BackgroundThere is a wide variation in susceptibility to health effects of arsenic, which, in part, may be due to differences in arsenic metabolism. Arsenic is metabolized by reduction and methylation reactions, catalyzed by reductases and methyltransferases.ObjectivesOur goal in this study was to elucidate the influence of various demographic and genetic factors on the metabolism of arsenic.MethodsWe studied 415 individuals from Hungary, Romania, and Slovakia by measuring arsenic metabolites in urine using liquid chromatography with hydride generation and inductively coupled plasma mass spectrometry (HPLC-HG-ICPMS). We performed genotyping of arsenic (+III) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), and methylene-tetrahydrofolate reductase (MTHFR).ResultsThe results show that the M287T (T→C) polymorphism in the AS3MT gene, the A222V (C→T) polymorphism in the MTHFR gene, body mass index, and sex are major factors that influence arsenic metabolism in this population, with a median of 8.0 μg/L arsenic in urine. Females < 60 years of age had, in general, higher methylation efficiency than males, indicating an influence of sex steroids. That might also explain the observed better methylation in overweight or obese women, compared with normal weight men. The influence of the M287T (T→C) polymorphism in the AS3MT gene on the methylation capacity was much more pronounced in men than in women.ConclusionsThe factors investigated explained almost 20% of the variation seen in the metabolism of arsenic among men and only around 4% of the variation among women. The rest of the variation is probably explained by other methyltransferases backing up the methylation of arsenic.

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Prostate cancer volume correlates with stage, grade, and progression after prostatectomy. When tumor volume is measured planimetrically, results are multiplied by a correction factor to compensate for tissue shrinkage caused by processing. Injection of formalin into prostatectomy specimens was suggested for improved fixation. Our aim was to investigate how this affects the prostate volume. We studied 142 radical prostatectomy specimens. All prostates were immersed in 10% formalin. In 84 prostates (59%) we also injected 20 ml of formalin before routine fixation. The prostates were weighed unfixed after injection and after final fixation. The specimens were sliced and totally embedded. The transverse diameters of the prostates were measured on unfixed specimens and microscopic sections. The average weight loss after final fixation was 5.8 and 8.6% for formalin-injected specimens and standard-fixed specimens, respectively (p<0.001). However, when total shrinkage was estimated from the transverse diameters, there was no difference related to fixation technique (p=0.59). The average linear shrinkage was 4.5%, corresponding to a volume correction factor of 1.15. We conclude that formalin injection for fixation of prostate tissue does not influence tumor volume calculation compared to conventional fixation.

Supplementary key words compound heterozygote • lipoprotein lipase • milk lipids • mammary gland • glycosylphosphatidylinositolanchored high density lipoprotein-binding protein 1 • endothelial cells LPL hydrolyzes triglycerides in plasma lipoproteins, making fatty acids available for use in cells ( 1,2 ). LPL also mediates the binding of lipoproteins to cell surfaces and receptors (3)(4)(5). Reduced LPL activity from mutations in LPL or its cofactor apolipoprotein CII lead to a striking accumulation of triglyceride-rich lipoproteins in the plasma (type I hyperlipoproteinemia) ( 6 ). Clinical symptoms and signs include abdominal pain with or without pancreatitis, eruptive xanthomas, and hepatosplenomegaly. Recently, mutations in the gene for apolipoprotein AV have been uncovered in some patients with unexplained chylomicronemia ( 7 ).LPL is synthesized primarily in parenchymal cells in skeletal muscle, heart, and adipose tissue ( 1, 2 ) but then fi nds its way into the lumen of capillaries, where it participates in the processing of the plasma lipoproteins. LPL is also synthesized in the mammary gland and appears in breast milk after parturition ( 8,9 ). Its function within the milk is unknown, but there is little doubt that LPL-mediated processing of lipoproteins within the capillaries of the mammary gland is important for providing the lipid nutrients to produce milk fat.Abstract We investigated a family from northern Sweden in which three of four siblings have congenital chylomicronemia. LPL activity and mass in pre-and postheparin plasma were low, and LPL release into plasma after heparin injection was delayed. LPL activity and mass in adipose tissue biopsies appeared normal. [ 35 S]Methionine incorporation studies on adipose tissue showed that newly synthesized LPL was normal in size and normally glycosylated. Breast milk from the affected female subjects contained normal to elevated LPL mass and activity levels. The milk had a lower than normal milk lipid content, and the fatty acid composition was compatible with the milk lipids being derived from de novo lipogenesis, rather than from the plasma lipoproteins. Given the delayed release of LPL into the plasma after heparin, we suspected that the chylomicronemia might be caused by mutations in GPIHBP1 . Indeed, all three affected siblings were compound heterozygotes for missense mutations involving highly conserved cysteines in the Ly6 domain of GPIHBP1 (C65S and C68G). The mutant GPIHBP1 proteins reached the surface of transfected Chinese hamster ovary cells but were defective in their ability to bind LPL (as judged by both cell-based and cell-free LPL binding assays). Thus, the conserved cysteines in the Ly6 domain are crucial for GPIHBP1 function.