Sterol regulatory element-binding protein 1 mediates liver X receptor-beta-induced increases in insulin secretion and insulin messenger ribonucleic acid levels

Liver X receptors (LXRalpha and LXRbeta) regulate glucose and lipid metabolism. Pancreatic beta-cells and INS-1E insulinoma cells express only the LXRbeta isoform. Activation of LXRbeta with the synthetic agonist T0901317 increased glucose-induced insulin secretion and insulin content, whereas deletion of the receptor in LXRbeta knockout mice severely blunted insulin secretion. Analysis of gene expression in LXR agonist-treated INS-1E cells and islets from LXRbeta-deficient mice revealed that LXRbeta positively regulated expression of ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding protein 1 (SREBP-1), insulin, PDX-1, glucokinase, and glucose transporter 2 (Glut2). Down-regulation of SREBP-1 expression with the specific small interfering RNA blocked basal and LXRbeta-induced expression of pancreatic duodenal homeobox 1 (PDX-1), insulin, and Glut2 genes. SREBP-1 small interfering RNA also prevented an increase in insulin secretion and insulin content induced by T0901317. Moreover, 5-(tetradecyloxy)-2-furoic acid, an inhibitor of the SREBP-1 target gene acetyl-coenzyme A carboxylase, blocked T0901317-induced stimulation of insulin secretion. In conclusion, activation of LXRbeta in pancreatic beta-cells increases insulin secretion and insulin mRNA expression via SREBP-1-regulated pathway. These data support the role of LXRbeta, SREBP-1, and cataplerosis/anaplerosis pathways in the control of insulin secretion in pancreatic beta-cells.     

Mitralklappenprolaps: Identifikation von Patienten mit erhöhtem Risiko und therapeutisches Management

Mitral valve prolapse shows a wide spectrum from a benign anatomic variant to a progressive disease with severe cardiovascular morbidity and mortality. Echocardiography is the most important tool for diagnosis and risk stratification. Predictors for high risk are significant thickening of mitral leaflet of > 5 mm ("classic" prolapse), moderate to severe mitral regurgitation and reduced left ventricular function. These patients have an increased risk of infective endocarditis, cerebral ischemia and sudden cardiac death. Because of the risk for the development of severe mitral regurgitation requiring surgery short follow-up intervals are necessary.In mitral prolapse syndrome cardiac clinical signs (palpitation, rhythm disorders, syncope, etc.) are associated with a prolapse that can be treated symptomatically with drugs after exclusion of other causes and significant mitral regurgitation requiring surgery.     

Aortenklappenstenose: von der Valvuloplastie zum perkutanen Klappenersatz

Calcified aortic stenosis is the predominant valve disease. Patients affected are most commonly elderly people, who often show associated comorbidities like reduced left ventricular function, impaired renal function, and pulmonary hypertension. The risk of open-heart surgery is elevated. Balloon aortic valvuloplasty enables a reduction of symptoms, an increase in physical performance, and, therefore, an improved quality of life. However, a reduction in mortality cannot be reached with this method. New techniques and improved equipment induced a "revival" of balloon aortic valvuloplasty, which has been introduced almost 20 years ago. In addition, brachytherapy after balloon valvuloplasty has recently been investigated and represents an interesting approach to reduce early restenosis. The technical improvement of balloon valvuloplasty is the percutaneous heart valve, which is under present clinical investigation. The antegrade/transseptal and retrograde approaches are used, as is the transapical access to the left ventricle. Even if long-term results are not yet available and the procedures still require technical improvement, especially minimization of catheter size, percutaneous valve replacement is a new chapter in the treatment of the calcified aortic stenosis.     

Limited effects on JAK2 mutational status after pegylated interferon alpha-2b therapy in polycythemia vera and essential thrombocythemia

Twenty-five patients with myeloproliferative diseases were treated with pegylated interferon alpha-2b. Prior to therapy, 15/25 patients had a JAK2(V617F) mutation. Eight JAK2-positive patients were on therapy in hematological complete remission at 24 months. Five of eight patients demonstrated a 1.2-3.6 fold reduction in the percentage of JAK2(V617F) cells.     

Bortezomib after dose-reduced allogeneic stem cell transplantation for multiple myeloma to enhance or maintain remission status

OBJECTIVE: We investigated the effect of at least two cycles of bortezomib (1.3 mg/m(2) intravenously, days 1, 4, 8, and 11) after dose-reduced allogeneic stem cell transplantation (SCT) on toxicity, CD3(+) cells, graft-versus-host disease (GvHD), and response in patients with multiple myeloma. METHODS: Eighteen patients with multiple myeloma without progressive disease were included. The proteasome inhibitor was given at median of 8 months after allografting to enhance or maintain remission status. RESULTS: Fourteen patients (78%) completed the proposed two cycles. Four patients had to discontinue therapy due to neurotoxicity (n = 3) or gastrointestinal toxicity (n = 1). Severe grade III/IV toxicity was seen for thrombocytopenia (50%), leukopenia (17%), or neuropathy (17%), which was more often seen in patients treated concomitantly with cyclosporine (p = 0.06). The median circulating CD3(+) cells decreased during treatment from 550 muL to 438 muL (p = 0.03), resulting in herpes zoster infection in three patients (17%). In three patients, a mild aggravation of existing acute or chronic GvHD of the skin, and in one patient de novo skin grade I acute GvHD was noted. In patients with measurable disease, complete remission, partial remission, and minor response was seen in 3 (30%), 5 (50%), and 2 (20%) patients, respective. CONCLUSION: Bortezomib after allogeneic SCT is effective but further studies are needed to balance the efficacy with potential hazards such as infectious complications, aggravation of GvHD, and neurotoxicity.