Increased plasma and joint tissue adrenomedullin concentrations in patients with rheumatoid arthritis compared to those with osteoarthritis

OBJECTIVE: To elucidate the pathophysiological role of adrenomedullin (AM) in rheumatoid arthritis (RA), plasma AM concentration was measured in patients with RA and in healthy contols. The concentration of AM in joint fluid, synovial tissue, and articular cartilage of patients with RA and osteoarthritis (OA) were measured and compared. METHODS: Twenty-six patients with RA (aged 62 +/- 4 yrs, all female), 10 healthy controls (aged 57 +/- 5 yrs, all female), and 10 patients with OA (aged 68 +/- 8 yrs, all female) were studied. We measured plasma levels of total and mature AM by immunoradiometric assay and levels of AM in joint tissue by radioimmunoassay. RESULTS: Plasma levels of AM in patients with RA (18.35 +/- 6.9 fmol/ml) were found to exceed those in healthy controls (11.64 +/- 2.8 fmol/ml). Moreover, plasma AM showed a significant positive correlation with plasma C-reactive protein (CRP). The correlation coefficient of total AM was 0.685, and that of mature AM was 0.624. Similarly, AM levels in synovium and joint fluid in patients with RA were significantly higher than in OA. In contrast, AM levels in articular cartilage were found to be low, with no significant difference in levels between patients with RA and OA. CONCLUSION: The relation between plasma AM levels and plasma CRP in patients with RA suggests that plasma AM levels increase with the activity of RA. Moreover, AM levels in synovium and joint fluid of patients with RA were significantly higher than those of patients with OA. Thus, AM probably plays a part in the regulation of the inflammatory process of RA.     

Familial hypercholesterolemia and apolipoprotein E4

The purpose of this study was to elucidate the relationship between two genetic factors associated with raised blood cholesterol, i.e. familial hypercholesterolemia (FH) and apolipoprotein (apo) E4. A group of 50 unrelated heterozygous FH patients aged 33-71 years were studied together with 129 normolipidemic subjects. A significantly higher frequency of apo E4 phenotypes was found in FH patients (30.0%) than in normolipidemic subjects (15.5%). FH patients were divided into two groups with and without apo E4. Plasma total cholesterol (Chol) and triglyceride (TG) levels were significantly higher, and plasma low density lipoprotein-cholesterol (LDL-Chol) level tended to be higher in FH patients with apo E4 than in those without apo E4. In addition, the prevalence of ischemic heart disease (IHD) was significantly higher in FH patients with apo E4 (73.3%) than in those without apo E4 (31.4%). No significant difference was noted in age and in the prevalence of obesity, diabetes, hypertension and smoking between the FH groups with and without apo E4. These results suggest that apo E4 is associated with higher levels of total Chol and TG and, at least in part, contributes to the predisposition to IHD in FH.     

UICC and Japanese stage classifications for carcinoma of the pancreas

The stage classification (SC) for carcinoma of the pancreas recommended by UICC (UICC-SC) was compared with that of Japan Pancreas Society (JPN-SC) using 229 patients encountered consecutively at the Second Department of Surgery, Nagasaki University School of Medicine over the past 20 yr. By UICC-SC, 51% of the patients belonged to stage IV and 38% to Stage III. By JPN-SC, 82% of the patients belonged to stage IV. Curative resection rates in JPN stage II and III were significantly higher than those in UICC-SC by the chi-squared test. In 60 patients undergoing resectional surgery, postoperative cumulative survival (PCS) curves and rates by each staging criterion (tumor size [T], lymph node metastasis [N], distant metastasis [M], serosal invasion [S], retroperitoneal invasion [Rp], and invasion to the portal venous systems [V]) were calculated by the Kaplan-Meier method. Among these prognostic factors, significant differences in the PCS curves were demonstrated only between Rp(-) and Rp(+), and between V(-) and V(+) according to the generalized Wilcoxon's text. In UICC-SC, the underestimation of these factors leads to a tendency to classify the patients in a less advanced stage than in JPN-SC. JPN-SC is more complex than UICC-SC. Continuing efforts are necessary to establish a more practical, simple, and universal staging system for the disease.     

Patient-specific radiotherapy quality assurance for estimating actual treatment dose

This study aimed to evaluate the optimal method for planning computed tomography (CT) for prostate cancer radiotherapy to avoid a dose difference of ≥3% between the actual and planned treatments using multiple acquisition planning CT (MPCT). We calculated the 3-dimensional (3D) displacement error between the pelvic bone and matching fiducial marker on MPCT and cone-beam CT scans of 25 patients who underwent prostate volumetric-modulated arc therapy for prostate cancer. The correlation of the 3D displacement error and the dose difference between planned and actual treatments was calculated using least squares second-order polynomial model. The 3D displacement error showed a moderate correlation with differences between planned and accumulated treatment doses (r = 0.587, p < 0.0001). Moreover, the improvement rate of the minimum 3D displacement error showed a strong correlation with the relative error between each MPCT image (r = 0.793, p < 0.0001). Significant differences were observed between planned and actual treatment doses (p < 0.0001) in the relative 3D displacement errors of <1 mm, 1 to 3 mm, and >3 mm. The 3D displacement error on MPCT (as the selection estimation index for optimal planning CT) is useful for monitoring patient-specific intensity-modulated radiation therapy quality assurance. This new method allows to estimate dose differences from the planned dose before commencing treatment, thereby ensuring high-quality therapy. As radiotherapy quality is critical for patient outcome, these findings may contribute to better management of prostate cancer.     

