Receptor for advanced glycation endproducts (RAGE) and vascular inflammation: Insights into the pathogenesis of macrovascular complications in diabetes

The incidence and severity of atherosclerosis is increased in patients with diabetes. Indeed, accelerated macrovascular disease in diabetic patients has emerged as a leading cause of morbidity and mortality in the United States and worldwide. Multiple investigations have suggested that there are numerous potential contributory factors that underlie these observations. Our laboratory has focused on the contribution of receptor for advanced glycation endproducts (RAGE) and its proinflammatory ligands, advanced glycation endproducts (AGEs) and S100/calgranulins in vascular perturbation, manifested as enhanced atherogenesis or accelerated restenosis after angioplasty. In rodent models of diabetic complications, blockade of RAGE suppressed vascular hyperpermeability, accelerated atherosclerotic lesion area and complexity in diabetic apolipoprotein E-deficient mice, and prevented exaggerated neointimal formation in hyperglycemic fatty Zucker rats subjected to injury of the carotid artery. In this review, we summarize these findings and provide an overview of distinct mechanisms that contribute to the development of accelerated diabetic macrovascular disease. Insights into therapeutic strategies to prevent or interrupt these processes are presented.     

Wireless capsule endoscopy for diagnosis of acute intestinal graft-versus-host disease

BACKGROUND: The small intestine is the most common location of intestinal graft-versus-host disease (GVHD). EGD with duodenal biopsies yields the highest diagnostic sensitivity, but the jejunum and ileum are not accessible by regular endoscopy. In contrast, wireless capsule endoscopy (WCE) is a noninvasive imaging procedure offering complete evaluation of the small intestine. OBJECTIVE: The objective was to compare the diagnostic value of EGD, including biopsies, with the results of WCE in patients with acute intestinal symptoms who received allogeneic blood stem cell transplantation and to analyze the appearance and distribution of acute intestinal GVHD lesions in these patients. DESIGN: An investigator-blinded, single-center prospective study. PATIENTS: Patients with acute intestinal symptoms after allogeneic stem cell transplantation underwent both EGD and WCE within 24 hours. Clinical data were recorded during 2 months of follow-up. RESULTS: Fourteen consecutive patients with clinical symptoms of acute intestinal GVHD were recruited. In 1 patient, the capsule remained in the stomach and was removed endoscopically. In 7 of 13 patients who could be evaluated, acute intestinal GVHD was diagnosed by EGD with biopsies, but 3 of these would have been missed by EGD alone. In all 7 patients with histologically confirmed acute intestinal GVHD, WCE revealed typical signs of GVHD. Lesions were scattered throughout the small intestine, but were most accentuated in the ileum. LIMITATIONS: This study had a small number of patients. CONCLUSIONS: WCE, which is less invasive than EGD with biopsies, showed a comparable sensitivity and a high negative predictive value for diagnosing acute intestinal GVHD. It may be helpful to avoid repeated endoscopic procedures in patients who have undergone stem cell transplantation.     

Surgery insight: the dilated ascending aorta--indications for surgical intervention

Awareness of the clinical significance of thoracic aortic aneurismal disease has increased in recent years. As diagnostic tools have improved our ability to identify aortic pathology, surgical outcomes have also improved, making intervention a life-saving option in the majority of cases. Here, we aim to examine the indications for surgical intervention on the dilated aorta, particularly the ascending segment. Studies of the natural history of ascending aortic aneurysms indicate that aneurysms exceeding 6 cm in maximum diameter are associated with a particularly high risk of complications. In the interest of providing some margin of safety, most surgeons would agree that intervention is indicated with an aortic diameter of 5.5 cm. Many would intervene even earlier (at 5.0 cm) for patients at low surgical risk, or for those with known connective tissue disorders such as Marfan's syndrome. In some cases, only the ascending aortic segment needs to be treated, while in others full root replacement is required. Reduction aortoplasty has been superseded largely by interposition graft replacement. The standard procedure involves replacement of the valve and root with a composite mechanical conduit or tissue root prosthesis, and results are excellent. Recently developed valve-sparing root reconstructive options, however, are promising and have encouraged an even more aggressive surgical stance.     

Retinal charge sensitivity and spatial discrimination obtainable by subretinal implants: key lessons learned from isolated chicken retina

In order to obtain functional parameters relevant to the designing of a subretinal implant, we carried out electrical stimulation experiments with isolated chicken retina. The median threshold for network activation with planar disc electrodes (diameter 10 microm) was 0.5 nC (625 microC cm(-2)) for anodal voltage impulses and 1.6 nC (2 mC cm(-2)) for cathodal impulses. Above threshold, the number of spikes evoked by a single voltage impulse increased up to saturation within a range of injected charge from 0.1 nC to 1 nC for anodal impulses and from 1 nC to 10 nC for cathodal impulses. Using needle electrodes with a tip diameter of 1 microm, we determined the electrical point spread function (EPSF) for subretinal stimulation. It had a half width in the range of 100 microm, which corresponds to a visual angle of 21' and to a visual acuity of 20/417 in the human eye. It is reasonable to conclude that with subretinal implants the minimum separable will be of the same dimension.     

Contrast-dose relation in first-pass myocardial MR perfusion imaging

PURPOSE: To determine the regime of linear contrast enhancement in human first-pass perfusion cardiovascular magnetic resonance (CMR) imaging to improve accuracy in myocardial perfusion quantification. MATERIALS AND METHODS: A total of 10 healthy subjects were studied on a clinical 1.5T MR scanner. Seven doses of Gd-DTPA ranging from 0.00125 to 0.1 mmol/kg of body weight (b.w.) were administered as equal volumes by rapid bolus injection (6 mL/second). Resting periods of 15 minutes were introduced after delivery of Gd doses >0.01 mmol/kg b.w. For each subject, two series of rest perfusion scans were performed using two different multislice saturation-recovery perfusion sequences. Maximum contrast enhancement and maximum upslope were obtained in the blood pool of the left ventricular (LV) cavity and in the myocardium. The range of linear contrast-dose relation was determined by linear regression analysis. RESULTS: MR signal intensity increased linearly for contrast agent concentrations up to 0.01 mmol/kg b.w. in the LV blood pool and up to 0.05 mmol/kg b.w. in the myocardium. For Gd concentrations exceeding these thresholds the signal intensity response was not linear with respect to the contrast agent dose. CONCLUSION: Quantitative evaluation of cardiac MR perfusion data needs to account for signal saturation in both the LV blood pool and the myocardium.     

Intramural hematoma and penetrating atherosclerotic ulcer of the aorta

Intramural hematoma and penetrating aortic ulcer are uncommon but potentially lethal thoracic aortic pathologies. Despite incomplete understanding of their natural history, they have emerged as anatomically appealing targets of endovascular therapy. Appropriate application of these technologies, however, must be predicated on an understanding of the fate of these lesions left untreated, and predictors of their misbehavior. We briefly review the current understanding of these entities.