.

Evaluation of MMR Status and PD-L1 Expression Using Specimens Obtained by EUS-FNB in Patients with Pancreatic Ductal Adenocarcinoma (PDAC).

Deficient DNA mismatch repair status (dMMR)/high microsatellite instability have been shown to be predictive biomarkers for immune checkpoint inhibitor drugs which block the programmed death protein-1/programmed death ligand-1 (PD-1/PD-L1) interaction between tumor cells and activated T cells. The aim of this study was to determine the prevalence of MMR status and quantification of PD-L1 expression in pancreatic endoscopic ultrasound-guided fine-needle biopsy (EUS FNB) specimens. Immunochemistry (IHC) was performed on consecutive archived treatment-naïve formalin-fixed paraffin-embedded EUS-FNB samples. The specimens were considered to have PD-L1 expression if PD-L1 was expressed in ≥1% of tumor cells and a high level of expression if ≥50%. Tumors with absent nuclear staining of DNA mismatch repair proteins (MLH1, MSH2, MSH6, or PMS2) were classified as dMMR. A total of 28 treatment-naïve patients who underwent EUS-FNB and had a final diagnosis of pancreatic ductal adenocarcinoma (PDAC) were included in the study. All the EUS-FNB samples were adequate for the evaluation of MMR and PD-L1 expression. None of the patients with PDAC included in the study had a dMMR tumor. PD-L1 expression was identified in 39% of the cohort (n = 11). Expression thresholds of ≥1%, ≥10%, and ≥50% in tumor cells were identified in 11 (39%), 4 (14%), and 1 (4%) patients, respectively. The evaluation of MMR status and PD-L1 can be successfully performed on EUS-FNB pancreatic specimens. Furthermore, MMR expression failed to show utility in recognizing immunotherapy vulnerability in pancreatic cancer; the only recommendation for testing remains for patients with heritable cancers. Meanwhile high PD-L1 expression was correlated with poor prognosis. This association may identify a subgroup of patients where immune checkpoints inhibitors could provide therapeutic benefits, spotlighting the role of EUS-FNB in the field of immune-oncology.

The Role of Thromboprophylaxis in Patients with Portal Vein Thrombosis: A Life-Threatening Complication after Laparoscopic Sleeve Gastrectomy Following 8 Years of Experience in a Bariatric Center of Excellence.

Porto-mesenteric vein thrombosis (PVMT) is a rare but life-threatening complication after laparoscopic sleeve gastrectomy (LSG). Laparoscopic sleeve gastrectomy (LSG) is considered the most common procedure for efficiently realizing weight loss and treating obesity-related co-morbidities. This study aimed to shed light on this relatively rare complication by presenting a series of patients who developed PMVT after LSG in light of the need to change the specific protocol of thromboprophylaxis in bariatric patients. We proposed to answer two questions: whether we should perform a thrombophilia workup as a standard practice and whether we should extend chemoprophylaxis to more than 3 weeks among all bariatric patients. This study also aimed to investigate the possible risk factors and eventually present our updated protocol for PMVT management and prophylaxis.

Real-time computer-aided diagnosis of focal pancreatic masses from endoscopic ultrasound imaging based on a hybrid convolutional and long short-term memory neural network model.

