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Background and aim Because the risk of colorectal cancer has not been well examined in fecal immunochemistry test (FIT)-positive patients who previously underwent colonoscopy, this study aimed to investigate this topic. Methods This was a single-center, observational study of prospectively collected data in Japan. FIT-positive, average-risk patients who underwent colonoscopy were divided into groups as follows: those who never underwent colonoscopy in the past (no colonoscopy group), those with a history of colonoscopy between 6 months and 5 years (0.5- to 5-year colonoscopy group), and those with a history of colonoscopy more than 5 years ago (> 5-year colonoscopy group). We investigated the prevalence of advanced neoplasia and invasive cancer among these groups using multiple logistic regression analysis. Results Detection rates of advanced neoplasia in the no colonoscopy group, 0.5- to 5-year colonoscopy group, and > 5-year colonoscopy group were 14.8% (240/1626), 3.9% (13/330), and 6.9% (17/248), respectively. Detection rates of invasive cancer in each aforementioned group were 5.7% (92/1,626), 0.3% (1/330), and 1.2% (3/248), respectively. Odds ratios of advanced neoplasia in the 0.5- to 5-year colonoscopy group and > 5-year colonoscopy were 0.23 (95% confidence interval [CI]: 0.13-0.42) and 0.40 (95% CI: 0.24-0.68), respectively, in multivariate analysis. The odds ratios of invasive cancer in each aforementioned group were 0.05 (95% CI: 0.01-0.37) and 0.19 (95% CI: 0.06-0.61), respectively. Conclusion Re-screening with the FIT should not be recommended for at least 5 years for average-risk patients after colonoscopy without high-risk neoplasms, because the risks of colorectal cancer are low in such patients.

Background Underwater endoscopic mucosal resection (U-EMR) has emerged as an alternative technique for the resection of colorectal lesions. This study aimed to evaluate our initial experience using U-EMR. Methods This is a single-center, retrospective case series study. We analyzed the clinical outcomes of consecutive patients who underwent U-EMR in our endoscopy center, from December 2015 to February 2017. Results Our analysis included 64 lesions, contributed by 38 patients, with a mean age of 68.6 years (range, 25 to 90 years). The study sample included 33 right-sided and 25 left-sided colon lesions, and seven rectal lesions, with an average size of 16.2 mm (6 - 40 mm). Of these, 46 lesions were polypoid and 18 ones non-polypoid. Histologically, 31 lesions were low-grade adenomas, eight ones were high-grade adenomas, 11 were mucosal cancers, four were submucosal cancers, and 10 were classified as "others". En bloc resection was achieved in 52 (81%) lesions, with an en bloc resection rate of 95% for lesions < 20 mm and 55% for lesions ≥ 20 mm. Complete resection of neoplastic epithelial lesions, defined by a negative pathological margin, was achieved in 32 of 59 neoplastic epithelial lesions (54%). We identified three cases (5%) of post-procedural bleeding and one case of perforation (2%). Conclusions U-EMR can be feasibly used for resection of colonic lesions, including lesions ≥ 20 mm, although the en bloc resection rate for these lesions was lower than for lesions < 20 mm.

Background Efficacy of a physician-controlled wire-guided cannulation of the bile duct has been reported. This study aimed to evaluate a novel sphincterotome with a short tip and a short wire, which can be bowed compactly compared to conventional sphincterotomes. Methods This was a single-arm, single-center, prospective study. We enrolled patients with choledocholithiasis and/or obstructive jaundice and/or cholangitis for whom endoscopic sphincterotomy was planned. The main outcome measurement was the proportion of successful selective bile duct cannulation by physician-controlled wire-guided cannulation within 10 min. Results The study cohort consisted of 40 patients. The proportion of successful selective bile duct cannulation within 10 min was 72.5% (n = 29). The proportion of post-endoscopic retrograde cholangiopancreatography pancreatitis was 2.5% (mild, n = 1) and the proportion of hemorrhage was 2.5% (moderate, n = 1). Conclusions Although physician-controlled wire-guided cannulation using a novel sphincterotome with a short tip and a short wire was not superior to wire-guided cannulation using conventional sphincterotomes reported in a previous study, it remains a safe and efficacious alternative in terms of successful biliary cannulation.

We report the first case demonstrating an association between Kawasaki disease (KD) and erythema nodosum (EN). A 3-year-old girl presented with EN as an initial manifestation of KD. At the initial visit, she showed high fever of 40°C, injection of the oropharynx, cervical lymphadenopathy, and red-purple cutaneous nodules, particularly on the lower limbs. She complained of severe pain in the neck and cutaneous lesions. Initially, the development of EN was attributed to Salmonella spp infection, which was detected in stool culture. However, the patient did not respond to high-dose ampicillin/sulbactam to which the Salmonella spp is sensitive. Echocardiography performed as screening for fever of unknown origin revealed medium-sized aneurysms of the left anterior descending artery. EN masked the diagnosis of KD, and the patient developed a coronary artery lesion. KD should be considered in the differential diagnosis of refractory EN in pediatric patients.

Since student participation is essential for successful classroom teaching, a growing number of studies are investigating how classroom teachers can encourage active participation by students. In l...

