Tyrosine kinase, phosphatidylinositol 3-kinase, and protein kinase C regulate insulin-stimulated NaCl absorption in the thick ascending limb

Tyrosine kinase, phosphatidylinositol 3-kinase, and protein kinase C regulate insulin-stimulated NaCl absorption in the thick ascending limb. We have previously shown a direct stimulatory effect of insulin on NaCl absorption in the medullary thick ascending limb of Henle's loop (mTAL). To further investigate the signal transduction involved, we determined whether tyrosine kinase, phosphatidylinositol 3-kinase (PI3-kinase), and/or protein kinase C (PKC) regulate insulin-stimulated NaCl absorption in the mTAL by in vitro microperfusion methods. In control experiments, insulin increased transepithelial voltage (Vte) and net lumen-to-bath Cl− flux (JCl). Genistein and methyl 2,5-dihydroxycinnamate, two specific tyrosine kinase inhibitors, abolished the effects of insulin. Wort-mannin, a specific PI3-kinase inhibitor, inhibited the action of insulin. The effects of insulin also were inhibited by staurosporin and calphostin C, which are dissimilar inhibitors of PKC. These results indicate that insulin stimulates NaCl absorption in the mTAL through tyrosine kinase, PI3-kinase, and PKC-mediated mechanisms. Moreover, because we have reported previously that insulin causes no detectable change in cytosolic free Ca2+ in the mTAL cells, the present results also suggest that insulin-induced PKC activation is not related to inositol 1,4,5-triphosphate (IP3) production

Golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis: results of the GO-FORTH study

Objective: To assess the efficacy and safety of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA). Methods: 269 Japanese patients with active RA despite treatment with MTX were randomised (1:1:1) to placebo + MTX (Group 1), golimumab 50 mg + MTX (Group 2) or golimumab 100 mg + MTX (Group 3). Subcutaneous golimumab/placebo was injected every 4 weeks; stable doses of oral MTX (6-8 mg/week) were continued. Patients were allowed to enter early escape (Group 1 added golimumab 50 mg, Group 2 increased golimumab to 100 mg, Group 3 continued golimumab 100 mg) based on swollen/tender joint counts at week 14. The primary study endpoint was achievement of at least 20% improvement in the American College of Rheumatology (ACR20) response criteria at week 14. To control for multiplicity of testing, treatment group comparisons were first made between combined Groups 2 and 3 versus Group 1, followed by comparisons of Group 2 and Group 3 versus Group 1. Results: The proportion of patients with an ACR20 response at week 14 was significantly higher in combined Groups 2 and 3 (73.4%, 127/173) and in each of Group 2 (72.1%, 62/86) and Group 3 (74.7%, 65/87) compared with Group 1 (27.3%, 24/88; p<0.0001 for all comparisons). Golimumab + MTX also elicited a significantly better response than placebo + MTX in other efficacy parameters, including disease activity score (DAS28) response/remission and radiographic assessments. During the 16-week fixed treatment regimen study period, 72.7%, 75.6% and 78.2% of patients had adverse events and 1.1%, 1.2% and 2.3% had serious adverse events in Groups 1, 2 and 3, respectively. Conclusion: In Japanese patients with active RA despite MTX therapy, golimumab + MTX was significantly more effective than MTX monotherapy in reducing RA signs/symptoms and limiting radiographic progression with no unexpected safety concerns

Factors associated with serum CA19-9 levels among healthy children: a cross-sectional study

