Alison Goldin

Advanced Glycation End Products Sparking the Development of Diabetic Vascular Injury

Advanced glycation end products (AGEs) are proteins or lipids that become glycated after exposure to sugars. AGEs are prevalent in the diabetic vasculature and contribute to the development of atherosclerosis. The presence and accumulation of AGEs in many different cell types affect extracellular and intracellular structure and function. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Activation of RAGE by AGEs causes upregulation of the transcription factor nuclear factor-kappaB and its target genes. Soluble AGEs activate monocytes, and AGEs in the basement membrane inhibit monocyte migration. AGE-bound RAGE increases endothelial permeability to macromolecules. AGEs block nitric oxide activity in the endothelium and cause the production of reactive oxygen species. Because of the emerging evidence about the adverse effects of AGEs on the vasculature of patients with diabetes, a number of different therapies to inhibit AGEs are under investigation.

Inhibition of Protein Kinase Cβ Does Not Improve Endothelial Function in Type 2 Diabetes

CONTEXT Antagonism of protein kinase Cbeta (PKCbeta) restores endothelial function in experimental models of diabetes and prevents vascular dysfunction in response to hyperglycemia in healthy humans. OBJECTIVE We tested the hypothesis that PKCbeta antagonism would improve vascular function in subjects with type 2 diabetes compared with healthy control subjects. DESIGN The effect of PKCbeta was evaluated in a randomized, placebo-controlled, double-blinded crossover trial. SETTING The study was performed in the outpatient setting of a university medical center. PARTICIPANTS Thirteen subjects with type 2 diabetes without evidence of cardiovascular disease and 15 healthy control subjects were recruited via newspaper advertisement. INTERVENTION Subjects underwent a randomized, double-blind, crossover, placebo-controlled trial of the selective PKCbeta antagonist ruboxistaurin mesylate. Subjects received each treatment for 14 d. MAIN OUTCOME MEASURE Endothelium-dependent and endothelium-independent vasodilation of forearm resistance vessels was measured with mercury-in-silastic, strain-gauge plethysmography during intraarterial administration of methacholine chloride and verapamil, respectively. Markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress were measured after each treatment. RESULTS Endothelium-dependent vasodilation of forearm resistance vessels was attenuated in diabetic subjects when compared with healthy subjects (P=0.001). Endothelium-independent vasodilation did not differ between groups (P value not significant). Ruboxistaurin did not significantly change endothelium-dependent or endothelium-independent vasodilation or blood-based markers of inflammation, fibrinolysis, endothelial damage, and oxidative stress in either diabetic or healthy subjects. CONCLUSION Endothelial dysfunction of forearm resistance vessels was not improved by 2 wk of selective PKCbeta inhibition in patients with diabetes. These results suggest that PKCbeta does not contribute significantly to vascular dysfunction in otherwise healthy patients with type 2 diabetes.

Current Approach to the Management of Eosinophilic Esophagitis in Adults.

Opinion statementEosinophilic esophagitis (EoE) is an increasingly diagnosed, immune-mediated disease characterized by inflammation of the esophagus in both children and adult, causing significant morbidity. Adults typically present with dysphagia and a history of food impaction. Diagnosis should be considered in patients with histological evidence of eosinophilia (≥15 eosinophils per high-power field) on esophageal biopsy. More recently, it has been observed that a significant percentage of patients with esophageal eosinophilia respond both clinically and histologically to PPI therapy. This disorder has been named PPI-responsive esophageal eosinophilia (PPI-REE). Recent studies suggest that patients with PPI-REE have similar clinical and endoscopic features of patients with EoE. Specifically, both PPI-REE and EoE patients have a strong disposition to allergy compared to patients without eosinophilia. As such, PPI-REE may represent a subset or variant of EoE. Effective treatment of EoE requires a multidisciplinary approach with gastroenterologists, pathologists, allergists, and nutritionists. Treatments include elimination and elemental diets, topical glucocorticoids (fluticasone and budesonide), and endoscopic dilation.

Approach to Esophageal Motility Disorders

Esophageal motility disorders are a broad category of diseases with a variety of symptoms, ranging from dysphagia to chest pain. The pathophysiology is not always fully understood, but may involve alterations in inhibitory or excitatory innervation of the smooth muscle of the distal esophagus and LES. High-resolution manometry is the gold standard for its diagnosis, and the Chicago classification offers an organizational framework for better evaluation and management. Major disorders of motility are generally pathologic, and include achalasia, EGJOO, DES, hypertensive esophagus, and diseases of absent peristalsis, such as scleroderma. Treatments are targeted at the particular diagnosis. In achalasia, endoscopic and surgical options are preferred. For the remaining motility diagnoses, medical management forms the mainstay of treatment, which can be limited by side effect profiles.

Su1461 Epidemiology of Solid Pseudopapillary Neoplasm in the United States

which can classify the cyst samples. Results: Sixty nine patients who underwent EUS-FNA (median age 66, range 20-90 years, including 32 males) with PCs ranging in size from 780 mm (median 18 mm) were included in the analysis. Median fluid CEA level was 144 ng/ml (range 0.2-392310). Mucinous lesions were diagnosed in 30 and non-mucinous in 39 patients. A total of 101 miRNAs were differentially expressed in mucinous cysts, out of which only 11 have been previously reported in literature to be overexpressed in mucinous PCs and/or pancreas cancer (mi10b, 181a, 212, 26a, 30a, 194, 200c, 200b, 99b, 192, and 31). Out of 101, 36 unique miRNAs were found to be overexpressed based on detectable expression in at least 50% of the lesions aspirated. Table 1 and Figure 1 depict the differential expression in the top group of miRNAs assessed. Conclusion: EUS-FNA is a reliable method for PC fluid acquisition and does not appear to affect the ability to profile miRNAs in the fluid. We report on a larger cohort of miRNAs differentially expressed in mucinous PCs than previously described. Further validation of our findings is warranted.