Three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia induced vascular damage (the hexosamine pathway, the advanced glycation end product (AGE) formation pathway and the diacylglycerol (DAG)-protein kinase C (PKC) pathway) are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. We have discovered that the lipid-soluble thiamine derivative benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-kappaB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-kappaB activation by activating transketolase, and also prevented experimental diabetic retinopathy. The ability of benfotiamine to inhibit three major pathways simultaneously might be clinically useful in preventing the development and progression of diabetic complications.

Since approximately 30% of the colorectal carcinoma patients that score negative in immunocytology staining of bone marrow samples have been reported to relapse, earlier diagnosis of the presence of malignant cells is needed. Our result that samples scoring positive in the described CEA-specific PCR test remained negative by two immunostaining methods suggests a higher sensitivity. We conclude that PCR amplification of CEA mRNA may lead to an earlier diagnosis of micrometastatic bone disease in patients with CEA-expressing carcinomas.

Biliary glycoprotein (BGP) is the human homologue of a cell adhesion molecule (CAM) of the rat designated Cell-CAM. The BGP gene is a member of the carcinoembryonic antigen gene family, which belongs to the immunoglobulin superfamily. BGP is expressed in cells of epithelial and myeloid origin. In granulocytes, BGP is a main antigen of the CD66 cluster of differentiation antigens that mediate the binding to endothelial E-selectin. Since BGP is a major human

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To examine intraocular concentrations of monocyte chemoattractant protein 1 (MCP-1), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and vascular endothelial growth factor (VEGF) in eyes with exudative age-related macular degeneration (AMD). Methods:The investigation included a study group of 28 patients (28 eyes) with exudative AMD and a control group of 25 patients (25 eyes) with cataract. The concentrations of MCP-1, sICAM-1, sVCAM-1, and VEGF in aqueous humor samples obtained during surgery were measured using a solid-phase chemiluminescence immunoassay. Results: The study group as compared with the control group had higher aqueous concentrations of sICAM-1 (mean [SD], 844 [2073] vs 246 [206] pg/mL, respectively; PϽ.001), sVCAM-1 (mean [SD], 7978 [7120] vs 2999 [1426] pg/mL, respectively; PϽ.001), and MCP-1 (mean [SD], 587 [338] vs 435 [221] pg/mL, respectively; P=.07). The concentration of VEGF did not vary significantly between the groups (P=.76). The MCP-1 concentration was significantly associated with macular thickness (r=0.40; P=.004). It decreased significantly with the type of subfoveal neovascular membrane (classic membrane type, occult membrane, retinal pigment epithelium detachment) (P=.009). The concentrations of sICAM-1, sVCAM-1, and VEGF were not significantly associated with membrane type and macular thickness (PՆ.18). Conclusions: Concentrations of MCP-1, sICAM-1, and sVCAM-1 are significantly associated with exudative AMD, even in the presence of normal VEGF concentrations. Intraocular MCP-1 concentrations are correlated with the subfoveal neovascular membrane type and the amount of macular edema. One may infer that MCP-1, sICAM-1, and sVCAM-1 could potentially be additional target molecules in therapy for exudative AMD.

CD66a, also called biliary glycoprotein (BGP), is a member of the carcinoembryonic antigen (CEA) family and of the immunoglobulin superfamily. CD66a is the human homologue of Cell-CAM, a well-defined cell adhesion molecule of the rat. In the present study a monoclonal antibody specific for CD66a was used to locate CD66a in human tissues. CD66a is expressed in epithelia, in certain endothelia, and in cells of the myeloid lineage. Hepatocytes were stained along the bile canaliculi. A characteristic apical membranous staining was observed in enterocytes, superficial absorptive cells of the colon, in the epithelia of esophageal and Brunner's glands, bile ducts and gallbladder, pancreatic ducts, proximal tubules of the kidney, prostate, endometrium, and mammary ducts. Selective staining of endothelia was present in glomeruli and vasa recta of the kidney, small placental vessels, adrenal sinusoids, endometrium, the prostate. Among the cells of the myeloid lineage, granulocytes and myelocytes were positive. The expression of CD66a by human cells and tissues is well comparable with the expression reported for Cell-CAM, the rat counterpart of CD66a. The wide tissue distribution of CD66a indicates that CD66a is a prominent human adhesion molecule.

OBJECTIVE-Carnosinase 1 (CN1) is a secreted dipeptidase that hydrolyzes L-carnosine. Recently, we have identified an allelic variant of human CN1 (hCN1) that results in increased enzyme activity and is associated with susceptibility for diabetic nephropathy in human diabetic patients. We therefore hypothesized that L-carnosine in the serum represents a critical protective factor in diabetic patients. RESEARCH DESIGN AND METHODS-L-carnosine serum levels were manipulated in db/db mice, a model of type 2 diabetes. In a transgenic approach, hCN1 cDNA was expressed under the control of a liver-specific promoter in db/db mice, mimicking the expression pattern of hCN1 in humans. RESULTS-Fasting plasma glucose as well as A1C levels rose significantly earlier and remained higher in transgenic animals throughout life. Body weights were reduced as a result of significant glucosuria. In an opposite approach, nontransgenic db/db mice were supplemented with L-carnosine. In these latter mice, diabetes manifested significantly later and milder. In agreement with the above data, serum fasting insulin levels were low in the transgenic mice and elevated by L-carnosine feeding. Insulin resistance and insulin secretion were not significantly affected by L-carnosine serum levels. Instead, a significant correlation of L-carnosine levels with ␤-cell mass was observed. CONCLUSIONS-hCN1-dependent susceptibility to diabetic nephropathy may at least in part be mediated by altered glucose metabolism in type 2 diabetic patients. Diabetes 56:2425-2432, 2007 P atients with type 2 diabetes often suffer serious complications of chronic hyperglycemia, including nephropathy, neuropathy, retinopathy, and accelerated development of cardiovascular disease. The prevalence of type 2 diabetes worldwide is 6% and projected to rise over the next decade, owing to the increasing age of the population and the surge of obesity (1). There is evidence of a genetic component in the risk for type 2 diabetes, including prevalence differences between racial groups and higher concordance rates among monozygotic than dizygotic twins (2). There is also evidence for a genetic component to the risk of diabetic nephropathy (3,4).Our group is interested in identifying variants of genes that modify the risk for diabetes complications, such as diabetic nephropathy. Recently, an association of diabetic nephropathy and an allelic variant within the leader peptide of carnosine dipeptidase 1 (carnosinase 1 [CN1]), which affected the efficiency of enzyme secretion, was identified and subsequently confirmed (5,6). CN1 is a dipeptidase that hydrolyzes L-carnosine (␤-alanyl-L-histidine) and to a lesser extent homocarnosine (7). The variant with the smallest number of leucine repeats was more common in the absence of diabetic nephropathy and was associated with lower CN1 serum levels. Leader peptide variants containing more than five leucine repeats were associated with an increased risk for diabetic nephropathy. From these genetic data in human patients, it was hypothesized that L-...

Numerous cytokines are associated with the presence and the amount of diabetic macular edema. Among these cytokines, ICAM-1 was the most significantly associated with the disease parameters.