Abstract\ud \ud \ud \ud Background\ud CA19-9 is a tumor marker mainly used for biliary tract, pancreas and colorectum. Since the marker applies usually for adults, the normal range of serum CA19-9 among children has been rarely reported. This is the first study reporting the distribution of serum CA19-9 levels among cancer-free children as well as their parents, taking into account the Lewis and secretor gene polymorphism and physical growth.\ud \ud \ud \ud Methods\ud Study subjects were 972 apparently healthy Japanese Brazilians including 476 children aged from 1 to 19 years.\ud \ud \ud \ud Results\ud The comparisons in five-year age groups demonstrated that the mean values of serum CA19-9 was lower in the boys than in the girls, and higher in younger age groups; 22.5 U/ml for 1–4 year-old (n=13), 17.4 U/ml for 5–9 year-old (n=36), 15.5 U/ml for 10–14 year-old (n=96) and 10.2 U/ml for 15–19 year-old (n=74) in boys, and 25.3 U/ml (n=11), 27.1 U/ml (n=50), 17.7 U/ml (n=105) and 13.5 U/ml (n=59) in girls, respectively. The difference in those geometric means was statistically significant among four age groups (p=0.006, ANOVA adjusted for sex). After Lewis and secretor genotypes, which are definitive factors of serum CA19-9, were taken into account, geometric mean of serum CA19-9 was associated with any of BMI (p<0.001), height (p<0.001) and weight (p<0.001) among children excluding those with le/le genotype. The associations were still significant when age was adjusted.\ud \ud \ud \ud Conclusions\ud Serum CA19-9 values were higher among children than among adults, and influenced by sex, height, weight, and BMI even after the adjustment for age as well as Le and Se genotypes.This study was supported in part by a Grant-in-Aid for Scientific Research on Special Priority Areas of Cancer from the Japanese Ministry of Education, Culture, Sports, Science, and Technology. We are grateful to Ms. Yoko Mitsuda and Ms. Keiko Shibata for their technical assistance

Comparison of Targeted vs Random Biopsies for Surveillance of Ulcerative Colitis-Associated Colorectal Cancer

Background & AimsA random biopsy is recommended for surveillance of ulcerative colitis (UC)-associated colorectal cancer. However, a targeted biopsy might be more effective. We conducted a randomized controlled trial to compare rates of neoplasia detection by targeted vs random biopsies in patients with UC.MethodsWe performed a study of 246 patients with UC for 7 years or more, seen at 52 institutions in Japan from October 1, 2008 through December 31, 2010. Patients were randomly assigned to the random group (4 random biopsies collected every 10 cm in addition to targeted biopsies, n = 122) or the target group (biopsies collected from locations of suspected neoplasia, n = 124). The primary end point was the number of neoplastic lesions detected in a single surveillance colonoscopy. We estimated the ratio and difference in the mean number of neoplastic lesions between the groups. We also evaluated the non-inferiority between the groups as an exploratory study. A non-inferiority margin of 0.65 (0.13 of 0.20) was considered for the ratio of the mean number of neoplastic lesions between groups.ResultsThe mean number of biopsies found to contain neoplastic tissue per colonoscopy was 0.211 (24 of 114) in the target group and 0.168 (18 of 107) in the random group (ratio of 1.251; 95% confidence interval, 0.679–2.306). The lower limit was above the non-inferiority margin of 0.65. Neoplasias were detected in 11.4% of patients in the target group and 9.3% of patients in the random group (P = .617). Larger numbers of biopsy samples per colonoscopy were collected in the random group (34.8 vs 3.1 in the target group; P < .001), and the total examination time was longer (41.7 vs 26.6 minutes in the target group; P < .001). In the random group, all neoplastic tissues found in random biopsies were collected from areas of the mucosa with a history or presence of inflammation.ConclusionsIn a randomized controlled trial, we found that targeted and random biopsies detect similar proportions of neoplasias. However, a targeted biopsy appears to be a more cost-effective method. Random biopsies from areas without any signs of present or past inflammation were not found to contain neoplastic tissues. Clinical Trial Registry: UMIN000001608