The concept of the quality loss derived by Taguchi has been accepted as the evaluation measure of quality instead of the traditional attribute property such as the proportion of non-conforming items. Since the variable single sampling plan having the desired operating characteristics indexed by the quality loss was proposed in 1997, various kinds of sampling plans indexed by the quality loss have been considered. Among them, there are two kinds of rectifying variable single sampling (RVSS) plans indexed by the quality loss. In the RVSS plans, two inspection schemes called the acceptance quality loss limit (AQLL) scheme and the permissible average outgoing surplus quality loss limit (PAOSQLL) scheme have been formulated. Note that the concepts of the AQLL and PAOSQLL schemes in the RVSS plans indexed by the quality loss are equivalent to those of the lot tolerance percent defective (LTPD) and the average outgoing quality limit (AOQL) schemes in the traditional rectifying attribute single sampling plans, respectively. On the other hand, in the sampling plan having the desired operating characteristics, an attribute repetitive group sampling plan was proposed for the purpose of reducing the average sampling number in the inspection. Recently, by applying the repetitive group sampling to the rectifying variable sampling plan for the AQLL scheme, the rectifying variable repetitive group sampling (RVRGS) plan for the AQLL scheme has been considered for the purpose of reducing the average total inspection (ATI). However, the RVRGS plan for the PAOSQLL scheme has not been investigated yet. Accordingly, the RVRGS plan for the PAOSQLL scheme must be investigated to complete the RVRGS plans indexed by the quality loss. In this article, the RVRGS plan for the PAOSQLL scheme is addressed. Then, the design procedure in the RVRGS plan for the PAOSQLL scheme is proposed for the purpose of reducing ATI. Through some numerical investigations, the effectiveness to reduce ATI by the RVRGS plan for the PAOSQLL scheme is confirmed.

The purpose of this study is to report the efficacy and safety of a combination of tocilizumab (TCZ) and high-dose corticosteroid (CS) in two patients with microscopic polyangiitis (MPA) and review the published current clinical evidence on TCZ in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), except for large vessel vasculitis (LVV) and polymyalgia rheumatica (PMR). Two MPA patients were treated with TCZ at 8 mg/kg every month for 1 year and CS (prednisolone 1 mg/kg/day for 2 weeks, followed by tapering) in a prospective single-arm, single-center, cohort, open-label pilot study (UMIN clinical trials: 000012072). We performed a systematic literature search (PubMed and ICHUSHI [Japan Medical Abstracts Society] until June 30, 2017) to identify published reports on patients with all vasculitis other than LVV/PMR, who were treated with TCZ. We successfully treated the first patient. However, the other patient had serious infection probably associated with the combination of TCZ and high-dose CS. The literature review identified 22 reports with a total of 34 patients who received TCZ for AAV, rheumatoid vasculitis, and other types of vasculitis, in addition to our patients. In 15 of 17 patients (88.2%) with primary and secondary AAV, especially MPA, TCZ induced clinical remission, although TCZ use for rheumatoid vasculitis and vasculitis with mucocutaneous lesions is controversial. This study suggested that TCZ therapy is a potential treatment strategy for patients with AAV. However, TCZ combined with high-dose of CS might not be an appropriate treatment. Future studies are needed to confirm our findings.

Background Pulsed cyclophosphamide or mycophenolate mofetil for lupus nephritis has limited efficacy. We previously reported a case of mixed-class IV + V lupus nephritis successfully treated with cyclophosphamide and tacrolimus. This study assessed the efficacy and safety of multitarget therapy with cyclophosphamide and tacrolimus for the treatment of lupus nephritis. Methods In a prospective, single-arm, open label pilot study, we recruited 15 patients aged 18-64 years with active lupus nephritis who met the American College of Rheumatology criteria for a diagnosis of systemic lupus erythematosus (1997). The treatment protocol was a starting dose of prednisolone of 0.6-1.0 mg/kg/day for 2 weeks and then tapered to a maintenance dose, intravenous cyclophosphamide (500 mg biweekly for 3 months) and tacrolimus (3.0 mg/day). Tacrolimus was continued as maintenance therapy. Complete remission was defined as a spot urine protein/creatinine ratio of 0.5 g/gCr with no active urine casts and a serum creatinine level that was either normal or within 30% of a previously abnormal baseline level. We retrospectively compared results for the study patients with those of 18 historical controls conventionally treated with cyclophosphamide and prednisolone. Results At baseline, the mean patient age was 41.5 ± 14.6 years (male:female ratio 2:13), urine protein/creatinine ratio 3.9 ± 2.3 g/gCr and serum creatinine 84.6 ± 34.6 µmol/L. Lupus nephritis classifications included classes IV ( n = 8), III + V ( n = 1), IV + V ( n = 5) and unclassified ( n = 1). Eleven patients completed the treatment protocol and four withdrew. At 6 months, 12 of 15 (80.0%) had achieved complete remission using intention-to-treat analysis, significantly more than historical controls (seven of 18 patients, 38.9%). A transient increase in serum creatinine and gastric symptoms occurred in three cases. One patient withdrew due to cytomegalovirus antigenemia and severe diabetes, and one patient died of thrombotic microangiopathy. Conclusions Multitarget therapy with cyclophosphamide and tacrolimus can be a therapeutic option for lupus nephritis. Clinical trials registration Combination therapy of tacrolimus and intravenous cyclophosphamide for remission induction of lupus nephritis, UMIN: 000004893, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=browsaction=browstype=summaryrecptno=R000005830language=E . Date of registration: 18 January 2011.

A 23-year-old female patient with ulcerative colitis (UC) who had been successfully treated with infliximab (IFX) plus 5-aminosalicylated acid (5-ASA) developed Takayasu arteritis (TAK). She refuse...

