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Consensus guidelines of the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology recommend first-degree relatives of individuals diagnosed with an adenoma before age 60 should be screened every 5 years with colonoscopy starting at age 40. This is the identical recommendation for those with a first-degree relative diagnosed with colorectal cancer (CRC) before age 60. There is good evidence that first-degree relatives of individuals diagnosed with CRC before age 60 are at substantially increased risk for developing cancer at a young age. However, it is unclear whether an individual with a first-degree relative with an adenoma diagnosed before age 60 is at increased risk of CRC. Because not all adenomas portend the same cancer risk in the individual who has the adenoma, they would not be expected to portend the same risk in their first-degree relatives. Because of these uncertainties, the US Preventive Services Task Force does not recommend more aggressive screening of first-degree relatives of individuals with an adenoma. The adenoma detection rate for individuals 50 to 59 years old without a first-degree relative with CRC is sufficiently high (approximately 25%-30%) that almost half the population would be high risk on the basis of one first-degree relative having an adenoma. Given the weakness of evidence supporting the guidelines, suboptimal levels of screening in the general population, and lack of resources to comply with the recommendation, first-degree relatives of individuals with adenomas should be screened as average-risk persons until more compelling data are available to justify more aggressive screening.

We used 2′,7′-bis(carboxyethyl)-5(6)-carboxyflourescein (BCECF), a pH-sensitive fluorescent dye, to study intracellular pH (pHi) regulation in neurons in CO2chemoreceptor and nonchemoreceptor regions in the pulmonate, terrestrial snail, Helix aspersa. We studied pHiduring hypercapnic acidosis, after ammonia prepulse, and during isohydric hypercapnia. In all treatment conditions, pHifell to similar levels in chemoreceptor and nonchemoreceptor regions. However, pHi recovery was consistently slower in chemoreceptor regions compared with nonchemoreceptor regions, and pHi recovery was slower in all regions when extracellular pH (pHe) was also reduced. We also studied the effect of amiloride and DIDS on pHi regulation during isohydric hypercapnia. An amiloride-sensitive mechanism was the dominant pHi regulatory process during acidosis. We conclude that pHe modulates and slows pHiregulation in chemoreceptor regions to a greater extent than in nonchemoreceptor regions by inhibiting an amiloride-sensitive Na+/H+ exchanger. Although the phylogenetic distance between vertebrates and invertebrates is large, similar results have been reported in CO2-sensitive regions within the rat brain stem.

The solution structures of the binuclear Mn centers in arginase, Mn catalase, and the Mn-substituted forms of the Fe enzymes ribonucleotide reductase and hemerythrin have been determined using X-ray absorption spectroscopy (XAS). X-ray absorption near edge structure (XANES) spectra for these proteins were compared to those obtained for Mn(II) models. The Mn model spectra show an inverse correlation between the XANES peak maximum and the root-mean-square (RMS) deviation in metal-ligand bond lengths. For these complexes, the XANES maxima appear to be more effective than the 1s --3d areas as an indicator of metal-site symmetry. Arginase and Mn-substituted ribonucleotide reductase have symmetric nearest neighbor environments with low RMS deviation in bond length, while Mn catalase and Mn-substituted hemerythrin appear to have a larger RMS bond length deviation. The 1s --3d areas for arginase and Mn-substituted ribonucleotide reductase are consistent with six coordinate Mn, while the 1s --3d areas for Mn catalase and Mn-substituted hemerythrin are larger, suggesting that one or both of the Mn ions are five-coordinate in these proteins. Extended x-ray absorption fine structure (EXAFS) spectra were used to determine the Mn2 core structure for the four proteins. In order to quantitate the number of histidine residues bound to the Mn2 centers, EXAFS data for the crystallographically characterized model hexakis-imidazole Mn(II) dichloride tetrahydrate were used to calibrate the Mn-imidazole multiple scattering interactions. These calibrated parameters allowed the outer shell EXAFS to be fit to give a lower limit on the number of bound histidine residues. The EXAFS spectra for Mn-substituted ribonucleotide reductase and arginase are nearly identical, with symmetric Mn-nearest neighbor environments and outer shell scattering consistent with a lower limit of one histidine per Mn2 core. In contrast, the EXAFS data for Mn catalase and Mn-substituted hemerythrin show two distinct Mn-nearest neighbor shells, modeled as Mn-O at ca. 2.1 A and Mn-N at ca. 2.3 A, and outer shell carbon scattering consistent with a lower limit of ca. 2-3 His residues per Mn2 core. Only Mn catalase shows clear evidence for Mn...Mn scattering. The observed Mn...Mn distance is 3.53 A, which is significantly longer than the approximately 3.3 A distances that are typically observed for Mn(II)2 cores with two single atom bridges, but which is typical of the distances seen in Mn(II)2 cores having one single atom bridge (e.g., aqua or hydroxo) together with one or two carboxylate bridges. The absence of EXAFS-detectable Mn...Mn interactions for the other three proteins suggests either that there are no single atom bridges in these cases or that the Mn...Mn interactions are more disordered.