Molecular Mechanism of the Urate-lowering Effects of Calcium Channel Blockers

Hyperuricemia has recently been recognized as one of the risk factors for cardiovascular diseases. Some calcium channel blockers(CCBs), commonly used in the treatment of hypertension, have been reported to decrease serum urate level. Here, we tried to elucidate the molecular mechanism of the urate-lowering effects of CCBs. We performed [^C]urate uptake in cells stably expressing human urate transporter 1, a major contributor of renal urate reabsorption and a major target of uricosuric drugs such as benzbromarone and losartan(HEK-URAT1), together with mock(HEK-mock)cells to analyze the uricosuric action of CCBs. We also measured the activity of human xanthine oxidase(XO)to determine whether CCBs have inhibitory effects on urate production. The CCBs tested were nifedipine, nilvadipine, nitrendipine, benidipine, nisoldipine, nicardipine, efonidipine, amlodipine, azelnidipine, verapamil and diltiazem. We found for the first time that at least seven CCBs in the dihydropyridine subgroup interacted with URAT1-mediated urate uptake in HEK-URAT1 cells. Among these CCBs, nifedipine, nilvadipine and nitrendipine strongly inhibited URAT1-mediated urate uptake. Their IC_s were 15.8, 0.018 and 0.40?μM, respectively. In contrast, urate production mediated by XO was weakly inhibited by nifedipine and nisoldipine. In summary, URAT1 interacted with various CCBs differently, whereas XO, a major enzyme for urate production in the liver, did not interact with most of CCBs. Although CCBs were not excreted from the urine basically, their urate-lowering effects may be associated with the inhibition of renal urate reabsorption mediated by renal urate transporters such as URAT1 with their metabolites, and the results for structure-activity information in this study will provide a clue for developing new uricosuric drugs targeting URAT1

Factors associated with serum CA19-9 levels among healthy children: a cross-sectional study

BACKGROUND: CA19-9 is a tumor marker mainly used for biliary tract, pancreas and colorectum. Since the marker applies usually for adults, the normal range of serum CA19-9 among children has been rarely reported. This is the first study reporting the distribution of serum CA19-9 levels among cancer-free children as well as their parents, taking into account the Lewis and secretor gene polymorphism and physical growth. METHODS: Study subjects were 972 apparently healthy Japanese Brazilians including 476 children aged from 1 to 19 years. RESULTS: The comparisons in five-year age groups demonstrated that the mean values of serum CA19-9 was lower in the boys than in the girls, and higher in younger age groups; 22.5 U/ml for 1–4 year-old (n=13), 17.4 U/ml for 5–9 year-old (n=36), 15.5 U/ml for 10–14 year-old (n=96) and 10.2 U/ml for 15–19 year-old (n=74) in boys, and 25.3 U/ml (n=11), 27.1 U/ml (n=50), 17.7 U/ml (n=105) and 13.5 U/ml (n=59) in girls, respectively. The difference in those geometric means was statistically significant among four age groups (p=0.006, ANOVA adjusted for sex). After Lewis and secretor genotypes, which are definitive factors of serum CA19-9, were taken into account, geometric mean of serum CA19-9 was associated with any of BMI (p<0.001), height (p<0.001) and weight (p<0.001) among children excluding those with le/le genotype. The associations were still significant when age was adjusted. CONCLUSIONS: Serum CA19-9 values were higher among children than among adults, and influenced by sex, height, weight, and BMI even after the adjustment for age as well as Le and Se genotypes

Remission induction by Raising the dose of Remicade in RA (RRRR) study: Rationale and study protocol for a randomized controlled trial comparing for sustained clinical remission after discontinuation of infliximab in patients with rheumatoid arthritis