Prophylactic granulocyte-colony stimulating factor(G-CSF)is necessary for some cancer patients receiving anti-cancer drugs. However, it is difficult for cancer patients in rural areas to receive G-CSF as outpatients because of inconvenient official transport, lack of public support, and low activity levels due to age. To resolve this problem, we began conducting a critical path(G-path)with regional medical institutions from 2011.We retrospectively surveyed the clinical records of cancer patients receiving prophylactic G-CSF using G-path at our hospital.Eighty-two patients who were administered a total of 254 cycles of chemotherapy were examined between January 2011 and December 2016. Diseases included malignant lymphoma(n=64), pancreatic cancer(n=7), soft tissue sarcoma(n=5), and others(n=6). The median age of the patients was 70(range: 24-94)years. Fifty-three patients visited medical offices, and 31 patients visited regional hospitals. In 245 of 254(96%)cycles, planned G-CSF administration was performed. In 37 of 254(15%)cycles, infectious episodes developed, but patients needed hospitalization for only 5 cycles(2%).Cooperation between clinics and hospitals using G-path reduced ambulatory burden and prevented severe infection. Cooperation in supportive care may allow for equal accessibility to cancer treatment.

Among children with Down syndrome, the frequency of motor rehabilitation intervention and the age at the start of this intervention are independently related to the age at onset of independent walking. Early motor rehabilitation, before age 6 months, may be effective in reducing motor delay in children with Down syndrome.

The acceptance of foreign comparator products is the most limiting factor for the development and regulatory assessment of generic medicines marketed globally. Bioequivalence studies have to be repeated with the local comparator products of each jurisdiction because it is unknown if the comparators of the different countries are the same product, with the consequent duplication of efforts by regulators and industry alike. The regulatory requirements on the acceptability of foreign comparator products of oral dosage forms differ between countries participating in the Bioequivalence Working Group for Generics of the International Pharmaceutical Regulators Programme. Brazil, Colombia, the European Union member States, Japan, Mexico, South Korea and the United States only accept bioequivalence studies with their local comparator. In contrast, Australia, Canada, New Zealand, Singapore, South Africa, Switzerland and Taiwan accept studies with foreign comparators under certain conditions. Canada limits its use to highly soluble drugs with a wide therapeutic range in immediate release products. Australia requires a comparison of the quantitative composition. In contrast, there are fewer restrictions on the acceptance of foreign comparators in New Zealand, Singapore, South Africa, Switzerland and Taiwan. For the WHO Prequalification of Medicines and for developing generics of the essential medicines the WHO lists comparators from different countries. In conclusion, there is currently no consensus amongst regulators on the acceptability of foreign comparator products.

Background:It is important to use vascular imaging modalities such as CT, MRI and PET-CT to evaluate disease activity of Takayasu arteritis (TAK). In particular, under treatment with tocilizumab (TCZ), redsidual vasculitic disease activity may remain even if serum CRP becomes negative. Contrast-enhanced CT,MRI and PET-CT can evaluate the morphology of blood vessel walls and the distribution of lesions and vasculitic activity, but it is invasive (radiation or contract media exposure), and costly. Ultrasound is superior in terms of morphological evaluation, cost, convenience, and low invasiveness. In particular, Superb Micro-vascular Imaging(SMI) is one of the micro blood flow display methods that can be installed in the ultrasound diagnostic device Aplio series.There are some case reports in which micro blood flow signals of the carotid artery walls were detected using SMI in Takayasu arteritis [1] [2]. Both reports indicate that SMI blood flow is a comparable indicator of disease activity as serum CRP.Objectives:To report the usefulness of SMI in 2 TAK patients who had negative serum CRP but had residual disease activity, leading to appropriate adjustment of treatment.Methods:Two TAK patients who had been newly diagnosed in our department from May 2015 to October 2018 and had received SMI to detect carotid artery wall blood flow signal were retrospectively analyzed.Results:Case 1A 32-year-old woman developed neck pain, headaches, fever and she had high serum levels of CRP (8.1 mg/dl) and elevated ESR (98 mm/h). Contrast-enhanced CT showed thickening of the carotid artery, left subclavian artery and thoracic aorta and SMI detected blood flow signal in carotid artery wall. Diagnosis of TAK was made. After 2-week treatment with 1 mg/kg/day of PSL, CRP became negative but the micro blood flow in carotid arterity walls was detedted by SMI. Therefore,subcutaneous TCZ (162 mg/week)was added in combination with PSL.One year later, micro blood flow disappeared and we could judge there was no vasculitis activity (Figure A).Before treatment starts2 weeks after starting treatmentOne year after starting treatmenttreatment-PSL 1mg/kg/day ongoingPSL 7mg/day ongoingTCZ 162 mg/week ongoingCRP(mg/dl)+ (8.1)−(0.0)−(0.0)SMI signal++−Figure 1.A. Clinical course of Case 1Case 2A 17-year-old woman developed proximal upper limb pain and fever with high serum CRP levels (7.1 mg/dl) and elevated ESR (>110 mm/h), and contrast-enhanced CT showed thickening of the carotid arteries and aortic arch. Two weeks after the start of PSL (1 mg/kg/day), CRP became negative at 0.3 mg/dl, but intramural blood flow detected by SMI remained. Then subcutaneous TCZ was added. Two weeks later, CRP became negative, and the SMI blood flow also disappeared (Figure B).Before treatment starts2 weeks after starting treatment4 weeks after starting treatmenttreatment-PSL 1mg/kg/day ongoingPSL 50 mg/day ongoingTCZ 162 mg/week addedCRP(mg/dl)+ (7.1)−(0.3)−(0.0)SMI signal++−Figure 2.B. Clinical course of Case 2Conclusion:Although SMI has the limitation that it cannot evaluate deep vascular lesions such as aorta, it is neither invasive nor costly and may be a good tool for evaluation of residual vasculitis activity of TAK.References:[1]Sato W, Sato T, Iino T, Seki K, Watanabe H. Visualization of arterial wall vascularization using superb microvascular imaging in active-stage Takayasu arteritis.European Heart Journal - Cardiovascular Imaging. 2019;20(6):719[2]Ito S, Tahara N, Hirakata S, et al. Signal intensity of superb micro-vascular imaging associates with the activity of vascular inflammation in Takayasu arteritis.Journal of Nuclear Cardiology:Official Publication of the American Society of Nuclear Cardiology. 2019 Mar DOI: 10.1007/s12350-019-01665-4.Acknowledgments:We thank Minako.Yamashita and Masahiro.setoyama for her technical assistance to conduct SMI.Disclosure of Interests:None declared

