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Aims/hypothesis: End-stage renal disease (ESRD) patients with diabetes have been regarded as being at the highest risk of cardiovascular disease. We therefore investigated the relationship between diabetes and the incidence of peripheral artery disease (PAD) in new haemodialysis patients. Methods: We enrolled 1,513 ESRD patients who had just begun haemodialysis therapy. They were divided into two groups: those with ( n = 739) and those without diabetes ( n = 774). The endpoint was the development of PAD, defined as ankle brachial pressure index ≤0.9 or toe brachial pressure index <0.7 in patients with an ankle brachial pressure index >0.9. Results: According to the Kaplan-Meier method, the 10 year event-free rate for development of PAD and lower limb amputation was significantly lower in the diabetes group than in the non-diabetes group (60.3% vs 82.8%, HR 2.99, 95% CI 2.27, 3.92, p < 0.0001 and 93.9% vs 98.9%, HR 5.59, 95% CI 2.14, 14.7, p = 0.0005 for PAD and lower limb amputation, respectively). In patients with diabetes, quartile analysis of HbA levels showed that the highest quartile group (≥6.8% [51 mmol/mol]) had significant development of PAD and lower limb amputation compared with lower quartile groups (PAD HR 1.63, 95% CI 1.17, 2.28, p = 0.0038; lower limb amputation HR 2.99, 95% CI 1.17, 7.70, p = 0.023). Conclusions/interpretation: Diabetes was a strong predictor of PAD after initiation of haemodialysis therapy in patients with ESRD. In addition, higher HbA levels were associated with increased risk of developing PAD and requiring limb amputation in such diabetic populations. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma (CC) is a highly malignant carcinoma. We attempted to clarify the prognostic significance of c-Met overexpression and its association with clinicopathological factors in patients with CC.Patients and Methods: One hundred and eleven patients with intrahepatic CC (IHCC) and 136 patients with extrahepatic CC (EHCC) who had undergone curative surgery were divided immunohistologically into c-Met(high) and c-Met(low) groups. Clinicopathological factors and outcomes were compared between the groups. c-Met and epidermal growth factor receptor (EGFR) expression was also examined in 10 CC cell lines.Results: The positivity of c-Met was 45.0% in IHCC and 68.4% in EHCC; c-Met(high) expression was demonstrated in 11.7% of IHCC and 16.2% of EHCC. c-Met(high) expression was significantly correlated with the 5-year survival rate for CC overall (P=0.0046) and for IHCC (P=0.0013), histopathological classification in EHCC, and for EGFR overexpression in both IHCC and EHCC. Coexpression and coactivation of c-Met and EGFR were also observed in CC cell lines. Multivariate analysis revealed that c-Met(high) expression was an independent predictor of poor overall and disease-free survival in patients with IHCC.Conclusions: c-Met overexpression is associated with EGFR expression and is a poor prognostic factor in CC. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses > or = 12.5 mg kg(-1) day(-1) (P<0.05), but higher doses (50 mg kg(-1) day(-1), P<0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg(-1) day(-1)) also significantly (P=0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) have been considered as potential therapeutic targets in cholangiocarcinoma, but no studies have yet clarified the clinicopathological or prognostic significance of these molecules. Immunohistochemical expression of these molecules was assessed retrospectively in 236 cases of cholangiocarcinoma, as well as associations between the expression of these molecules and clinicopathological factors or clinical outcome. The proportions of positive cases for EGFR, VEGF, and HER2 overexpression were 27.4, 53.8, and 0.9% in intrahepatic cholangiocarcinoma (IHCC), and 19.2, 59.2, and 8.5% in extrahepatic cholangiocarcinoma (EHCC), respectively. Clinicopathologically, EGFR overexpression was associated with macroscopic type (P=0.0120), lymph node metastasis (P=0.0006), tumour stage (P=0.0424), lymphatic vessel invasion (P=0.0371), and perineural invasion (P=0.0459) in EHCC, and VEGF overexpression with intrahepatic metastasis (P=0.0224) in IHCC. Multivariate analysis showed that EGFR expression was a significant prognostic factor (hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.52-4.69; P=0.0006) and also a risk factor for tumour recurrence (HR, 1.89; 95% CI, 1.05-3.39, P=0.0335) in IHCC. These results suggest that EGFR expression is associated with tumour progression and VEGF expression may be involved in haematogenic metastasis in cholangiocarcinoma. [ABSTRACT FROM AUTHOR]

Objective: The detrimental effect of positive airway pressure on right ventricular (RV) performance is controversial and the aim of this study was to determine the effects of constant positive airway pressure without ventilatory fluctuation on RV performance with the aid of a pulmonary arterial catheter equipped with a rapid response thermistor for measuring RV ejection fraction (RVEF) and RV end-diastolic volume index (RVEDVI).Design: A prospective, clinical study.Setting: The central operating theatre of a university hospital.Patients: Nine patients who had major surgery and required right heart catheterization for normal clinical management.Measurements and Results: Cold indicator was injected into the RV 4 or 5 times for each airway pressure (0, 10 or 20 cmH2O) which was maintained manually stable for 15 s, and 9 paired data were analyzed by repeated-measures analysis of variance. They are separated into two groups; RVEF at zero airway pressure greater (A group) or less (B group) than 0.4. In A group (7 patients), increasing airway pressures (0 vs 10 vs 20 cmH2O) did not affect RVEF (0.55 +/- 0.05 vs 0.54 +/- 0.06 vs 0.56 +/- 0.04), RVEDVI (69 +/- 36 vs 73 +/- 29 vs 58 +/- 20 ml.m-2), or stroke volume index (SVI: 38 +/- 18 vs 40 +/- 17 vs 33 +/- 13 ml.beat-1.m-2); however, in B (2 patients), RVEF (0.35 and 0.38 vs 0.31 and 0.28 vs 0.19 and 0.17) and SVI (35 and 28 vs 32 and 27 vs 27 and 23) decreased, while RVEDVI increased (99 and 73 vs 103 and 97 vs 146 and 132).Conclusions: In most patients, the changes in RVEF, SVI, and RVEDVI did not occur under constant positive airway pressure, therefore the changes reported in mechanically ventilated patients may not attributable to the extent of positive airway pressure but rather to abrupt increases in airway pressure. These appears, however, to be patients whose RV function is so disturbed that they cannot cope with increased afterloads. [ABSTRACT FROM AUTHOR]

The localization of mutarotase in rat kidney was investigated by fluorescein-labelled and peroxidase-labelled antibody techniques, and by method of isolation of the nuclei and cytoplasm in non-aqueous solvents. In these immunohistochemical studies, mutarotase was almost exclusively recognized in the nuclei of epithelial cells of renal tubules and glomeruli in rat. The specific activity of mutarotase was found to be 1.5 times higher in the nuclei (122 units/g dry wt) than that in the cytoplasm (80 units/g dry wt) isolated with non-aqueous solvents. These results suggest that mutarotase may be involved in the metabolism of D-glucose in nuclei. [ABSTRACT FROM AUTHOR]