Inflammatory bowel disease (IBD) refers to 2 chronic inflammatory diseases of the intestine, ie, ulcerative colitis and Crohn's disease. IBD results from environmental factors (eg, bacterial antigens) triggering a dysregulated immune response in genetically predisposed hosts. Although the basis of IBD is incompletely understood, a number of recent studies have implicated defective innate immune responses in the pathogenesis of IBD. In this regard, there is much interest in therapies that activate innate immunity (eg, recombinant granulocyte-macrophage colony-stimulating factor).In this study, we screened expression and function of circulating leukocyte granulocyte-macrophage colony-stimulating factor receptor (CD116) messenger RNA and surface protein in 52 IBD patients and 52 healthy controls.Our results show that both granulocyte and monocyte CD116 levels, but not CD114 or interleukin-3Rα, were significantly decreased in IBD compared to control (P.001) and disease controls (irritable bowel syndrome; P.001; rheumatoid arthritis; P.025). IBD-associated CD116 repression was more prominent in patients with ulcerative colitis compared to Crohn's disease (P.05), was independent of disease activity (P.05), and was not influenced by current medications (P.05). Receiver operating characteristic curve analysis revealed that leukocyte CD116 expression is a sensitive (85%) and specific (92%) biomarker for IBD. Moreover, granulocyte CD116-mediated function (phosphorylation of signal transducers and activators of transcription 3) paralleled decreased expression of CD116 in IBD granulocytes compared to control (P.001).These studies identify defective expression and function of CD116 as a distinguishing feature of IBD and implicate an associated defect in innate immune responses toward granulocyte-macrophage colony-stimulating factor.

Although haptoglobin polymorphism has been shown to be a genetic risk factor in coronary artery disease, its mechanisms of action are incompletely defined. Recently, a macrophage scavenger receptor for the uptake of haptoglobin-hemoglobin (Hp-Hb) complexes was cloned and designated CD163. Macrophage expression of CD163 is increased by glucocorticoids, IL-10 and IL-6. To better understand the in vivo response of CD163 to an inflammatory stimulus and glucocorticoid treatment, we studied 18 patients who underwent elective coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). We report a rapid increase in plasma levels of soluble CD163 by 1 h post-declamping the aorta during CABG surgery with CPB. Furthermore, we demonstrate significant increases in monocyte CD163 on post-operative day 1; 14-fold for patients pre-treated with methylprednisolone and 3-fold for those who did not receive exogenous glucocorticoids. These findings show CD163 to be rapidly mobilized in response to systemic inflammatory stimuli and to be affected significantly by glucocorticoids in vivo. The proposed role of CD163 as a Hp-Hb scavenger and anti-inflammatory molecule, in conjunction with the results of this study, make CD163 an intriguing target for potential manipulation of the acute response to inflammation.