Because the risk of colorectal cancer has not been well examined in fecal immunochemistry test (FIT)-positive patients who previously underwent colonoscopy, this study aimed to investigate this topic.This was a single-center, observational study of prospectively collected data in Japan. FIT-positive, average-risk patients who underwent colonoscopy were divided into groups as follows: those who never underwent colonoscopy in the past (no colonoscopy group), those with a history of colonoscopy between 6 months and 5 years (0.5- to 5-year colonoscopy group), and those with a history of colonoscopy more than 5 years ago ( 5-year colonoscopy group). We investigated the prevalence of advanced neoplasia and invasive cancer among these groups using multiple logistic regression analysis.Detection rates of advanced neoplasia in the no colonoscopy group, 0.5- to 5-year colonoscopy group, and 5-year colonoscopy group were 14.8% (240/1626), 3.9% (13/330), and 6.9% (17/248), respectively. Detection rates of invasive cancer in each aforementioned group were 5.7% (92/1,626), 0.3% (1/330), and 1.2% (3/248), respectively. Odds ratios of advanced neoplasia in the 0.5- to 5-year colonoscopy group and 5-year colonoscopy were 0.23 (95% confidence interval [CI]: 0.13-0.42) and 0.40 (95% CI: 0.24-0.68), respectively, in multivariate analysis. The odds ratios of invasive cancer in each aforementioned group were 0.05 (95% CI: 0.01-0.37) and 0.19 (95% CI: 0.06-0.61), respectively.Re-screening with the FIT should not be recommended for at least 5 years for average-risk patients after colonoscopy without high-risk neoplasms, because the risks of colorectal cancer are low in such patients.

Background Japan is the ultra-ageing society ahead of any other country in the world, which ageing rate (the ratio of the population aged 65 and older to the total population) was reported to be 27.3% on October 1, 2016. The rate of aged patients, who followed up at the division of rheumatology in Saitama medical centre, had exceeded 40%. Objectives The aim of our study is to reveal recent clinical features and problems of elderly onset rheumatoid arthritis (EORA) patients for better management. Methods Patients had a diagnosis by 1987 classification criteria or 2010 ACR/EULAR criteria. We firstly listed up RA patients who were followed up our hospital from April 1 to September 30, and above aged 65 years old as of September 30. Then we retrospectively collected clinical information of EORA patients who onset above 60 years old, diagnosed and made starts of treatment in our hospital, and observed more than 6 months, from medical records. Results One hundred eighty eight EORA patients were enrolled in this study. Female were 116 (62.0%). Mean observation period from first visit until September 30, was 68 months. Rheumatoid factor positive rate was 67.0%. Anti-CCP antibody-positive was 68.2% (107/157), and most of them (65.5%, 70/107) had high antibody titer over 100 U/mL. At the time of diagnosis, average CRP was 3.1 mg/dL. Respiratory complications were seen in 26.1% (49 cases), including 28 interstitial lung disease, 10 COPD/emphysema, 7 non-tuberculous mycobacteriosis/obsolete tuberculosis, and 6 bronchiectasis. Other complications were diabetes 16.5% (past 25 cases, new 6), hypertension 38.3% (past 66, new 6), and hyperlipidemia 23.9% (past 33, new 12). Histories of cerebrovascular or cardiovascular events were seen in 10.6% (20 cases), and history of malignancy was seen in 6.9% (13 cases). During observation period, newly developed malignancy was seen in 14 cases (14.1/1000 person-years) including 4 MTX related lympho-proliferative disorders (MTX-LPD), 3 gastrointestinal cancer, 3 gynaecological cancer, 2 lung cancer, and so on. Infectious adverse event were occurred in 35 patients (35.3/1000 person-years). From the point of treatment, corticosteroids were prescribed in 32%, csDMARDs 88%, and biological DMARDs (BIO) 47%. Of 89 EORA patient treated with BIO, average DAS28-ESR was 5.77, and HAQ-DI 1.48 at the baseline. Twenty-nine cases were started to treat with BIO as monotherapy, 13 cases as switching to BIO from csDMARDs, and 47 as addition BIO to csDMARDs. During observation period, reasons of cessation of the first BIO were remission in 21, adverse events in 19 (7 infections, 6 injection-site/infusion reaction, 3 malignancies, and so on), insufficient response in 16, and patient’s hope in 2. Conclusions RF/anti-CCP antibody positive rate was lower than general RA population, but slightly higher than previous reports on EORA.1) BIO could be discontinued in 24% of 89 patients who received BIO because of remission. On the other hand, the frequency of infection and malignancy was still higher in EORA patients. So it is necessary to adjust anti-rheumatic therapy for poor prognostic cases, and we should be careful to follow up EORA patients. References [1] Boeters DM, et al. Arthritis Res Ther. 2017May 31;19(1):115. [2] Sugimoto N, et al. Rheumatol Int. 2017Nov;37(11):1871–1878. Disclosure of Interest T. Kurasawa: None declared, Y. Okada: None declared, A. Shibata: None declared, S. Saito: None declared, K. Chino: None declared, A. Okuyama: None declared, H. Takei: None declared, T. Kondo: None declared, K. Amano Grant/research support from: Chugai Pharmaceutical Co. Ltd., Speakers bureau: Chugai Pharmaceutical Co. Ltd., Daiichi-Sankyo Co., Ltd., Pfizer Japan Inc., Mitsubishi Tanabe Pharma Corporation

