Diabetic nephropathy ensues from events involving earliest changes in the glomeruli and podocytes, followed by accumulation of extracellular matrix in the mesangium. Postulated mechanisms include roles for vascular endothelial growth factor (VEGF), produced by podocytes and contributing to enhanced excretion of urinary albumin and recruitment/activation of inflammatory cells, and transforming growth factor-beta (TGF-beta), elicited largely from mesangial cells and driving production of extracellular matrix. RAGE, a receptor for advanced glycation endproducts (AGEs) and S100/calgranulins, displays enhanced expression in podocytes of genetically diabetic db/db mice by age 13 weeks. RAGE-bearing podocytes express high levels of VEGF by this time, in parallel with enhanced recruitment of mononuclear phagocytes to the glomeruli; events prevented by blockade of RAGE. By age 27 weeks, soluble RAGE-treated db/db mice displayed diminished albuminuria and glomerulosclerosis, and improved renal function. Diabetic homozygous RAGE null mice failed to develop significantly increased mesangial matrix expansion or thickening of the glomerular basement membrane. We propose that activation of RAGE contributes to expression of VEGF and enhanced attraction/activation of inflammatory cells in the diabetic glomerulus, thereby setting the stage for mesangial activation and TGF-beta production; processes which converge to cause albuminuria and glomerulosclerosis.

Methylglyoxal hydroimidazolones are quantitatively major AGEs of human lens proteins. These substantial modifications of lens proteins may stimulate further glycation, oxidation, and protein aggregation leading to the formation of cataract.

A study was conducted in northern Iran in areas of very high, high and moderately low incidence of oesophageal cancer. Morphine metabolites in urine as an indicator of opium use, and a variety of nutritional and biochemical measures, including salivary antipyrine half-life, were determined in households with a case of oesophageal cancer and in control households. Results on 1,590 individuals showed that the prevalence of appreciable levels (greater than or equal to 1 microgram/ml) of urinary morphine metabolites was much higher in areas of high and very high incidence of oesophageal cancer than in low-incidence areas, particularly for those under age 50 years in both sexes, where a 6-fold difference was seen. Members of households with a case of oesophageal cancer had a higher prevalence of positive urinary morphine metabolite findings than members of control households from the same village. Salivary anti-pyrine half-life (AP-T1/2), as a measure of hepatic drug metabolizing capacity, was estimated in 120 subjects. No relationship was seen with use of opium, region of residence, case-control status of household, age or sex. Experimental studies have meanwhile identified mutagenic substances with carcinogenic potential in opium pipe scrapings, used widely in the study region, opium pyrolysates and morphine pyrolysates. Our data give additional support to the hypothesis that opium use, in the form of its pyrolysates, is one of the factors involved in the aetiology of oesophageal cancer in the region.

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