Comparative effects of topiroxostat and febuxostat on arterial properties in hypertensive patients with hyperuricemia

Elevated serum uric acid is a cardiovascular risk factor in patients with hypertension, even when blood pressure (BP) is well controlled. Xanthine oxidoreductase inhibitors (XORi) reduce serum uric acid levels and have several other potential effects. This multicenter, randomized, open‐label study compared the effects of two XORi, topiroxostat and febuxostat, on arterial stiffness, uric acid levels, and BP in hypertensive patients with hyperuricemia. Patients received topiroxostat 40–160 mg/day or febuxostat 10–60 mg/day, titrated to maintain serum uric acid <6 mg/dl, for 24 weeks. The primary endpoint was change in the cardio‐ankle vascular index (CAVI) from baseline to 24 weeks. There were no significant changes in CAVI from baseline to 24 weeks (from 9.13 to 9.16 [feboxustat] and 8.98 to 9.01 [topiroxostat]). Compared with baseline, there were significant reductions in serum uric acid (–2.9 and –2.5 mg/dl; both p < 0.001) and morning home systolic BP (–3.6 and –5.1 mm Hg; both p < 0.01) after 24 weeks'' treatment with febuxostat and topiroxostat. BP decreased to the greatest extent in the subgroup of patients with uncontrolled blood pressure at baseline. Topiroxostat, but not febuxostat, significantly decreased plasma xanthine oxidoreductase activity versus baseline. The urinary albumin‐creatinine ratio (UACR) decreased significantly from baseline to 24 weeks with topiroxostat (–20.8%; p = 0.021), but not febuxostat (–8.8%; p = 0.362). In conclusion, neither topiroxostat nor febuxostat had any significant effects on arterial stiffness over 24 weeks'' treatment.     

Blood cell, liver function, and response changes by PEG-interferon-α2b plus ribavirin with polaprezinc therapy in patients with chronic hepatitis C

Purpose Zinc has been reported to ameliorate hematologic side effects and improve liver function. In addition to its various effects, zinc supplementation in chronic hepatitis C patients with genotype 1b of high viral load enhanced the response to interferon (IFN) monotherapy. This study was aimed at clarifying whether zinc could improve hematologic side effects, improve liver function, and enhance the response to therapy in patients with chronic hepatitis C treated with pegylated-interferon (PEG-IFN) plus ribavirin (RBV). Methods The 32 patients enrolled in the study were randomly divided into two groups: a PEG-IFN-α2b plus RBV with zinc group (PEG/RBV + zinc, n = 16) and a PEG-IFN-α2b plus RBV group (PEG/RBV, n = 16). HCV-RNA, serum zinc, ALT, white blood cell, red blood cell, platelet, and hemoglobin (Hb) levels were examined. Results Serum zinc levels were significantly higher in the PEG/RBV with zinc group than in the PEG/RBV without zinc group at 4, 8, and 12 weeks. No significant differences were observed in the clearance of HCV-RNA between the two groups. The outcome of the treatment was similar; results of laboratory examinations including ALT before, during, and after therapy revealed no significant differences between the two groups at any point in all items except serum zinc levels. A sustained virological response rate was observed in 50.0% in the PEG/RBV with zinc group and 43.8% in the PEG/RBV without zinc group, with no significant difference between the two groups. Conclusions The study demonstrated no evidence that zinc ameliorates hematologic side effects, improves liver function, and enhances the response to the therapy in chronic hepatitis C receiving PEG-IFN-α2b plus RBV.     

Incidence and predictors of ischemic stroke during hospitalization for congestive heart failure

Heart failure (HF) increases the risk of ischemic stroke. Data regarding the incidence and predictors of ischemic stroke during hospitalization for HF are limited. The study population of this retrospective cohort study consisted of patients with congestive HF, consecutively admitted to our center from October 2010 to April 2014. We excluded patients complicated with acute myocardial infarction, infective endocarditis, and takotsubo cardiomyopathy. We also excluded those with dialysis or mechanical circulatory support. We investigated the incidence of ischemic stroke during hospitalization for HF. Thereafter, we divided the patients without oral anticoagulants at admission into two groups: patients with ischemic stroke and those without it, and explored the predictors of ischemic stroke. A total of 558 patients (287 without atrial fibrillation (AF), 271 with AF) were enrolled. The mean age was 76.8 ± 12.3 years, and 244 patients (44 %) were female. The mean left-ventricular ejection fraction was 47.4 %. Oral anticoagulants were prescribed in 147 patients (8 without AF, 139 with AF). During hospitalization (median length 18 days), symptomatic ischemic stroke (excluding catheter-related) occurred in 15 patients (2.7 % of the total, 8 without AF, 7 with AF). Predictors significantly associated with increased risk of ischemic stroke in patients without oral anticoagulants were as follows; short-term increases in blood urea nitrogen after admission (at day 3; odds ratio (per 1 md/dl): 1.06, 95 % confidence interval (CI) 1.01–1.11, p = 0.02, and at day 7; odds ratio: 1.03, 95 % CI 1.00–1.07, p = 0.03, respectively), and previous stroke (odds ratio; 3.33, 95 % CI 1.01–11.00, p = 0.04). The incidence of ischemic stroke during hospitalization for HF was high, even in patients without AF. Previous stroke and short-term increases in blood urea nitrogen was significantly associated with the incidence of ischemic stroke.     