Differential diagnosis of focal pancreatic masses is based on endoscopic ultrasound (EUS) guided fine needle aspiration biopsy (EUS-FNA/FNB). Several imaging techniques (i.e. gray-scale, color Doppler, contrast-enhancement and elastography) are used for differential diagnosis. However, diagnosis remains highly operator dependent. To address this problem, machine learning algorithms (MLA) can generate an automatic computer-aided diagnosis (CAD) by analyzing a large number of clinical images in real-time. We aimed to develop a MLA to characterize focal pancreatic masses during the EUS procedure. The study included 65 patients with focal pancreatic masses, with 20 EUS images selected from each patient (grayscale, color Doppler, arterial and venous phase contrast-enhancement and elastography). Images were classified based on cytopathology exam as: chronic pseudotumoral pancreatitis (CPP), neuroendocrine tumor (PNET) and ductal adenocarcinoma (PDAC). The MLA is based on a deep learning method which combines convolutional (CNN) and long short-term memory (LSTM) neural networks. 2688 images were used for training and 672 images for testing the deep learning models. The CNN was developed to identify the discriminative features of images, while a LSTM neural network was used to extract the dependencies between images. The model predicted the clinical diagnosis with an area under curve index of 0.98 and an overall accuracy of 98.26%. The negative (NPV) and positive (PPV) predictive values and the corresponding 95% confidential intervals (CI) are 96.7%, [94.5, 98.9] and 98.1%, [96.81, 99.4] for PDAC, 96.5%, [94.1, 98.8], and 99.7%, [99.3, 100] for CPP, and 98.9%, [97.5, 100] and 98.3%, [97.1, 99.4] for PNET. Following further validation on a independent test cohort, this method could become an efficient CAD tool to differentiate focal pancreatic masses in real-time.

Proprioceptive recalibration following implicit visuomotor adaptation is preserved in Parkinson's disease.

Individuals with Parkinson's disease (PD) and healthy adults demonstrate similar levels of visuomotor adaptation provided that the distortion is small or introduced gradually, and hence, implicit processes are engaged. Recently, implicit processes underlying visuomotor adaptation in healthy individuals have been proposed to include proprioceptive recalibration (i.e., shifts in one's proprioceptive sense of felt hand position to match the visual estimate of their hand experienced during reaches with altered visual feedback of the hand). In the current study, we asked if proprioceptive recalibration is preserved in PD patients. PD patients tested during their "off" and "on" medication states and age-matched healthy controls reached to visual targets, while visual feedback of their unseen hand was gradually rotated 30° clockwise or translated 4 cm rightwards of their actual hand trajectory. As expected, PD patients and controls produced significant reach aftereffects, indicating visuomotor adaptation after reaching with the gradually introduced visuomotor distortions. More importantly, following visuomotor adaptation, both patients and controls showed recalibration in hand position estimates, and the magnitude of this recalibration was comparable between PD patients and controls. No differences for any measures assessed were observed across medication status (i.e., PD off vs PD on). Results reveal that patients are able to adjust their sensorimotor mappings and recalibrate proprioception following adaptation to a gradually introduced visuomotor distortion, and that dopaminergic intervention does not affect this proprioceptive recalibration. These results suggest that proprioceptive recalibration does not involve striatal dopaminergic pathways and may contribute to the preserved visuomotor adaptation that arises implicitly in PD patients.

Prognostic biomarkers related to tumoral microenvironment in pancreatic ductal adenocarcinoma: a systematic review.

Over the past decades, pancreatic ductal adenocarcinoma (PDAC) has been coming into view due to increased mortality, the 5-year survival rate being the lowest of all cancers (around 6%). In PDAC, microenvironmental components possess prognostic relevance. The aim of this article is to perform a review of studies evaluating the composition of the tumor microenvironment to identify tumor microenvironment-related prognostic biomarkers in patients with PDAC. A literature search has been performed in three major databases PubMed®, Embase®, Web of Science® using the search terms: pancreatic adenocarcinoma in combination with one of the following: alpha-smooth muscle actin (α-SMA), collagen I, cluster of differentiation (CD)31, CD105, CD3-CD4-CD8, CD68 and CD206. Total number of articles identified through database searching was 1185. After title and abstract review, we have selected 92 articles in which the markers sought were studied. Tumor microenvironment-related biomarkers appear to also possess role in monitoring the response to treatment. Thus, CD105 angiogenetic immunomarker, stromal immunomarkers such as α-SMA and collagen I, immune cells markers represented by CD4∕CD8 ratio, CD206 and CD68 were correlated with negative prognosis, while CD3+, CD8+ immune cells markers and CD31 angiogenetic immunomarker proved to be correlated with good prognosis. Furthermore, most studies were performed on resected specimens and culture cells, while only a few studies used specimens obtained through endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). To increase the therapeutic response and reduce toxicity, prognostic targets should be determined on a large scale, not only based on resected specimens. EUS-FNB represents a feasible method to provide sufficient tissue for diagnosis and additional immunohistochemistry analysis.