Use of the conjugate of disulphated ursodeoxycholic acid with p-aminobenzoic acid for the detection of intestinal bacteria.

The disulphate ester of ursodeoxycholyl-p-aminobenzoic acid (PABA-UCDA) was synthesised and compared with PABA-UDCA for its use in detection of intestinal bacteria. This compound, PABA-UDCA disulphate, had characters in common with PABA-UDCA in that it was deconjugated by cholylglycine hydrolase to release free PABA and bacteria that split glycocholic acid deconjugated PABA-UDCA disulphate. Further, in rat experiments urinary excretions of PABA were measured for six hours after oral administration of 15 mg PABA-UDCA disulphate. Ten control rats excreted (mean (SE) 188.2 (13.6) micrograms of PABA; 10 rats with an intestinal stagnant loop excreted more (530.1 (30.1) micrograms; p < 0.001): whereas 10 rats in each of three groups pretreated by oral administration of various antibiotics excreted less (polymixin B+tinidazole, 4.9 (1.6) micrograms; kanamycin, 31.0 (4.7) micrograms; clindamycin 40.9 (5.5) micrograms; p < 0.001). By contrast with PABA-UDCA, PABA-UDCA disulphate was not actively absorbed from any part of the small intestine in everted gut sac experiments, and showed poor recovery from bile after its intraileal instillation in rats. This indicated that PABA-UDCA disulphate is a single pass type substance in the gut and its oral administration test reflects the sum of the activities of bacteria in the small intestine and colon. The disulphate was easily soluble in water and this allowed its application in an in vitro test involving PABA-UDCA disulphate incubation with intraperitoneal pus (PABA-UDCA disulphate incubation test) from patients with peritonitis. This test was carried out on six patients with peritonitis, and the severity of bacterial peritonitis was expressed quantitatively. From the results obtained PABA-UDCA disulphate was considered a good material to detect intestinal bacteria.     

Relationship between serum IgA/C3 ratio and progression of IgA nephropathy

OBJECTIVE: The serum IgA/C3 ratio might be considered to serve as a diagnostic marker for patients with IgA nephropathy (IgAN), but its value as a marker of the severity of histological lesions or prognosis is unknown. METHODS: We studied the serum IgA/C3 ratio, using standardized reference material, in 86 patients with IgAN and in 32 with non-IgAN. The patients with IgAN were divided according to the severity of histological lesions (mild IgAN, n=29 and severe IgAN, n=57) based on Japanese clinical guidelines. RESULTS: The serum IgA level was significantly higher, while its C3 level was lower in patients with severe IgAN compared to those with non-IgAN. However, these levels were not different between patients with mild IgAN and non-IgAN. In contrast, the serum IgA/C3 ratio obviously differed among the three groups (2.47+/-0.96 vs. 3.63+/-1.44 vs. 4.72+/-1.86; p<0.01, ANOVA). Kaplan-Meier analysis of the patients with IgAN classified according to the mean serum IgA/C3 ratio revealed that the group with high serum IgA/C3 (4.5 and above) had a significantly poorer renal outcome (p<0.05, log-rank test), since the cumulative renal survival rate at 5 years was 84.4% vs. 100%. The ratio (%) of patients with severe IgAN in whom hematuria disappeared, was significantly higher in the low, than in the high serum IgA/C3 group (41.9% vs. 15.4%; p<0.05, t-test). CONCLUSION: The serum IgA/C3 ratio appears to reflect the histological severity of IgAN and could serve as a marker of the progression of IgAN.     

Antifibrotic effect of adrenomedullin on coronary adventitia in angiotensin II-induced hypertensive rats

OBJECTIVE: The extracellular matrix (ECM) determines the structural integrity of the heart and vasculature, participating in cardiovascular remodeling. We previously reported that adrenomedullin (AM) inhibited cellular proliferation and protein synthesis of cardiac fibroblasts; however, the precise mechanisms of AM actions as an antifibrotic factor remain unknown. The purpose of this study was to examine the biological actions of AM against the profibrotic factor angiotensin II (Ang II) in coronary adventitia. METHODS AND RESULTS: Rats with hypertension induced by Ang II infusion were administered 0.06 mug/kg/min recombinant human AM subcutaneously for 14 days. The AM infusion significantly (p<0.05) reduced the Ang II-induced increase of coronary adventitial fibroblasts expressing Ki-67 and alpha-smooth muscle actin (alpha-SMA) in the left ventricle, by 65%, and 62%, respectively, without affecting systolic blood pressure, left ventricle/body weight, or cross-sectional area of myocardial fibers. Collagen deposition of coronary arteries was reduced by the AM infusion (-24%, p<0.01), and these effects of AM were accompanied by significant reductions in gene expression of type 1 collagen (-49%, p<0.05) and transforming growth factor-beta1 (TGF-beta1) (-55%, p<0.01). In cultured cardiac fibroblasts, 10(-7) mol/L AM exerted an inhibitory effect on TGF-beta1-induced alpha-SMA expression (p<0.01) that was mimicked by 8-bromo-cAMP and attenuated by the protein kinase A inhibitor H-89. CONCLUSION: AM decreased Ang II-induced collagen deposition surrounding the coronary arteries, inhibiting myofibroblast differentiation and expressions of ECM-related genes in rats. The present findings further support the biological action of AM as an antifibrotic factor in vascular remodeling.