Infliximab, an inhibitor of TNF-α, is one of the most widely used biological disease-modifying antirheumatic drugs. Recent studies indicated that baseline serum TNF-α could be considered as a key indicator for optimal dosing of infliximab for RA treatment to achieve the clinical response and its sustained remission. The Remission induction by Raising the dose of Remicade in RA (RRRR) study is an open-label, parallel group, multicenter randomized controlled trial to compare the proportions of clinical remission based on the simplified disease activity index (SDAI) after 1 year of treatment and its sustained remission rate after another 1 year between the investigational treatment strategy (for which the dose of infliximab was chosen based on the baseline serum TNF) and the standard strategy of 3 mg/kg per 8 weeks of infliximab administration in infliximab-naïve patients with RA showing an inadequate response to MTX. The primary endpoint is the proportion of patients who kept discontinuation of infliximab 1 year after discontinued infliximab at the time of 54 weeks after the first administration of infliximab. The secondary endpoints are the proportion of clinical remission based on SDAI and changes in SDAI from baseline at each time point, other clinical parameters, quality of life measures and adverse events. Target sample size of randomized patients is 400 patients in total. The main results of the RRRR study are expected to be published at the end of 2017

Factors associated with serum CA19-9 levels among healthy children: a cross-sectional study

Abstract Background CA19-9 is a tumor marker mainly used for biliary tract, pancreas and colorectum. Since the marker applies usually for adults, the normal range of serum CA19-9 among children has been rarely reported. This is the first study reporting the distribution of serum CA19-9 levels among cancer-free children as well as their parents, taking into account the Lewis and secretor gene polymorphism and physical growth. Methods Study subjects were 972 apparently healthy Japanese Brazilians including 476 children aged from 1 to 19 years. Results The comparisons in five-year age groups demonstrated that the mean values of serum CA19-9 was lower in the boys than in the girls, and higher in younger age groups; 22.5 U/ml for 1–4 year-old (n=13), 17.4 U/ml for 5–9 year-old (n=36), 15.5 U/ml for 10–14 year-old (n=96) and 10.2 U/ml for 15–19 year-old (n=74) in boys, and 25.3 U/ml (n=11), 27.1 U/ml (n=50), 17.7 U/ml (n=105) and 13.5 U/ml (n=59) in girls, respectively. The difference in those geometric means was statistically significant among four age groups (p=0.006, ANOVA adjusted for sex). After Lewis and secretor genotypes, which are definitive factors of serum CA19-9, were taken into account, geometric mean of serum CA19-9 was associated with any of BMI (p<0.001), height (p<0.001) and weight (p<0.001) among children excluding those with le/le genotype. The associations were still significant when age was adjusted. Conclusions Serum CA19-9 values were higher among children than among adults, and influenced by sex, height, weight, and BMI even after the adjustment for age as well as Le and Se genotypes

Factors associated with serum CA19-9 levels among healthy children: a cross-sectional study

Abstract Background CA19-9 is a tumor marker mainly used for biliary tract, pancreas and colorectum. Since the marker applies usually for adults, the normal range of serum CA19-9 among children has been rarely reported. This is the first study reporting the distribution of serum CA19-9 levels among cancer-free children as well as their parents, taking into account the Lewis and secretor gene polymorphism and physical growth. Methods Study subjects were 972 apparently healthy Japanese Brazilians including 476 children aged from 1 to 19 years. Results The comparisons in five-year age groups demonstrated that the mean values of serum CA19-9 was lower in the boys than in the girls, and higher in younger age groups; 22.5 U/ml for 1–4 year-old (n=13), 17.4 U/ml for 5–9 year-old (n=36), 15.5 U/ml for 10–14 year-old (n=96) and 10.2 U/ml for 15–19 year-old (n=74) in boys, and 25.3 U/ml (n=11), 27.1 U/ml (n=50), 17.7 U/ml (n=105) and 13.5 U/ml (n=59) in girls, respectively. The difference in those geometric means was statistically significant among four age groups (p=0.006, ANOVA adjusted for sex). After Lewis and secretor genotypes, which are definitive factors of serum CA19-9, were taken into account, geometric mean of serum CA19-9 was associated with any of BMI (p<0.001), height (p<0.001) and weight (p<0.001) among children excluding those with le/le genotype. The associations were still significant when age was adjusted. Conclusions Serum CA19-9 values were higher among children than among adults, and influenced by sex, height, weight, and BMI even after the adjustment for age as well as Le and Se genotypes