The AGE inhibitor pyridoxamine inhibits lipemia and development of renal and vascular disease in Zucker obese rats

BACKGROUND: In previous studies, pyridoxamine (PM) limited the formation of advanced glycation end products (AGEs) and development of nephropathy in streptozotocin-diabetic rats without affecting glycemic control. However, the lipid-lowering effects of PM and the correlation of plasma cholesterol and triglycerides with AGEs in skin collagen suggested that lipids might be an important source of AGEs in the diabetic rat. This study addresses the effects of hyperlipidemia on formation of advanced glycation and lipoxidation end products (AGE/ALEs) and the effects of PM on hyperlipidemia, hypertension, AGE/ALE formation, and development of nephropathy in the nondiabetic, Zucker obese rat. METHODS: Three groups of Zucker rats were studied: lean (Fa/fa), untreated fatty (fa/fa), and fa/fa treated with PM (2 g/L drinking water). Blood pressure, plasma lipids and creatinine, and urinary albumin were measured monthly. AGE/ALEs were measured in skin collagen by high-performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS). Changes in wall thickness of the aorta and renal arterioles were evaluated by light microscopy. RESULTS: AGE/ALEs formation was increased two- to threefold in skin collagen of obese versus lean rats. PM inhibited the increases in AGE/ALEs in collagen, and significantly decreased the rise in plasma triglycerides, cholesterol, and creatinine, corrected hypertension and thickening of the vascular wall, and nearly normalized urinary protein and albumin excretion in Zucker fa/fa rats. CONCLUSION: Lipids are an important source of chemical modification of tissue proteins, even in the absence of hyperglycemia. PM inhibited AGE/ALE formation and hyperlipidemia and protected against renal and vascular pathology in a nondiabetic model.     

Mycobacterium tuberculosis-specific CD8+ T cells preferentially recognize heavily infected cells

Both CD4+ and CD8+ T cells are important for successful immunity to tuberculosis and have redundant effector functions, such as cytolysis and release of potent antimycobacterial cytokines such as interferon-gamma and tumor necrosis factor-alpha. We hypothesized that CD8+ T cells play a unique role in host defense to Mycobacterium tuberculosis infection as well. Possibilities include preferential and/or enhanced release of granular constituents and/or preferential recognition of heavily infected cells. Utilizing human, Mycobacterium tuberculosis-specific, CD4+ and CD8+ T cell clones, we demonstrate that, after recognition of antigen-presenting cells displaying peptide antigen, CD4+ T cells preferentially release interferon-gamma, whereas CD8+ T cells preferentially lyse antigen-presenting cells. Furthermore, utilizing dendritic cells infected with Mycobacterium tuberculosis expressing green fluorescent protein, we show that CD8+ T cells preferentially recognize heavily infected cells that constitute the minority of infected cells. These data support the hypothesis that the central role of CD8+ T cells in the control of infection with Mycobacterium tuberculosis may be that of surveillance; in essence, recognition of cells in which the containment of Mycobacterium tuberculosis is no longer effective.     

Evidence for functional endothelial cell damage in early diabetic retinopathy

Summary Two aspects of endothelial cell function were examined in two matched groups of male insulin-dependent diabetics, six with background retinopathy and seven without retinopathy. Leakage of fluorescein from the retinal capillaries was estimated by vitreous fluorophotometry. In addition, factors VIII/von Willebrand (vWF) and VIII-related antigen (VIII-RAG), which are synthesized by the endothelial cells, were measured, together with VIII-antihaemophilic factor (VIII-AHF). The patients without retinopathy had normal leakage of fluorescein in the macula (mean ± SEM: 1.10±0.10 g × 10^-8/ml) and the posterior vitreous (0.45±0.11 g × 10^-8/ml), and normal circulating levels of vWF (123% of a normal reference plasma ± 18%), VIII-RAG (137±14%) and VIII-AHF (112±18%). In contrast, the patients with background retinopathy showed higher leakage of fluorescein in the macula (6.34±1.74 g ×10^-8/ml; p<0.01), and the posterior vitreous (3.09±0.94 g ×10^-8/ml; p<0.02), as well as increased levels of vWF (177±16%; p<0.05). There was a trend towards increased VIII-RAG (195±24%; p<0.1), but not VIII-AHF (126 ±13%). Alterations of endothelial cell function thus accompany the development of retinopathy. It cannot be said from the present study whether these alterations also precede the appearance of retinopathy.     

The incremental benefit of two quadrant lavage for peritoneal cytology at staging laparoscopy for oesophagogastric adenocarcinoma

Background

Patients with positive peritoneal cytology from oesophagogastric cancer have a poor prognosis. The purpose of this study was to compare lavage cytology from the pelvis alone with the pelvis and subphrenic areas at staging laparoscopy in patients with potentially resectable oesophagogastric adenocarcinoma.

Methods

Between November 2006 and November 2010, all patients with operable oesophagogastric adenocarcinoma on spiral CT considered fit for surgical resection underwent staging laparoscopy. Subphrenic and pelvic peritoneal lavage for cytology was performed followed by laparoscopic biopsy of any visible peritoneal disease. Patients were divided into groups: macroscopic peritoneal metastases (P+), no macroscopic peritoneal disease with negative cytology (P?C?), no macroscopic peritoneal disease with positive pelvic cytology (P?PC+), no macroscopic peritoneal disease with positive subphrenic cytology (P?SC+), or both (P?PSC+).

Results

A total of 316 staging laparoscopy procedures were performed; 245 patients (78 %) were P?C?, 28 (9 %) were P+, and 43 (14 %) were P?C+, of whom 29 (9 %) were P?PSC+, 10 (3 %) were P?SC+, and 4 (1 %) were P?PC+. Pelvic cytology alone had 76.7 % sensitivity for peritoneal disease, and subphrenic cytology alone had 90.7 % sensitivity.

Conclusions

Peritoneal lavage for cytology at staging laparoscopy has an incremental benefit for staging oesophagogastric adenocarcinoma in the absence of macroscopic metastatic disease. Subphrenic washings have the highest yield of positive results. Performing isolated pelvic washings for cytology will understage 23.3 % of patients with microscopic peritoneal disease. The routine use of subphrenic in combination with pelvic lavage for cytology at staging laparoscopy in patients with oesophagogastric adenocarcinoma has an incremental benefit in detecting cytology-positive disease over either pelvic or subphrenic cytology alone.     

Quality of life measurement in patients with oesophageal cancer.

Quality of life (QOL) measurement may aid decision making in the treatment of patients with oesophageal cancer but must be clinically valid to be useful. This study considered if the European Organisation for Research and Treatment of Cancer QOL questionnaire, the QLQ-C30, showed differing results in two clinically distinct groups of patients with oesophageal cancer and also investigated the correlation between dysphagia grade and various scales of QOL. Patients treated by oesophagectomy reported significantly better physical, emotional, cognitive, and global health scores than those in the palliative treatment group. Patients who received palliative treatment had significantly worse pain, fatigue, appetite loss, constipation, and dysphagia. The correlations between dysphagia grade and each of the QOL scales and items in both groups of patients were poor. This questionnaire differentiates clearly between the two clinically distinct groups of patients, but to be an entirely appropriate indicator of QOL in patients with oesophageal cancer, an additional specific oesophageal module including a dysphagia scale is required.