Immunohistochemical characterization, distribution, and ultrastructure of lymphocytes bearing T-cell receptor gamma/delta in inflammatory bowel disease

Phenotypic characterization and distribution of gamma/delta T lymphocytes in the intestinal mucosa were investigated in ulcerative colitis and Crohn's disease by immunohistochemistry. The ratio of delta(+) cells to CD3(+) cells in the intraepithelial space of colon was decreased in Crohn's disease (13%) and strikingly decreased in ulcerative colitis (8%) compared with the control (36%). Delta(+) cells in the lamina propria were also decreased, particularly in the distal ileum of Crohn's disease (4%), compared with the control (15%). On the contrary, the cells gathered at the severe inflammatory sites with other inflammatory cells, including beta(+) cells, and were densely distributed in the T-cell zone around lymphoid follicles. Phenotypic characterization showed that delta(+) lamina proprial lymphocytes of colon were mainly CD4(-)CD8(-) in the control (80%) and Crohn's disease (59%). However, in ulcerative colitis, CD4(-)CD8(-) delta(+) lymphocytes were rarely found (3%). This reflects the difference of immunologic background between the two diseases. Immunoelectron microscopically, these cells in inflammatory bowel disease were rich with vesicular structures in cytoplasms, whereas those in the control group contained electron-opaque granules. The decrease and the morphological change may be closely related to the weakness of mucosal defense.     

Elevated plasma CL-K1 level is associated with a risk of developing disseminated intravascular coagulation (DIC)

Collectin kidney 1 (CL-K1) is a recently identified collectin that is synthesized in most organs and circulates in blood. CL-K1 is an innate immune molecule that may play a significant role in host defense. As some collectins also play a role in coagulation, we hypothesized that an effect of CL-K1 may be apparent in disseminated intravascular coagulation (DIC), a gross derangement of the coagulation system that occurs in the setting of profound activation of the innate immune system. DIC is a grave medical condition with a high incidence of multiple organ failure and high mortality and yet there are no reliable biomarkers or risk factors. In our present study, we measured plasma CL-K1 concentration in a total of 659 specimens, including 549 DIC patients, 82 non-DIC patients and 27 healthy volunteers. The median plasma CL-K1 levels in these cohorts were 424, 238 and 245 ng/ml, respectively, with no significant difference in the latter two groups. The incidence of elevated plasma CL-K1 was significantly higher in the DIC patients compared to the non-DIC patients, resulting in an odds ratio of 1.929 (confidence interval 1.041–3.866). Infection, renal diseases, respiratory diseases, and cardiac diseases were more frequently observed in the DIC group than in the non-DIC group. In the DIC group, vascular diseases were associated with elevated plasma CL-K1 levels while age and acute illness had little effect on plasma CL-K1 levels. Independent of DIC, elevated plasma CL-K1 levels were associated with respiratory disease and coagulation disorders. These results suggest that specific diseases may affect CL-K1 synthesis in an organ dependent manner and that elevated plasma CL-K1 levels are associated with the presence of DIC. Further investigations in cohorts of patients are warranted. We propose that elevated plasma CL-K1 may be a new useful risk factor and possibly biomarker for the prediction of developing DIC.     

Carcinoma of the ampulla of Vater: Is radical lymphadenectomy beneficial to patients with nodal disease?

This study was undertaken to evaluate the effectiveness of radical lymphadenectomy in ampullary cancer with nodal disease. Thirty-five patients underwent the Whipple procedure with radical lymphadenectomy. The location and number of positive nodes was characterized. Eighteen patients (51%) had positive nodes. Patients without nodal disease (pNO group) had an actuarial 5-year survival rate of 81%. Seven patients with metastasis confined to the pancreaticoduodenal nodes had a 5-year survival rate of 67%, which was comparable to the pNO group (N.S.) and better than the 27% 5-year survival rate in patients with positive superior mesenteric nodes (P < 0.05). Eleven patients with one to three positive nodes had a 5-year survival rate of 71%, which was also comparable to the pNO group (N.S.) and better than the 0% 5-year survival rate in patients with four or more positive nodes (P < 0.01). Radical lymphadenectomy is effective against a limited degree of nodal disease. © 1996 Wiley-Liss, Inc.     

Imatinib attenuates severe mouse dystrophy and inhibits proliferation and fibrosis-marker expression in muscle mesenchymal progenitors

Imatinib mesylate inhibits signaling of tyrosine kinase receptors, including PDGFRα, and has been used for human cancer therapy. Recent studies have indicated that imatinib is also effective in treatment of some chronic diseases with fibrosis. Fibrosis is the feature of Duchenne muscular dystrophy. It has been reported that imatinib attenuates fibrosis in mdx mice. Recently we revealed that PDGFRα is specifically expressed in muscle mesenchymal progenitors, which are the origin of muscle fibrosis. Here, we show that imatinib ameliorates the muscular pathology of DBA/2-mdx, a more severe mouse muscular dystrophy. In addition, imatinib inhibits both the proliferation and fibrosis marker expression induced by PDGF-AA in muscle mesenchymal progenitors in vitro. Importantly, the effective dose of imatinib on muscle mesenchymal progenitors did not inhibit myoblast proliferation. These results suggest that imatinib targets mesenchymal progenitors, and that a therapeutic strategy targeting mesenchymal progenitors could be a potential treatment for muscular dystrophies.     

Experimental allergic encephalomyelitis (EAE) in mice. I. Induction of EAE with mouse spinal cord homogenate and myelin basic protein.

The condition of experimental allergic encephalomyelitis (EAE) induction was investigated in several mice strains. SJL and C3H/He strains were found to be susceptible. A single immunization with mouse spinal cord, complete Freund's adjuvant (CFA) and pertussis vaccine produced clinical signs of EAE in SJL and C3H/He strains after 11 to 18 days. Isogenic spinal cord produced EAE in C3H/He strain. A single immunization with myelin basic protein from bovine spinal cord in CFA and pertussis vaccine produced EAE in SJL strain. EAE susceptibility of SJL strain correlated with the amount of mycobacteria used for sensitization. It was necessary to give pertussis vaccine intravenously in all cases.