Background Polymyalgia rheumatic (PMR) is a chronic inflammatory rheumatic disease in the elderly people. Glucocorticoid (GC) is still definitely a mainstay for the treatment of PMR, but long-term GC therapy is a major risk factor of osteoporotic fractures, diabetes, hyperlipidemia, cardio-cerebral vascular events, glaucoma, etc. So GC-free treatment strategies for PMR are awaited for some PMR patients with these comorbidities. IL-6 is involved in the pathogenesis of PMR and several case reports have already shown the efficacy of tocilizumab (TCZ), anti-IL-6 receptor antibody, in PMR patients1,2) and there is a report of TCZ mono-therapy as the first-line therapy in PMR3). Objectives To assess the efficacy and safety of TCZ mono-therapy for PMR Methods Thirteen PMR patients (male 3, female 10) who had been diagnosed by 2012 ACR/EULAR classification criteria from Jan 2013 to Feb 2015 were enrolled in our single-centre, prospective study (IRB application No. 638, UMIN No. 000008812) after obtaining the written informed consent. TCZ (8 mg/kg) was administered biweekly for the first 8 weeks (5 infusions) and every 4 weeks thereafter for 40 weeks (total 15 infusions). ESR, CRP, patient’s global health assessed by visual analogue scale (VAS), PMR activity score4) were evaluated every 4 week prospectively. Primary endpoint was remission rate at week 52. Remission was defined as PMR activity score less than 1.54). Patients were followed up for another one year without any treatment and flare rate was assessed at week 104. Results Baseline patients’ characteristics revealed various kinds of comorbidities in 11 patients; hypertension in 7, hyperlipidemia in 5, diabetes mellitus in 3, osteoporotic vertebral fractures in 2, history of angina pectoris in 1, history of brain infarction in 1, history of hematemesis due to NSAID ulcer in 1 and glaucoma in one patient. Nine patients could complete this 104 week trial and all 9 patients could achieve remission at week 52 and 8 of 9 patients fulfilled remission criteria at week 104. Two patients discontinued TCZ because of no response at week 6 (No.1) and week 16 (No. 8) respectively. One patient (No.2), who were in clinical remission of PMR, dropped out from this study due to pemphigoid at week 50 and received GC therapy. Patient No. 12 abandoned TCZ at week 12 because of lung infiltrates although she was treated successfully with TCZ mono-therapy, and she had been in remission without any treatment until week 104. The other 3 patients could obtain remission with GC therapy at week 52. There were no serious adverse events during 104 week treatment period. Conclusions TCZ mono-therapy was effective in most (9 out of 13) PMR patients although response was not so rapid as compared to GC. TCZ mono-therapy may be a good alternative therapy instead of GC for elderly patients with various comorbidities. References [1] Unizony S, et al.: Arthritis Care Res2012;64(11):1720–1729. [2] Macchioni P, et al.: Semin Arthritis Rheum2013;43(1):113–118. [3] Devauchelle-Pensec V, et al.: Ann Rheum Dis2016;75(8):1506–1510. [4] Leeb BF, et al.: Arthritis Rheum2007;57(5):810–815. Disclosure of Interest K. Amano Grant/research support from: Chugai Pharmaceutical Co. Ltd., Speakers bureau: Chugai, Daiichi-Sankyo, Pfizer Japan, Tanabe-Mitsubishi, K. Chino: None declared, Y. Okada: None declared, A. Shibata: None declared, S. Saito: None declared, T. Kurasawa: None declared, A. Okuyama: None declared, H. Takei: None declared, R. Sakai: None declared, T. Kondo: None declared

Dimerization in signal transduction is a dynamically regulated process and a key regulatory mechanism. Signal transducer and activator of transcription 3 (STAT3) dimerizes after tyrosine phosphorylation upon cytokine stimulation. Because only the STAT3 dimer possesses the trans-activation activity, dimerization is an indispensable process for cytokine signaling. Here we report the detection of dynamic STAT3 dimerization in living cells using the homoFluoppi system. This method allowed us to validate the presence of an intact Src homology 2 domain and STAT3 Tyr705 phosphorylation, which facilitate puncta formation and homodimerization. Puncta formation was reversible, as determined by a decreased punctate signal after washout of oncostatin M. We analyzed STAT3 mutants, which have been reported in patients with hyper IgE syndrome and inflammatory hepatocellular adenoma (IHCA). Analysis of the IHCA mutants using homoFluoppi revealed constitutive activity independent of cytokine stimulation and novel insight into kinetics of dimer dissociation process. Next, we used homoFluoppi to screen for inhibitors of STAT3 dimerization, and identified 3,4-methylenedioxy-β-nitrostyrene as a novel inhibitor. The results of this study show that homoFluoppi is a useful research tool for the analysis of proteins like STAT3 that dynamically dimerize, and is applicable for the screening of dimerization modulators.

