Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles

Release of membrane vesicles, a process conserved in both prokaryotes and eukaryotes, represents an evolutionary link, and suggests essential functions of a dynamic extracellular vesicular compartment (including exosomes, microparticles or microvesicles and apoptotic bodies). Compelling evidence supports the significance of this compartment in a broad range of physiological and pathological processes. However, classification of membrane vesicles, protocols of their isolation and detection, molecular details of vesicular release, clearance and biological functions are still under intense investigation. Here, we give a comprehensive overview of extracellular vesicles. After discussing the technical pitfalls and potential artifacts of the rapidly emerging field, we compare results from meta-analyses of published proteomic studies on membrane vesicles. We also summarize clinical implications of membrane vesicles. Lessons from this compartment challenge current paradigms concerning the mechanisms of intercellular communication and immune regulation. Furthermore, its clinical implementation may open new perspectives in translational medicine both in diagnostics and therapy

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Small-bowel neoplasms in patients undergoing video capsule endoscopy: a multicenter European study

Background and study aim: Small-bowel tumors account for 1%-3% of all gastrointestinal neoplasms. Recent studies with video capsule endoscopy (VCE) suggest that the frequency of these tumors may be substantially higher than previously reported. The aim of the study was to evaluate the frequency, clinical presentation, diagnostic/therapeutic work-up, and endoscopic appearance of small-bowel tumors in a large population of patients undergoing VCE. Patients and methods: Identification by a questionnaire of patients with VCE findings suggesting small-bowel tumors and histological confirmation of the neoplasm seen in 29 centers of 10 European Countries. Results: Of 5129 patients undergoing VCE, 124 (2.4%) had small-bowel tumors (112 primary, 12 metastatic). Among these patients, indications for VCE were: obscure gastrointestinal bleeding (108 patients), abdominal pain (9), search for primary neoplasm (6), diarrhea with malabsorption (1). The main primary small-bowel tumor type was gastrointestinal stromal tumor (GIST) (32%) followed by adenocarcinoma (20%) and carcinoid (15%); 66% of secondary small-bowel tumors were melanomas. Of the tumors, 80.6% were identified solely on the basis of VCE findings. 55 patients underwent WE as the third procedure after negative bidirectional endoscopy. The lesions were single in 89.5 % of cases, and multiple in 10.5%. Retention of the capsule occurred in 9.8% of patients with small-bowel tumors. After VICE, 54/124 patients underwent 57 other examinations before treatment; in these patients enteroscopy, when performed, showed a high diagnostic yield. Treatment was surgery in 95% of cases. Conclusions: Our data suggest that VCE detects small-bowel tumors in a small proportion of patients undergoing this examination, but the early use of this tool can shorten the diagnostic workup and influence the subsequent management of these patients

Increased diagnostic yield of small bowel tumors with PillCam: the role of capsule endoscopy in the diagnosis and treatment of gastrointestinal stromal tumors (GISTs). Italian single-center experience.

Background. Gastrointestinal stromal tumors (GISTs) are rare tumors, accounting for 1-3% of all gastrointestinal malignancies; they are, however, the most common gastric and small bowel mesenchymal tumors. The length and relative inaccessibility of the small bowel have long constrained the diagnosis of GISTs mainly presenting with chronic or intermittent bleeding as the sole clinical manifestation. Aim. To report on the prevalence of small bowel GISTs in a prospectively recorded series of patients undergoing capsule endoscopy (CE). Patients and methods. Between 2001 and 2007 five hundred patients were referred to our endoscopy unit for small bowel evaluation with capsule endoscopy. We retrospectively evaluated all charts. The main indications for CE were obscure-occult or obscure-overt bleeding. Two hundred eighty-nine patients underwent CE for either obscure-occult or obscure-overt bleeding and 211 for other indications. Patient outcome and care processes were measured by follow-up telephone interviews and chart review. Statistical computations were performed using Fisher\u2019s exact test and Student\u2019s t-test. Results. CE identified a small bowel tumor in 20 patients (4.0%) and 9 tumors turned out to be GISTs (45.0%). Traditional endoscopic and radiological imaging failed to detect the GIST in all these cases. In one case a small bowel GIST was diagnosed by angiography and CE proved false negative. Overall, CE was able to diagnose a small bowel GIST in 9 out of 10 cases. All patients underwent surgical treatment and showed normalized hemoglobin levels at follow-up. The main limitation of this study is the small number of cases. Conclusions. CE is an effective and sensitive diagnostic device compared with conventional radiology and plays an important role in the algorithm for the diagnostic work-up of suspected small bowel tumors