Increased serum soluble CD147 levels in patients with systemic sclerosis: association with scleroderma renal crisis

CD147 is a glycosylated membrane protein that belongs to the immunoglobulin superfamily. This study aimed to determine serum soluble CD147 (sCD147) levels and their clinical associations in patients with systemic sclerosis (SSc). Serum sCD147 levels were examined by enzyme-linked immunosorbent assay in 61 SSc patients and 24 healthy individuals. Serum sCD147 levels were significantly elevated in SSc patients compared with healthy individuals (P < 0.001). Among patients with SSc, there were no differences in serum sCD147 levels between limited cutaneous (n = 30) and diffuse cutaneous SSc (n = 31). Patients with SSc who had elevated sCD147 levels had renal crisis more often than those with normal sCD147 levels (13% vs 0%; P < 0.05). Serum sCD147 levels were increased in patients with SSc and associated with the presence of renal crisis. These results suggest that sCD147 may have a role in the development of renal crisis in SSc. Measurement of serum sCD147 may be useful for risk stratification for renal crisis in SSc.     

Age-related production of osteoclasts and the changes of serum levels of vascular endothelial growth factor (VEGF) and receptor activator for nuclear factor (NF)-κB ligand (RANKL) in osteopetrotic (op/op) mice

ObjectiveExpression of osteoclasts in osteopetrotic (op/op) mice is substantially reduced by the absence of functional macrophage colony-stimulating factor (M-CSF). However, it has been reported that osteoclasts do gradually appear in the bones of op/op mice and spontaneously correct the osteopetrosis.DesignAge-related production of osteoclasts and the changes of serum levels of vascular endothelial growth factor (VEGF) and receptor activator for nuclear factor (NF)-κB ligand (RANKL) in op/op mice were examined.ResultsThe number of femoral osteoclasts, and the serum levels of VEGF, both gradually increased in op/op mice after birth and reached a peak in 120- and 60-day-old mice, respectively. However, the serum levels of RANKL showed an inverse relationship to osteoclast number.ConclusionsThese findings suggest that the appearance of osteoclasts may be influenced by the serum levels of VEGF and that the serum levels of RANKL may be influenced by the appearance of osteoclasts.     

Oral administration of itraconazole solution has superior efficacy in experimental oral and oesophageal candidiasis in mice than its intragastric administration

OBJECTIVE: The therapeutic activities of cyclodextrin-associated itraconazole oral solution (itraconazole OS) by two administration routes in experimental oral and oesophageal candidiasis in mice were examined and compared. METHODS: Using experimental oral and oesophageal candidiasis models in ICR mice, we investigated the efficacy of oral and intragastric administration of itraconazole OS and checked the concentration of itraconazole and its metabolite hydroxyitraconazole (OH-itraconazole) in tongues or oesophagus tissue after administration of itraconazole OS. RESULTS: Oral administration of itraconazole OS at doses of 0.8, 4.0 or 20 mg/kg/day clearly decreased the number of viable Candida albicans cells in the oral cavity of mice with oral candidiasis in a dose-dependent manner at 3 days after infection. Intragastric administration of itraconazole OS at doses of 4 and 20 mg/kg/day once a day were also effective but to a lesser degree than that of oral administration. In the oesophageal candidiasis model, oral administration of itraconazole OS displayed superior therapeutic efficacy to the intragastric route. In coincidence with the greater efficacy, itraconazole was detected in lesional tissues after oral administration of itraconazole OS. CONCLUSIONS: Oral administration of itraconazole OS displayed therapeutic efficacy against murine oral and oesophageal candidiasis superior to that achieved by intragastric administration. This can be explained by there being higher concentrations of itraconazole in tongues or oesophagus tissues after administration of the suspension by the oral route.     

A prospective study on the prognostic significance of urokinase-type plasminogen activator levels in breast cancer tissue

Urokinase-type plasminogen activator (u-PA), which cleaves plasminogen to yield plasmin, is a serine protease of fibrinolysis and is presumed to play a key role in extracellular proteolysis and facilitate the migration of cancer cells. This study was conducted prospectively to evaluate the prognostic significance of u-PA antigen level in breast cancer tissues. u-PA concentrations in the cytosol of 226 breast cancer tissues were determined prospectively by enzyme-linked immunosorbent assay using cytosol fractions prepared for steroid hormone assay. The median follow-up period of the patients was 60 months. Various prognostic factors were evaluated by univariate analysis or multivariate analysis using the Cox proportional-hazards method. Patients with primary breast cancer containing high levels of u-PA had a significantly shorter disease-free survival than patients with low levels of u-PA antigens. In multivariate analysis, a high level of u-PA was an independent risk factor for disease-free survival, being independent of age, axillary node status, and estrogen receptor status. Among the major prognostic factors, a high u-PA antigen level, lymph node involvement, and a positive estrogen receptor status were the most important for predicting relapse-free survival (P=0.044, P<0.0001, P=0.0039). This first prospective study confirmed the prognostic significance of the u-PA antigen level in association with other major prognostic factors. The results of our present study suggest that u-PA in breast cancer tissue might be involved in breast cancer invasion and metastasis. Received: 20 November 1996 / Accepted: 9 June 1997     

Circulating advanced glycation end products (AGEs) and soluble form of receptor for AGEs (sRAGE) are independent determinants of serum monocyte chemoattractant protein-1 (MCP-1) levels in patients with type 2 diabetes