This study aims to explicate interviewer and candidate conversational practices in L2 job interviews as they relate to the assessment of a candidate’s qualification for a particular position. The data consisted of 27 audio-recorded job interviews for the position of student assistant in English classes at a Japanese university. The analysis of these interactional data, conducted using conversational analysis methodology, revealed that the inadequacy of a candidate’s response is constructed by means of the interviewer’s subsequent pursuit of a relevant answer from the candidate. In addition, a candidate’s ability to build rapport by providing sequentially linked joke-serious responses evoked a positive evaluation from the interviewer. The findings indicate that a candidate’s understanding of expected behaviors and ability to accommodate his or her behaviors in a manner relevant to the interaction result in a positive assessment.

Two antigenically distinct B strain lineages of influenza virus have co-circulated since the mid-1980s; however, inactivated trivalent influenza vaccines contain only one B lineage. The mismatch between the circulating and vaccine lineages has been a worldwide issue. In this study, an inactivated quadrivalent influenza vaccine (QIV) candidate containing two B lineages was manufactured and its immunogenicity and safety evaluated in an open-label, uncontrolled trial. In this phase II trial, 50 subjects aged 20-64 years received two doses of QIV s.c. 1 to 4 weeks apart. Sera were collected pre- and post-vaccination and safety assessed from the first vaccination to 21 ± 7 days after the second vaccination. After the first vaccination, hemagglutination inhibition titers against each strain increased markedly; the seroconversion rate, geometric mean titer ratio and seroprotection rate being 94.0%, 24.93, and 100.0%, respectively, for the A/H1N1pdm09 strain; 94.0%, 12.47, and 98.0%, respectively, for the A/H3N2 strain; 54.0%, 4.99, and 66.0%, respectively, for B/Yamagata strain, and 72.0%, 6.23 and 80.0%, respectively, for the B/Victoria strain, thus fulfilling the criteria of the European Medical Agency's Committee for Medicinal Products for Human Use. Also, the QIV induced sufficient single radial hemolysis and neutralizing antibodies against all four vaccine strains. No noteworthy adverse events were noted. The results of this trial demonstrate that QIV is well tolerated and immunogenic for each strain, suggesting that QIV potentially improves protection against influenza B by resolving the issue of B lineage mismatch.

Channel-like grooves are formed on the surface of frozen aqueous sucrose. They are filled with a freeze concentrated solution (FCS) and act as an efficient size-tunable separation field for micro and nanoparticles. The width of the channel can be easily varied by changing the temperature. Because the channel width decreases with decreasing temperature, particles become immobilized due to physical interference from the ice wall when the temperature reaches a threshold point specific to the particle size. Surface modification of particles can add a factor of chemical interaction between the particles and ice walls. In this study, anti-freeze proteins (AFPs) are anchored on 1µm-polystyrene (PS) particles, and their behavior in the surface grooves on the ice is studied. The threshold temperature is an effective criterion for evaluating chemical interactions between particles and ice walls. The AFP binding on 1µm PS particles lowers the threshold temperature by 2.5°C, indicating interactions between AFPs on the PS particles and the ice wall. Because the AFPs studied here show selectivity towards the prism plane, it is critical that the prism plane of the ice crystal is in contact with the FCS in the surface grooves.

To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission.Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28 - erythrocyte sedimentation rate [ESR] ≤ 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR3.2 at two consecutive visits.Twenty-five patients were enrolled; 87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five.A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.

A 78-year-old man with hypertension, nephrosclerosis, and angina pectoris visited his family doctor with a history of fatigue and leg edema. He had a history of percutaneous coronary intervention 5 years prior, and was taking low-dose aspirin. Blood tests revealed hypoalbuminemia, gastrointestinal

