Pathophysiological role of Amadori-glycated proteins in diabetic microangiopathy

Early and advanced nonenzymatic glycation of proteins are increased in diabetes. Although Amadori-glycated proteins are the major glycated modifications, most studies so far have focused on the role of advanced glycation end-products (AGEs) in diabetes-related vascular complications. It was only recently that the role of Amadori-glycated proteins has come under consideration. Here we review data that point to an important role of Amadori-modified glycated serum proteins in diabetic microangiopathy. Amadori-glycated albumin induces the activation of glomerular mesangial and endothelial cells to a phenotype that may be linked to the pathogenesis of diabetic microangiopathy, that is, by the stimulation of protein kinase C, activation of transforming growth factor beta, and the expression of extracellular matrix proteins. In type 1 diabetic patients, levels of Amadori-glycated proteins are independently associated with nephropathy and retinopathy. Reduction of Amadori-glycated albumin levels in diabetic animal models ameliorates the progression of nephropathy and retinopathy, indicating a causal role of Amadori-glycated proteins in the pathogenesis of diabetic nephropathy and retinopathy. Based on these data, inhibition of Amadori-glycated albumin may be a target for reduction of diabetic vascular complications.     

Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation

Donor-derived T cells have been proposed to play a role in pathogenesis of chronic graft-versus-host disease (cGVHD). The impact of ex vivo T-cell depletion (TCD) on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation-based myeloablative conditioning regimen. GVHD prophylaxis included TCD plus cyclosporine (CSA) or unmodified grafts with CSA plus methotrexate (M/C). Median recipient age was 31.2 years (range, 0.5-55.6 years); median follow-up time since randomization was 4.2 years. The mean number of T cells infused was 1 log lower on the TCD arm. The incidence of cGVHD at 2 years was similar between the TCD and M/C arms, 29% versus 34% (P = .27), respectively. Survival at 3 years from diagnosis of cGVHD was also similar, (TCD 51% versus M/C 58%; P = .29). The proportion of patients with cGVHD who discontinued immunosuppression at 5 years was not different (TCD 72% versus M/C 63%; P = .27), and incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed cGVHD.     

Renin–angiotensin system inhibition is not associated with increased sudden cardiac death,cardiovascular mortality or all-cause mortality in patients with aortic stenosis

Background

Renin–angiotensin system inhibition (RASI) is frequently avoided in aortic stenosis (AS) patients because of fear of hypotension. We evaluated if RASI with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) increased mortality in patients with mild to moderate AS.

Methods

All patients (n = 1873) from the Simvastatin and Ezetimibe in Aortic Stenosis study: asymptomatic patients with AS and preserved left ventricular (LV) ejection fraction were included. Risks of sudden cardiac death (SCD), cardiovascular death and all-cause mortality according to RASI treatment were analyzed by multivariable time-varying Cox models and propensity score matched analyses.

Results

769 (41%) patients received RASI. During a median follow-up of 4.3 ± 0.9 years, 678 patients were categorized as having severe AS, 545 underwent aortic valve replacement, 40 SCDs, 103 cardiovascular and 205 all-cause deaths occurred. RASI was not associated with SCD (HR: 1.19 [95%CI: 0.50–2.83], p = 0.694), cardiovascular (HR: 1.05 [95%CI: 0.62–1.77], p = 0.854) or all-cause mortality (HR: 0.81 [95%CI: 0.55–1.20], p = 0.281). This was confirmed in propensity matched analysis (all p > 0.05). In separate analyses, RASI was associated with larger reduction in systolic blood pressure (p = 0.001) and less progression of LV mass (p = 0.040).

Conclusions

RASI was not associated with SCD, cardiovascular or all-cause mortality in asymptomatic AS patients. However, RASI was associated with a potentially beneficial decrease in blood pressure and reduced LV mass progression.     

Patient-reported burden of intensified surveillance and surgery in high-risk individuals under pancreatic cancer surveillance

Familial Cancer - In high-risk individuals participating in a pancreatic cancer surveillance program, worrisome features warrant for intensified surveillance or, occasionally, surgery. Our...     

A placebo-controlled crossover study of oral clonidine in acute anorexia nervosa

The alpha 2-adrenergic agonist clonidine has been reported to increase feeding in several species. This study evaluated the effects of clonidine (500-700 micrograms/day), administered per os, to four treatment-resistant anorexia nervosa patients in a long-term placebo-controlled crossover trial. All patients increased their body weight significantly. Clonidine administration, however, did not influence the rate of weight gain, nor did clonidine affect hunger or satiety sensations. Similarly, 24-hour urinary 3-methoxy-4-hydroxyphenylglycol levels and levels of anxiety and depression were unchanged by clonidine. By contrast, clonidine showed significant hemodynamic effects; clonidine lowered systolic and diastolic blood pressure, reduced pulse rate, and produced sedation. Discontinuation of clonidine was associated with a small but significant weight loss compared to a small weight increase during the initiation of clonidine treatment. The results suggest that clonidine may not be indicated in the treatment of anorexia nervosa.     