BACKGROUND: Atherosclerosis is an inflammatory disease. Monocyte chemoattractant protein-1 (MCP-1) is an essential chemokine responsible for the recruitment of monocytes to inflammatory lesions in the vasculature, an initial step of atherosclerosis. Since serum levels of MCP-1 are higher in patients with type 2 diabetes, inhibition of MCP-1 may be a novel therapeutic target for prevention of accelerated atherosclerosis in diabetes. However, little is known about the regulation and determinants of serum MCP-1 levels in patients with diabetes. In this study, we examined the determinants of serum MCP-1 levels in type 2 diabetic patients. METHODS: Eighty-six consecutive outpatients with type 2 diabetes (36 male and 50 female; mean age 68.4+/-9.6) underwent a complete history and physical examination, determination of blood chemistries, MCP-1, tumour necrosis factor-alpha, adiponectin, advanced glycation end products (AGEs), and soluble form of receptor for AGEs (sRAGE). We examined the association between MCP-1 levels and those in anthropometric, metabolic and inflammatory variables in these subjects. RESULTS: Univariate regression analysis showed that serum levels of MCP-1 were positively associated with AGEs (r=0.386, p<0.001) and sRAGE (r=0.315, p<0.001). After adjusting for age and sex, AGEs (p<0.001) and sRAGE (p<0.05) still remained significant. CONCLUSION: The results demonstrate for the first time that circulating levels of AGEs and sRAGE are independent determinants of serum MCP-1 levels in patients with type 2 diabetes. Our present observations suggest the AGEs-RAGE system may be mainly involved in the elevation of MCP-1 in type 2 diabetic patients.     

Safety,reliability, and operability of cochlear implant electrode arrays coated with biocompatible polymer

Conclusion: Polymer-coated electrodes can reduce surgically-induced trauma associated with the insertion of a cochlear implant (CI) electrode array. Objectives: To evaluate if insertion trauma in CI surgery can be reduced by using electrode arrays coated with 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer. Methods: We analyzed characteristics of the Contour Advance® electrode arrays coated with MPC polymer. To assess surgical trauma during electrode insertion, polymer-coated or uncoated (n = 5 each) animal electrode arrays were implanted in guinea pig cochleae and operability and electrophysiological and histological changes were assessed. Results: Under light and scanning electron microscopy, polymer-coated electrodes did not appear different from uncoated electrodes, and no change was observed after mechanical stressing of the arrays. Electrode insertion was significantly easier when polymer-coated electrodes were used. Auditory brainstem response (ABR) thresholds did not differ between groups, but p1-n1 amplitudes of the coated group were larger compared with the uncoated group at 32 kHz at 28 days after surgery. The survival of outer hair cells and spiral ganglion cells was significantly greater in the polymer-coated group.     

Insulin resistance and angiographical characteristics of coronary atherosclerosis.

Insulin resistance (IR) is frequently observed in patients with coronary heart disease (CHD). The relationship between IR and the angiographical characteristics of coronary atherosclerosis were investigated in 66 patients with coronary artery lesions. Insulin resistance was assessed by a 75-g oral glucose tolerance test and homeostasis model assessment (HOMA). The angiographical characteristics of coronary atherosclerosis (i.e., the severity of CHD) were defined by both Gensini's score (GS) (a higher degree of coronary artery stenosis or a proximal lesion was assigned a higher score than a distal lesion) and the number of significantly stenosed vessels. When GS was examined as a categorical variable classified by tertile values (Group A, n = 22: 1< or =GS< or =14; Group B, n = 22: 15< or =GS< or =32; and Group C, n = 22: 33< or =GS), patients with a high GS (Group C) had significantly (p<0.05) higher values of fasting plasma insulin, insulin response, and HOMA IR than patients with a low GS (Group A) (12.6+/-1.2 microU/ml vs. 6.9+/-1.2 microU/ml, 122.2+/-11.9 microU ml(-1) h(-1) vs. 72.9+/-12.9 microU ml(-1) h(-1), and 2.9+/-0.3 vs. 1.5+/-0.3, respectively).The values in Group B patients (9.4+/-1.2,microU/mI, 108.5+/-12.5 microU ml(-1) h(-1), and 2.1+/-0.3, respectively) were intermediate between those in Groups A and C. The area of insulin/area of glucose ratio was significantly (p<0.05) higher in Groups B and C than in Group A (0.54+/-0.06 microU/mg, 0.54+/-0.06 microU/mg, and 0.32+/-0.06 microU/mg, respectively). However, no significant differences were observed in variables of glucose tolerance, serum lipid, lipoproteins, fibrinogen, uric acid, and blood pressure among the 3 groups. Significant (p<0.05) positive associations were found between GS, the number of diseased coronary arteries, and fasting immunoreactive insulin, insulin response, the area of insulin/area of glucose ratio and HOMA IR by logistic regression analysis. After adjusting for the number of diseased coronary arteries, the association between GS and IR was not significant, suggesting that IR contributed to the severity of coronary atherosclerosis but not to the distribution of lesions. In conclusion, IR was associated with the severity of CHD as measured by both Gensini's score and the number of diseased coronary arteries, and increased the risk of CHD regardless of the location of the lesions.     

Early cytotoxic lymphocyte expansion contributes to a deep molecular response to dasatinib in patients with newly diagnosed chronic myeloid leukemia in the chronic phase: results of the D‐first study

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)‐CML, patient data of D‐First study ( ClinicalTrials.gov NCT01464411) were analyzed. Fifty‐two CML‐CP patients enrolled to this study were treated with dasatinib (100 mg day^?1) and all were followed‐up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML‐CP. Am. J. Hematol. 90:819–824, 2015. © 2015 Wiley Periodicals, Inc.