Background Polymyalgia rheumatic (PMR) is a chronic inflammatory rheumatic disease in the elderly people. Glucocorticoid (GC) is still definitely a mainstay for the treatment of PMR, but long-term GC therapy is a major risk factor of osteoporotic fractures, diabetes, hyperlipidemia, cardio-cerebral vascular events, glaucoma, etc. So GC-free treatment strategies for PMR are necessary for some patients with PMR. IL-6 is involved in the pathogenesis of PMR and quite a few case reports have already shown the efficacy of tocilizumab (TCZ) in PMR patients and some of them received TCZ monotherapy without GC. Objectives To assess the efficacy and safety of TCZ monotherapy for PMR Methods Thirteen PMR patients (male 3, female 10) who had been diagnosed by 2012 ACR/EULAR classification criteria from Jan 2013 to Feb 2015 were enrolled in our study (IRB application No. 638, UMIN registration No. 000008812) after obtaining the written informed consent. TCZ (8 mg/kg) was administered biweekly for the first 2 months (5 infusions) and every 4 weeks thereafter for 40 weeks (total 48 weeks). ESR, CRP, patient9s global health assessed by visual analog scale (VAS), PMR activity score were evaluated every 4 week prospectively and were evaluated at week 52. Remission was defined as PMR activity score less than 1.5. Results Baseline patients9 characteristics revealed various kinds of comorbidities in 11 patients; hypertension in 7, hyperlipidemia in 5, diabetes mellitus in 3, osteoporotic vertebral fractures in 2, history of angina pectoris in 1, history of brain infarction in 1, history of hematemesis due to NSAID ulcer in 1 and glaucoma in one patient. Nine patients could complete this 52-week trial and could achieve remission at week 52. Two patients discontinued TCZ because of no response at week 6 (No.1) and week 16 (No. 8) respectively. One patient (No.2), who were in clinical remission of PMR, dropped out from this study due to pemphigoid at week 50 and received GC therapy. Patient No. 12 abandoned TCZ at week 12 because of lung infiltrates although she was treated successfully with TCZ monotherapy, and she had been in remission without any treatment until week 52. The other 3 drop-out patients could obtain remission with GC therapy at week 52. There were no serious adverse events during 52-week treatment period. Conclusions TCZ mono-therapy was effective in most (9 out of 13) PMR patients although response was not so rapid as compared to GC. TCZ mono-therapy may be a good alternative therapy instead of GC for elderly patients with various comorbidities. References Unizony S, et al.: Arthritis Care Res 2012; 64(11):1720–1729. Macchioni P, et al.: Aemin Arthritis Rheum 2013; 43(1): 113–118. Toussirot E, et al.: J Rheumatol 2016 43(1): 249–251. Leeb BF, et al.: Arthritis Rheum 2007; 57(5): 810–815. Acknowledgements We will thank Izumi Oshima, Takashi Kukita for data collection and management of this study. Disclosure of Interest K. Amano Grant/research support from: Chugai Pharnmaceutical Co.Ltd., K. Chino: None declared, Y. Okada: None declared, A. Shibata: None declared, A. Okuyama: None declared, T. Kurasawa: None declared, H. Takei: None declared, T. Kondo: None declared

Background Adult-onset Still9s disease (AOSD) is a systemic inflammatory disease of unknown etiology. Corticosteroids still provide mainstay AOSD therapy despite various adverse effects. Recently, AOSD patients have been successfully treated with anti-cytokine therapies such as with TNF-α blocking agents, an IL-1 receptor antagonist, and an anti-IL-6 receptor monoclonal antibody. Among these case reports, TCZ seems to be highly effective for treating patients refractory to TNF antagonists and IL-1 antagonist. Objectives To assess the efficacy and safety of tocilizumab (TCZ) monotherapy for the induction therapy of adult onset Still9s disease (AOSD) in a prospective single-arm, single-center, cohort, pilot study. Methods Seven AOSD patients (male 2, female 5) who had agreed with our prospective trial since April 2010 till May 2015 were enrolled. Our study protocol is that patients received 8 mg/kg of intravenous TCZ fortnightly for the first two months (five courses), then monthly for the next 5 months and after that they stop TCZ therapy and we monitor symptoms about AOSD relapses. In this report, we evaluated the efficacy and safety in 52 week. Efficacy was evaluated by serum markers (WBC, CRP and serum ferritin), clinical symptoms and ratio of patients who required additional therapy, and safety was evaluated by adverse events for 52 week. Results The mean age was 41.4. The ratio of fever, arthralgia, rash and sore throat are 100% (n=7/7), 100% (n=7/7), 85.7% (n=6/7) and 71.4% (n=5/7) respectively. LOCF analysis revealed that WBC, CRP and serum ferritin level decreased significantly from 14757±4667/μl to 6985±2903/μl, from 13.4±7.1mg/dl to 0.3±0.6mg/dl and from 6927±5376ng/ml to 2416±5589ng/ml at month 7 (TCZ final infusion) respectively (each, P Conclusions TCZ monotherapy can be an alternative treatment strategy for AOSD in some patients. References Sakai R, et al.:Clin Rheumatol. 2012 Mar;31(3):569–74. Ortiz-Sanjuan F et al.: Arthritis Rheumatol. 2014 Jun;66(6):1659–65. Disclosure of Interest T. Kondo: None declared, Y. Okada: None declared, A. Shibata: None declared, K. Chino: None declared, T. Kurasawa: None declared, A. Okuyama: None declared, H. Takei: None declared, K. Amano Grant/research support from: Chugai Pharmaceutical Co.Ltd.

For language teachers who are concerned about referring to their own and students’ identities other than in the roles of ‘teacher’ and ‘student’ in the classroom, this conversation analytic study aims to give insights into the use of identity. Detailed analysis of the data of English for a Specific Purpose (ESP) classrooms indicates that contrasting the teacher’s and students’ non-default situated identities, such as senpai (‘senior’ in English) with kohai (‘junior’ in English) and sociologist with scientist, is a way for the language teacher to perform the role of ‘teacher’ effectively in ESP classrooms: the practice constructs an epistemic gradient among the teacher and the students and makes some actions accountable by the participants, who is ascribed a superior epistemic status with an identity. The study concludes with a discussion of the contribution the use of identity can make to ESP/LSP (language for specific purposes) and suggestions for ESP/LSP course development.