Occlusion of the pancreatic duct versus pancreaticojejunostomy: a prospective randomized trial

OBJECTIVE: Using a prospective randomized study to assess postoperative morbidity and pancreatic function after pancreaticoduodenectomy with pancreaticojejunostomy and duct occlusion without pancreaticojejunostomy. SUMMARY BACKGROUND DATA: Postoperative complications after pancreaticoduodenectomy are largely due to leakage of the pancreaticoenterostomy. Pancreatic duct occlusion without anastomosis of the pancreatic remnant may prevent these complications. METHODS: A prospective randomized study was performed in a nonselected series of 169 patients with suspected pancreatic and periampullary cancer. In 86 patients the pancreatic duct was occluded without anastomosis to pancreatic remnant, and in 83 patients a pancreaticojejunostomy was performed after pancreaticoduodenectomy. Postoperative complications were the endpoint of the study. All relevant data concerning patient demographics and postoperative morbidity and mortality as well as endocrine and exocrine function were analyzed. At 3 and 12 months after surgery, evaluation of weight loss, stools, and the use of antidiabetics and pancreatic enzyme was repeated. RESULTS: Patient characteristics were comparable in both groups. There were no differences in median blood loss, duration of operation, and hospital stay. No significant difference was noted in postoperative complications, mortality, and exocrine insufficiency. The incidence of diabetes mellitus was significantly higher in patients with duct occlusion. CONCLUSIONS: Duct occlusion without pancreaticojejunostomy does not reduce postoperative complications but significantly increases the risk of endocrine pancreatic insufficiency after duct occlusion.     

Type I interferons in the treatment of pancreatic cancer: mechanisms of action and role of related receptors

OBJECTIVE: We evaluated the role of type I interferons (IFNs) and IFN receptors in the regulation of cell growth in 3 human pancreatic adenocarcinoma cell lines (BxPC-3, MiaPaCa-2, and Panc-1). BACKGROUND: Chemotherapy and radiotherapy have a marginal role in the management of pancreatic adenocarcinoma. The addition of IFN-alpha showed promising results in early clinical trials. METHODS: Cell proliferation and apoptosis were evaluated by DNA measurement and DNA fragmentation, respectively. Type I IFN receptor (IFNAR-1 and IFNAR-2 subunits) was determined by quantitative RT-PCR and immunocytochemistry. Cell cycle distribution was evaluated by propidium iodide staining and flow-cytometric analysis. RESULTS: The incubation with IFN-beta for 6 days showed a potent inhibitory effect on the proliferation of BxPC-3 (IC(50), 14 IU/mL) and MiaPaCa-2 (IC(50), 64 IU/mL). The inhibitory effect of IFN-beta was stronger than IFN-alpha in all 3 cell lines and mainly modulated by the stimulation of apoptosis, although cell cycle arrest was induced as well. The expression of the type I IFN receptors was significantly higher in BxPC-3 (the most sensitive cell line to IFN) and mainly localized on the membrane, whereas in Panc-1 (the most resistant cell line) about 60% to 70% of cells were negative for IFNAR-2c with a mainly cytoplasmic staining for IFNAR-2c. CONCLUSION: The antitumor activity of IFN-beta is more potent than IFN-alpha in pancreatic cancer cell lines through the induction of apoptosis. Further studies should investigate in vivo whether the intensity and distribution of IFNAR-1 and IFNAR-2c may predict the response to therapy with IFN-alpha and IFN-beta in pancreatic cancer.     

Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients

Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n?=?9). Within the infarction area of AMI patients (n?=?73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium.     

Cryo scanning electron microscopy of Plasmodium falciparum‐infected erythrocytes

Plasmodium falciparum invades erythrocytes as an essential part of their life cycle. While living inside erythrocytes, the parasite remodels the cell's intracellular organization as well as its outer surface. Late trophozoite‐stage parasites and schizonts introduce numerous small protrusions on the erythrocyte surface, called knobs. Current methods for studying these knobs include atomic force microscopy and electron microscopy. Standard electron microscopy methods rely on chemical fixation and dehydration modifying cell size. Here, a novel method is presented using rapid freezing and scanning electron microscopy under cryogenic conditions allowing for high resolution and magnification of erythrocytes. This novel technique can be used for precise estimates of knob density and for studies on cytoadhesion.