Hypertension induces compensatory left ventricular hypertrophy by a mechanism involving gap junction lateralization and overexpression of CD36, PKC and MMP-2.

Hypertension-induced left ventricular hypertrophy evolves initially as an adaptive response meant to minimize ventricular wall stress. The mechanisms involved in the preservation of the cardiac function during the "compensatory" phase of the left ventricular hypertrophy are still unclear. Therefore, we aimed at uncovering fine changes that aid the heart to cope with the increased stress in hypertension. Male golden Syrian hamsters were given NG-nitro-L-arginine methyl ester (L-NAME) for 16 weeks, and they became hypertensive (HT), developing left ventricular hypertrophy with no impaired contractility or fibrosis. As compared to age-matched control hamsters, the hypertrophied left ventricles in L-NAME-induced HT hamsters exhibited the following structural and molecular changes: (i) accumulation of lipid droplets (LDs) within cardiomyocytes and relocation of gap junctions to the lateral membrane of cardiomyocytes or close to mitochondria (revealed by electron microscopy); (ii) overexpression of the cluster of differentiation 36 (CD36) fatty acid transporter, protein kinase C (PKC), and matrix metalloproteinase-2 (MMP-2), enhanced activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway, and unchanged expression of the connexin 43 (Cx43) and N-cadherin junctional proteins (assessed by Western blot); (iii) increased protein carbonyl content, assessed with a 2,4-Dinitrophenylhydrazine (DNPH)-based spectrophotometric assay, indicative of an enhanced reactive oxygen species (ROS) production; and (iv) augmented MMP-2 activity (determined by gelatin zymography). These changes may participate in an orchestrated adaptive hypertrophic growth response that helps to maintain cardiac performance, in HT hamsters. Together, these findings could provide support for designing future strategies meant to prevent the transition from compensatory left ventricular hypertrophy to decompensated heart failure.

Extracellular Vesicles from Adipose Tissue Stem Cells in Diabetes and Associated Cardiovascular Disease; Pathobiological Impact and Therapeutic Potential.

Adipose tissue-derived stem cells (ADSCs) are pluripotent mesenchymal stem cells found in relatively high percentages in the adipose tissue and able to self-renew and differentiate into many different types of cells. "Extracellular vesicles (EVs), small membrane vesicular structures released during cell activation, senescence, or apoptosis, act as mediators for long distance communication between cells, transferring their specific bioactive molecules into host target cells". There is a general consensus on how to define and isolate ADSCs, however, multiple separation and characterization protocols are being used in the present which complicate the results' integration in a single theory on ADSCs' and their derived factors' way of action. Metabolic syndrome and type 2 diabetes mellitus (T2DM) are mainly caused by abnormal adipose tissue size, distribution and metabolism and so ADSCs and their secretory factors such as EVs are currently investigated as therapeutics in these diseases. Moreover, due to their relatively easy isolation and propagation in culture and their differentiation ability, ADSCs are being employed in preclinical studies of implantable devices or prosthetics. This review aims to provide a comprehensive summary of the current knowledge on EVs secreted from ADSCs both as diagnostic biomarkers and therapeutics in diabetes and associated cardiovascular disease, the molecular mechanisms involved, as well as on the use of ADSC differentiation potential in cardiovascular tissue repair and prostheses.

Short Term Outcomes of Using Fecal Immunochemical Test for a Pilot Colorectal Cancer Screening Program. A Single Center Study on 3024 Consecutive Patients.

