In Vitro Impact of Pro-Senescent Endothelial Microvesicles on Isolated Pancreatic Rat Islets Function

BackgroundIschemia-driven islet isolation procedure is one of the limiting causes of pancreatic islet transplantation. Ischemia-reperfusion process is associated with endothelium dysfunction and the release of pro-senescent microvesicles. We investigated whether pro-senescent endothelial microvesicles prompt islet senescence and dysfunction in vitro.Material and methodsPancreatic islets were isolated from male young rats. Replicative endothelial senescence was induced by serial passaging of primary porcine coronary artery endothelial cells, and microvesicles were isolated either from young passage 1 (P1) or senescent passage 3 (P3) endothelial cells. Islet viability was assessed by fluorescence microscopy, apoptosis by flow cytometry, and Western blot. Function was assessed by insulin secretion and islet senescence markers p53, p21, and p16 by Western blot. Microvesicles were stained by the PKH26 lipid fluorescent probe and their islet integration assessed by microscopy and flow cytometry.ResultsRegardless of the passage, half microvesicles were integrated in target islets after 24 hours incubation. Insulin secretion significantly decreased after treatment by senescent microvesicles (P3: 1.7 ± 0.2 vs untreated islet: 2.7 ± 0.2, P < .05) without altering the islet viability (89.47% ± 1.69 vs 93.15% ± 0.97) and with no significant apoptosis. Senescent microvesicles significantly doubled the expression of p53, p21, and p16 (P < .05), whereas young microvesicles had no significant effect.ConclusionPro-senescent endothelial microvesicles specifically accelerate the senescence of islets and alter their function. These data suggest that islet isolation contributes to endothelial driven islet senescence.     

A novel study on amyloid β peptide 40, 42 and 40/42 ratio in Saudi autistics

Objectives  

We examined whether plasma concentrations of amyloid beta (Aβ) as protein derivatives play a central role in the etiology of autistic features.     

The GLP-1 Receptor Agonist Liraglutide Increases Myocardial Glucose Oxidation Rates via Indirect Mechanisms and Mitigates Experimental Diabetic Cardiomyopathy

BackgroundType 2 diabetes (T2D) increases risk for cardiovascular disease. Of interest, liraglutide, a therapy for T2D that activates the glucagon-like peptide-1 receptor to augment insulin secretion, reduces cardiovascular-related death in people with T2D, though it remains unknown how liraglutide produces these actions. Notably, the glucagon-like peptide-1 receptor is not expressed in ventricular cardiac myocytes, making it likely that ventricular myocardium-independent actions are involved. We hypothesized that augmented insulin secretion may explain how liraglutide indirectly mediates cardioprotection, which thereby increases myocardial glucose oxidation.MethodsC57BL/6J male mice were fed either a low-fat diet (lean) or were subjected to experimental T2D and treated with either saline or liraglutide 3× over a 24-hour period. Mice were subsequently euthanized and had their hearts perfused in the working mode to assess energy metabolism. A separate cohort of mice with T2D were treated with either vehicle control or liraglutide for 2 weeks for the assessment of cardiac function via ultrasound echocardiography.ResultsTreatment of lean mice with liraglutide increased myocardial glucose oxidation without affecting glycolysis. Conversely, direct treatment of the isolated working heart with liraglutide had no effect on glucose oxidation. These findings were recapitulated in mice with T2D and associated with increased circulating insulin levels. Furthermore, liraglutide treatment alleviated diastolic dysfunction in mice with T2D, which was associated with enhanced pyruvate dehydrogenase activity, the rate-limiting enzyme of glucose oxidation.ConclusionsOur data demonstrate that liraglutide augments myocardial glucose oxidation via indirect mechanisms, which may contribute to how liraglutide improves cardiovascular outcomes in people with T2D.     

Does patient education increase antimuscarinic treatment persistence in overactive bladder syndrome?

