Alpha-tocopherol, one of the eight isoforms of vitamin E, is the most potent fat-soluble antioxidant known in nature. For years, it was thought that alpha-tocopherol only functioned as a scavenger of lipid peroxyl radicals, specifically, oxidized low-density lipoprotein (oxLDL), thereby serving as a chief antioxidant for the prevention of atherosclerosis. In recent years, the many roles of alpha-tocopherol have been uncovered, and include not only antioxidant functions, but also pro-oxidant, cell signaling and gene regulatory functions. Decades of clinical and preclinical studies have broadened our understanding of the antioxidant vitamin E and its utility in a number of chronic, oxidative stress-induced pathologies. The results of these studies have shown promising, albeit mixed reviews on the efficacy of alpha-tocopherol in the prevention and treatment of heart disease, cancer and Alzheimer's disease. Future studies to uncover cellular and systemic mechanisms may help guide appropriate clinical treatment strategies using vitamin E across a diverse population of aging individuals.

The entity 'angioendotheliomatosis proliferans systemisata' was first described 28 years ago as a cutaneous small vessel neoplasm of presumed endothelial origin. Since then, 101 similar cases have been reported under a variety of different names, most with systemic as well as cutaneous lesions, and a lymphoid histogenesis of the tumour cell is now favoured. Review of these cases has shown a characteristic clinical presentation with predominant neurological and dermatological features, although the diagnosis was made at autopsy in 53 per cent of patients. Most therapeutic regimens have proved ineffective with a median survival of 5 months from date of clinical presentation. Aggressive combination chemotherapy can produce complete and lasting remission and a partial response to steroids is sometimes seen. We have examined a case of this condition showing unusual clinical features. Immunohistochemical studies confirm the lymphoid origin of the tumour cells with B cell phenotype. Antigen receptor gene rearrangement studies indicate the presence of the same clonal population of B cells in multiple sites. We suggest that the term 'angioendotheliomatosis proliferans systemisata' should be dropped and support the use of 'angiotropic large cell lymphoma' to describe this unusual condition.

Diabetic nephropathy is the leading cause of end stage renal disease. The urinary albumin to creatinine ratio is used as a predictor for the development of nephropathy but it is neither sensitive nor specific. Here we used liquid chromatography/mass spectrometry on urine of eight normoalbuminuric patients with type 2 diabetes from the VA Diabetes Trial to identify candidate markers for loss of renal function. Initial verification of 7 markers (agrin, haptoglobin, mannan-binding lectin serine protease 2, LAMP-2, angiotensinogen, NGAL and uromodulin) in the urine of an additional 30 patients showed that haptoglobin was the best predictor of early renal functional decline. We then measured this in the urine of 204 patients with type 2 diabetes who did not yet have significant kidney disease (eGFR stage 2 or better and an albumin to creatinine ratio less than 300 mg/g). In comparing the highest to lowest tertile, the odds ratio for having early renal function decline was 2.70 (CI 1.15, 6.32) using the haptoglobin to creatinine ratio compared to 2.50 (CI 1.14, 5.48) using the albumin to creatinine ratio after adjusting for treatment group and use of ACE inhibitors. Addition of the haptoglobin to creatinine ratio to a model using the albumin to creatinine ratio to predict early renal function decline resulted in improved predictive performance. Thus, the haptoglobin to creatinine ratio may be useful to predict patients with type 2 diabetes at risk of nephropathy prior to the development of macroalbuminuria or reduced GFR.

Intracellular polyamine pools are homeostatically maintained by processes involving biosynthesis, catabolism, and transport. Although most polyamine-based anticancer strategies target biosynthesis, we recently showed that activation of polyamine catabolism at the level of spermidine/spermine N 1 -acetyltransferase-1 (SSAT) suppresses tumor outgrowth in a mouse prostate cancer model. Herein, we examined the effects of differential SSAT expression on intestinal tumorigenesis in the Apc Min/+ (MIN) mouse. When MIN mice were crossed with SSAT-overproducing transgenic mice, they developed 3-and 6-fold more adenomas in the small intestine and colon, respectively, than normal MIN mice. Despite accumulation of the SSAT product, N 1 -acetylspermidine, spermidine and spermine pools were only slightly decreased due to a huge compensatory increase in polyamine biosynthetic enzyme activities that gave rise to enhanced metabolic flux. When MIN mice were crossed with SSAT knock-out mice, they developed 75% fewer adenomas in the small intestine, suggesting that under basal conditions, SSAT contributes significantly to the MIN phenotype. Despite the loss in catabolic capability, tumor spermidine and spermine pools failed to increase significantly due to a compensatory decrease in biosynthetic enzyme activity giving rise to a reduced metabolic flux. Loss of heterozygosity at the Apc locus was observed in tumors from both SSAT-transgenic and -deficient MIN mice, indicating that loss of heterozygosity remained the predominant oncogenic mechanism. Based on these data, we propose a model in which SSAT expression alters flux through the polyamine pathway giving rise to metabolic events that promote tumorigenesis. The finding that deletion of SSAT reduces tumorigenesis suggests that small-molecule inhibition of the enzyme may represent a nontoxic prevention and/or treatment strategy for gastrointestinal cancers. (Cancer Res 2005; 65(12): 5390-8)

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