Background: In Romania, colorectal cancer does not benefit yet from a national screening program. In order to decrease the harm and burden of colorectal cancer (CRC), opportunistic programs relying on endoscopy has been adopted by each centre according to its capacity. A colorectal cancer (CRC) screening programme based on faecal immunochemical test (FIT) was launched at Ponderas Academic Hospital (PAH) in 2019. Aim: The present study analyses the outcomes after the first 1500 tests in the PAH-FIT-CRC Screening Program. We have also aimed to compare the efficiency of the FIT testing program with the screening colonoscopies performed in our Center, withing the same time interval (2019). Methods: The test was recommended in asymptomatic patients over 45 years, and it was followed by a colonoscopy when the test results were positive. Furthermore, we performed a retrospective observational study gathering data from all the consecutive patients prospectively included in the respective databases of our hospital, comparing the efficacy of the two colorectal cancer screening methods (FIT versus colonoscopy). Results: Between 01.01.2019 and 01.01.2020, 1524 screening colonoscopies were performed, and the resulting data were compared with those obtained in the FIT group (1500 FIT tests freely distributed). In the screening colonoscopy group, the polyp detection rate was 38.98% and 22 (1.44%) adenocarcinomas were identified. In the FIT group, the FIT uptake rate was 71% with a positivity rate of 21.7%. The colonoscopy compliance rate for positive FIT patients was 29.4%, with only 2 adenocarcinomas detected. Conclusions: Following data analysis, the need for improvement of uptake rate and colonoscopy compliance rate was suggested, due to the lower acceptance of FIT tests and colonoscopies, especially among men. Moreover, special efforts should be made in order to improve quality indicators for screening colonoscopies (especially adenoma detection rate) with the purpose of decreasing interval CRC.

Evolution of Inflammatory and Oxidative Stress Markers in Romanian Obese Male Patients with Type 2 Diabetes Mellitus after Laparoscopic Sleeve Gastrectomy: One Year Follow-Up.

Geography is one of the key drivers of the significant variation in the etiopathogenic profile and prevalence of type 2 diabetes mellitus (T2DM) and obesity, therefore geographically based data are fundamental for implementing the appropriate interventions. Presently, the selection criteria of T2DM and obesity patients for laparoscopic sleeve gastrectomy (LSG) have not reached a worldwide consensus-highlighting the need for sharing experts' guidance in the preoperative evaluation, choice of the interventional procedure, perioperative management and patient long-term care. The aim of the current study was to evaluate the impact of LSG on T2DM (T2DM) remission in Romanian obese male patients, based on a multiparametric, prospective investigation. We have conducted a randomized controlled study on 41 obese male participants with the body mass index (BMI) ≥ 30 kg/m2, aged 30-65 years, which were randomly divided in two study groups: one receiving conventional treatment and the second undergoing LSG. The clinical and anthropometrical parameters, resting metabolic rate, general biochemical status, adipocytes profile, gastrointestinal hormones levels, proinflammatory, oxidant and antioxidant profiles were determined at three time points: V1 (baseline), V2 (after six months) and V3 (after 12 months). Glycated hemoglobin (HbA1c), blood glucose levels, BMI, weight, visceral fat level, HDL-cholesterol, incretin hormones, proinflammatory and the oxidative stress status were significantly improved in the LSG versus conventional treatment group. This is the first study reporting on the evaluation of metabolic surgery impact on Romanian obese male patients with T2DM. Our results confirm that LSG could contribute to T2DM remission in patients with diabesity, but this beneficial effect seems to be critically influenced by the duration of T2DM rather than by the obesity status. Our results show that, in addition to the parameters included in the prediction algorithm, the proinsulin levels, proinsulin/insulin ratio and the visceral fat percentage could bring added value to the assessment of metabolic status.

Integrins α4ß1 and αVß3 are Reduced in Endothelial Progenitor Cells from Diabetic Dyslipidemic Mice and May Represent New Targets for Therapy in Aortic Valve Disease.