Overactive bladder syndrome (OAB) is a chronic condition that requires long‐term management. Patient education may have role in decreasing the unfavourable effects of long‐term treatment of OAB. The aim of the study was to evaluate the effect of detailed patient education on the patients' persistence with antimuscarinic treatment for OAB. A total of 140 patients with the diagnosis of OAB were included in this study. Patients were randomly divided into two groups. Patients in Group 1 were given information by the same urology doctor about the disease and treatment. Patients in Group 2 were given information by a urology nurse. Patients were recalled in the first, third and sixth months of treatment. The treatment persistency was evaluated in the whole study population and between the groups. The persistency rates of the whole group were 88·6% in the first month, 65·7% in the third month and 45·7% in the sixth month. At the end of the sixth month, 42·8% of males and 47·1% of females were taking antimuscarinics (p = 0·580). The persistence rate of Groups 1 and 2 were 82·8 and 94·3% at the first month. (p = 0·034). It decreased to 31·4% in the first and 60% in the second group at the sixth month (p = 0·001). The persistence rate of antimuscarinic treatment is low. Patient education is simple and effective way of increasing persistence. Clinicians must pay attention to inform their patients about the disease and possible side effects of treatment. An educated health provider may be very helpful in educating patients for OAB.     

The Avon Patellofemoral Joint Replacement: Mid-Term Prospective Results from an Independent Centre

Background

Approximately 10% of patients with osteoarthritis (OA) of the knee have unicompartmental OA confined to the patellofemoral joint (PFJ). The main surgical options are total knee replacement (TKR) and PFJ replacement (PFJR). PFJR has a number of advantages over TKR, including being less invasive, preserving the unaffected parts of the knee, allowing faster recovery and better range of motion and function. We report our prospective mid-term results of the Avon PFJR for established isolated PFJ arthritis in 61 consecutive procedures.

Methods

Sixty-one Avon PFJRs were performed in 57 patients. The outcome measures were the new Oxford knee score (OKS), Hungerford and Kenna score (HKS), and Crosby Insall knee scores. Only patients with severe isolated PFJ OA were included. The diagnosis was based on a combination of clinical, radiological and, where available, arthroscopic findings.

Results

Mean follow-up was 5.09 years (range, 12 to 124 years). There were 2 revisions in the first 5 years. The median HKS score was 80 (interquartile range, 70 to 95) and the mean OKS was 31.8 (± standard deviation, 8.7) at 5 years. These were significantly better (p < 0.001) than the preoperative scores.

Conclusions

The Avon prosthesis gives good functional outcomes in the medium term and survives well. Our data support other studies in the literature and is the largest independent prospective study to date.     

Cyclooxygenase-1, not cyclooxygenase-2, is responsible for physiological production of prostacyclin in the cardiovascular system

Prostacyclin is an antithrombotic hormone produced by the endothelium, whose production is dependent on cyclooxygenase (COX) enzymes of which two isoforms exist. It is widely believed that COX-2 drives prostacyclin production and that this explains the cardiovascular toxicity associated with COX-2 inhibition, yet the evidence for this relies on indirect evidence from urinary metabolites. Here we have used a range of experimental approaches to explore which isoform drives the production of prostacyclin in vitro and in vivo. Our data show unequivocally that under physiological conditions it is COX-1 and not COX-2 that drives prostacyclin production in the cardiovascular system, and that urinary metabolites do not reflect prostacyclin production in the systemic circulation. With the idea that COX-2 in endothelium drives prostacyclin production in healthy individuals removed, we must seek new answers to why COX-2 inhibitors increase the risk of cardiovascular events to move forward with drug discovery and to enable more informed prescribing advice.     

Purpura thrombotique thrombocytopénique et autres syndromes de microangiopathie thrombotique au cours de l’infection par le virus de l’immunodéficience humaine

Human immunodeficiency virus (HIV) infection represents a risk factor for thrombotic microangiopathy. HIV-associated thrombotic microangiopathies encompass two entities with distinct pathophysiology, clinical presentation, treatment and prognosis. Thrombotic thrombocytopenic purpura associated with human immunodeficiency virus is typically characterized by a sudden onset in a patient with a moderate immune deficiency and a few events of opportunistic diseases, and a profound acquired deficiency in the von Willebrand factor cleaving protease ADAMTS13. This diagnosis requires a well-codified management including daily therapeutic plasma exchanges, a highly active antiretroviral therapy and eventually immunomodulatory drugs. The prognosis is good with a response rate and an overall survival comparable to that of HIV-negative thrombotic thrombocytopenic purpura. On the opposite, HIV-associated thrombotic microangiopathy with a progressive onset that occurs in profoundly immunocompromised patients with past history of multiple opportunistic diseases usually have a detectable ADAMTS13 activity and a worse prognosis. Usual treatment is poorly efficient. Forthcoming studies should assess the role of immunomodulatory drugs such as rituximab in the setting of HIV-associated thrombotic microangiopathy, and identify possible risk factors associated with the occurrence of these diseases.