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The prevalence of organic colonic diseases in patients who met the Rome III criteria was at an acceptably low level, indicating that the Rome III criteria are adequately specific for the diagnosis of IBS without performing a colonoscopy examination.

The Soluble Insulin Receptor Study Group* OBJECTIVE-Insulin binds to the ␣-subunit of the insulin receptor (IR␣) and subsequently exerts its effects in the cells. The soluble ectodomains of several receptors have been found to circulate in the plasma. Therefore, we hypothesized that soluble human insulin receptor (hIR) ectodomain (␣-subunit and a part of ␤-subunit) may exist in the plasma of diabetic patients. RESEARCH DESIGN AND METHODS-We identified soluble hIR ectodomain in human plasma by a two-step purification followed by immunoblotting and gel-filtration chromatography. Furthermore, we established an hIR␣-specific enzyme-linked immunosorbent assay and measured the plasma IR␣ levels in patients with diabetes. We also investigated this phenomenon in streptozotocin-induced diabetic hIR transgenic mice.RESULTS-Soluble hIR␣, but not intact hIR␤ or whole hIR, exists in human plasma. The plasma IR␣ levels were significantly higher in type 1 (2.00 Ϯ 0.60 ng/ml; n ϭ 53) and type 2 (2.26 Ϯ 0.80; n ϭ 473) diabetic patients than in control subjects (1.59 Ϯ 0.40 ng/ml; n ϭ 123 (P Ͻ 0.001 vs. control). Plasma IR␣ level was positively correlated with blood glucose level, and 10 -20% of the insulin in plasma bound to hIR␣. In the in vivo experiments using diabetic hIR transgenic mice, hyperglycemia was confirmed to increase the plasma hIR␣ level and the half-life estimated to be ϳ6 h. sponded to the insulin receptor (IR) in healthy human plasma. Furthermore, the IR ␣-subunit (IR␣) and IR ␤-subunit (IR␤) were found to be secreted into the incubation medium by various cultured cell lines (6), and IR shedding from cultured human lymphocytes has been reported (7). Thus, the existence of soluble IR in human serum has been suspected. However, no detailed clinical investigation has yet been carried out. We previously reported that an injection of purified human insulin receptor (hIR) ␣-subunit (hIR␣) increased the blood glucose level in mice (8). Furthermore, transgenic mice secreting soluble IR␣ into the plasma showed chronic hyperglycemia (9). Here, we established novel enzyme-linked immunosorbent assay (ELISA) systems to measure both the ectodomain (␣-subunit and a part of ␤-subunit) of IR and full length of IR. With these ELISA systems, we report that soluble hIR␣ with parts of extracellular region of hIR␤, but not as a whole IR or with intact hIR␤, is present in human plasma and that its plasma level is elevated in patients with elevated blood glucose. The ectodomain of IR may be cleaved, at least in part, by hyperglycemic state-associated mechanisms. CONCLUSIONS-We RESEARCH DESIGN AND METHODSInsulin receptor sandwich ELISA systems. We developed two kinds of ELISA systems to specifically measure hIR␣ and full-length IR, respectively (details available in an online appendix at http://dx.doi.org/10.2337/db07-0394). Study subjects. Healthy Japanese volunteers with no diabetic history or familial diabetic history (in relatives within the third degree) residing in the Tokushima district (n ϭ 123) and confirmed to have normal gl...

Thymidine phosphorylase (dThdPase)/platelet-derived endothelial cell growth factor, is expressed at higher levels in tumor tissues compared to the adjacent normal tissues in a variety of human carcinomas. The higher expression is associated with an increase of intratumoral microvessel density (IMVD) and an unfavorable patient prognosis. We examined the role of dThdPase in apoptosis, IMVD, P53 expression and patient prognosis of human stages II and III esophageal squamous cell carcinomas (SCC). dThdPase expression was noted in 52 of the 78 esophageal SCC (66.7%), regardless of tumor stages and histologic grades. Mean IMVD was 117.9 +/- 32.6 in the dThdPase-positive cases and 103.1 +/- 21.5 in the dThdPase-negative cases, the value being significantly higher in the former (P < 0.05). Similarly, median (range) apoptotic index (AI: percentage of apoptotic cells) was significantly lower in the dThdPase-positive SCC, 1.8 (0.4-6.5), than in the dThdPase-negative SCC, 3.7 (0.6-7.0) (P < 0.01). AI and IMVD showed a significant inverse correlation (r = - 0.31, P = 0.005). There was also no significant difference in the frequency of P53 expression between the dThdPase-positive SCC and the negative SCC. No statistical difference was noted regarding the postoperative survival rate between the dThdPase-positive and the negative SCC. Although dThdPase expression was not associated with patient prognosis, the expression provided an advantage for tumor growth of human esophageal SCC, not only by increasing the intratumoral microvessels, but also attenuation of apoptosis, which might occur via a p53 gene-independent pathway.

The FHIT gene, encompassing the FRA3B fragile site at chromosome 3p14.2, is a candidate tumor suppressor gene involved in multiple tumors, including esophageal carcinoma. We analyzed Fhit expression using an immunohistochemical method in invasive carcinoma, carcinoma in situ (CIS) and dysplasia, in paraffin sections of 75 esophageal squamous cell carcinomas (ESCs) to further elucidate the role of Fhit protein in esophageal carcinogenesis. In addition, we also examined whether Fhit expression correlated with p53 expression and apoptosis. Compared to adjacent normal mucosa, significant loss or reduction of Fhit expression was noted in 67 of 75 (89.3%) invasive ESCs, in 13 of 19 (68.4%) CIS lesions, and in 10 of 23 (43.5%) dysplastic lesions. There was a progressive loss or reduction of Fhit expression with progressive increases in the severity of histopathological changes (p < 0.001). However, there was no association between Fhit expression and clinicopathological findings, including tumor stage, lymph node metastasis, or overall survival. Moreover, Fhit expression was not significantly associated with p53 expression and apoptosis. These results indicate that abnormal Fhit expression is a common event in the early stage of ESC development and may occur independently of p53 expression and apoptosis mechanisms.