Diabetes reduces the number and induces dysfunction in circulating endothelial progenitor cells (EPCs) by mechanisms that are still uncovered. This study aims to evaluate the number, viability, phenotype, and function of EPCs in dyslipidemic mice with early diabetes mellitus and EPC infiltration in the aortic valve in order to identify possible therapeutic targets in diabetes-associated cardiovascular disease. A streptozotocin-induced diabetic apolipoprotein E knock-out (ApoE-/-) mouse model was used to identify the early and progressive changes, at 4 or 7 days on atherogenic diet after the last streptozotocin or citrate buffer injection. Blood and aortic valves from diabetic or nondiabetic ApoE-/- animals were collected.EPCs were identified as CD34 and vascular endothelial growth factor receptor 2 positive monocytes, and the expression levels of α4ß1, αVß3, αVß5, ß1, αLß2, α5 integrins, and C-X-C chemokine receptor type 4 chemokine receptor on EPC surface were assessed by flow cytometry. The number of CD34 positive cells in the aortic valve, previously found to be recruited progenitor cells, was measured by fluorescence microscopy. Our results show that aortic valves from mice fed 7 days with atherogenic diet presented a significantly higher number of CD34 positive cells compared with mice fed only 4 days with the same diet, and diabetes reversed this finding. We also show a reduction of circulatory EPC numbers in diabetic mice caused by cell senescence and lower mobilization. Dyslipidemia induced EPC death through apoptosis regardless of the presence of diabetes, as shown by the higher percent of propidium iodide positive cells and higher cleaved caspase-3 levels. EPCs from diabetic mice expressed α4ß1 and αVß3 integrins at a lower level, while the rest of the integrins tested were unaffected by diabetes or diet. In conclusion, reduced EPC number and expression of α4ß1 and αVß3 integrins on EPCs at 4 and 7 days after diabetes induction in atherosclerosis-prone mice have resulted in lower recruitment of EPCs in the aortic valve.

Clinical impact of strain histogram EUS elastography and contrast-enhanced EUS for the differential diagnosis of focal pancreatic masses: A prospective multicentric study.

BACKGROUND: Recent advances in EUS techniques (real-time EUS elastography and contrast-enhanced EUS) have allowed a better characterization of focal pancreatic masses. Mean strain histograms (SHs) are considered a good parameter for the semi-quantitative evaluation of focal pancreatic masses, alongside complementary contrast-enhanced EUS parameters which can be quantified during both the early arterial and late venous phase. MATERIALS AND METHODS: The study design was prospective, blinded, and multicentric, assessing real-time EUS elastography and contrast-enhanced EUS results for the characterization of focal pancreatic masses using parametric measurements, in comparison with pathology which is the gold standard. SHs were performed based on the embedded software of the ultrasound system, with the values being reversed as opposed to our initially published data on hue histograms. Consequently, a cutoff of 80 was derived from previous multicentric trials. Contrast-enhanced EUS also allowed the focal masses to be classified as hyper-, iso-, or hypoenhanced in comparison with the normal pancreatic parenchyma. EUS-FNA was then performed for all patients, with a positive cytological diagnosis taken as a final proof of malignancy for the pancreatic masses. The diagnoses obtained by EUS-FNA were verified further either by surgery or during a clinical follow-up of at least 6 months. RESULTS: A total number of 97 consecutive patients with focal pancreatic masses were included in the study. Based on previously defined cutoffs of 80, the values of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the mean SHs for the diagnosis of pancreatic cancer were 100%, 29.63%, 78.65%, 100%, and 80.41%, respectively. Corresponding values for contrast-enhanced EUS (taking into consideration hypoenhencement as a predictive factor of malignancy) were 98.57%, 77.78%, 92%, 95.45%, and 92.78%, respectively. Combining contrast enhancement-EUS (hypoenhencement) and semi-quantitative EUS elastography (SH cutoffs <80), the resulting values corresponding for sensitivity, specificity, and accuracy were 98.57%, 81.48%, and 93.81%, respectively. CONCLUSION: The current study using objective parametric tools for both EUS elastography and contrast-enhanced EUS confirmed the results of previous studies and meta-analyses that indicated a complementary role for the differential diagnosis of focal pancreatic masses. Moreover, the best values for the receiver operating curves were obtained using a sequential clinical algorithm based on the initial use of elastography, followed by contrast enhancement.