OBJECTIVE We attempted to clarify the influence of polymorphisms of nuclear receptors on carbamazepine therapy. PARTICIPANTS AND METHODS The common polymorphisms of nuclear receptors--a tentative pregnane X receptor (PXR)*1B, hepatocyte nuclear factor 4α (HNF4α) rs2071197 (c.115+308G>A), and cytochrome P450 3A5*3 polymorphisms--were genotyped in 168 Japanese patients with epilepsy. The associations of these polymorphisms with the disposition, clinical efficacy, and incidence of adverse effects of carbamazepine treatment were retrospectively investigated in 104 patients treated with carbamazepine alone. The associations with disposition were also assessed in 64 patients treated with carbamazepine and other antiepileptic drugs, which constituted the internal replication group, and in the combined 168 patients. RESULTS Neither polymorphism alone affected the carbamazepine disposition, but a significant interactive effect of PXR*1B and HNF4α rs2071197 polymorphisms on the concentration-to-dose (C/D) ratios was observed (P=0.027). The C/D ratios among patients with the HNF4α G/G genotype were higher in PXR*1B carriers than in PXR*1B noncarriers, which was confirmed in the internal replication and combined groups. In patients with the HNF4α G/G genotype, the rate of freedom from seizures until 3 months after starting carbamazepine therapy was significantly greater and the time required to reach the dose required for seizure freedom was shorter in PXR*1B carriers than in PXR*1B noncarriers. CONCLUSION These results suggest that PXR*1B, in combination with HNF4α rs2071197, might be associated with the C/D ratios and the duration to reach the maintenance dose of carbamazepine therapy, thus indicating an influence upon the autoinduction of the carbamazepine metabolism.

411 Background: FOLFIRINOX (FFX) is a standard therapy for unresectable/recurrent pancreatic cancer, but it is associated with a high frequency of severe adverse events, especially blood toxicity. Human pegylated granulocyte colony-stimulating factor (PEG-G-CSF) can reduce the outpatient frequency during outpatient chemotherapy. However, there are few reports on the effectiveness of PEG-G-CSF in preventing febrile neutropenia during FFX. We retrospectively investigated the usefulness of PEG-G-CSF in reducing the incidence of FN during FFX. Methods: From June 2014 to January 2017, 40 patients with unresectable pancreatic cancer received FFX (including modified FFX) at our hospital. Twenty-three patients were administered PEG-G-CSF as primary/secondary preventive therapy (G group) and 17 were not administered any G-CSF (NG group). Results: The median patient ages in the G and NG groups were 65 (range, 48-78) and 63 (range, 42-81) years, respectively, and the male to female ratios were 13:10 and 11:6, respectively. There were 13 and 10 patients, respectively, in the G group with performance statuses of 0 and 1 and 8 and 9 such patients, respectively, in the NG group. Seventeen and five patients in the G and NG groups, respectively, had metastatic disease and six and two patients, respectively, had locally advanced disease. The respective response rates (RRs) in the G and NG groups were 30% and 6% (p = 0.0608), and the respective disease control rates (DCRs) were 30% and 41% (p = 0.0407). The median progression-free survivals in the G and NG groups were 7.3 (95% confidence interval [CI], 3–9.4) and 4.5 (95% CI, 1.9–8.5) months, respectively (p = 0.173), and the respective overall survivals were 16.9 (95% CI, 10.2–NA) and 14.2 (95% CI, 7.8–20.5) months (p = 0.302). Conclusions: The DCR was significantly greater in the G group than in the NG group, and the RR tended to be greater in the G group than in the NG group. A high tumor shrinking effect of FFX with PEG-G-CSF indicated that it might be useful as a neoadjuvant chemotherapy. A prospective study is needed to examine first-line chemotherapy in unresectable/recurrent pancreatic cancer and neoadjuvant chemotherapy in borderline/locally advanced pancreatic cancer.

Background and aim The significance of examination time of esophagogastroduodenoscopy (EGD) for asymptomatic examinees is yet to be established. We aimed to clarify whether endoscopists who allot more examination time can detect higher numbers of neoplastic lesions among asymptomatic examinees. Methods We reviewed a database of consecutive examinees who underwent EGD in our hospital from April 2010 to September 2015. Staff endoscopists were classified into fast, moderate, and slow groups based on the mean examination time of EGD without a biopsy. The neoplastic lesion detection rate among these groups was compared using multiple logistic regression. Results Of the 55,786 consecutive examinees who underwent EGD, 15,763 asymptomatic examinees who were screened by staff doctors were analyzed. The mean examination time of 13,661 EGDs without biopsy was 6.2 min (range, 2–18 min). When cutoffs of 5 and 7 min were used, 4 endoscopists were classified into the fast (mean duration, 4.4 ± 1.0 min), 12 into the moderate (6.1 ± 1.4 min), and 4 into the slow groups (7.8 ± 1.9 min). The neoplastic lesion detection rates in the fast, moderate, and slow groups were 0.57% (13/2,288), 0.97% (99/10,180), and 0.94% (31/3,295), respectively. Compared with that in the fast group, the odds ratios for the neoplastic lesion detection rate in the moderate and slow groups were 1.90 (95% confidence interval [CI], 1.06–3.40) and 1.89 (95% CI, 0.98–3.64), respectively. Conclusion Endoscopists who do not allot adequate examination time may overlook neoplastic lesions in the upper gastrointestinal tract. This article is protected by copyright. All rights reserved.

Background and study aims: An iincreasing number of reports describe endoscopic ultrasound-guided hepaticogastrostomy for malignant biliary obstruction in patients with endoscopic retrograde cholangiopancreatography failure. However, this procedure has not yet been standardized; as a result, the rate of adverse events, including bile leakage and stent migration, is relatively high. Here, we report our experience with four cases of endoscopic ultrasound-guided hepaticogastrostomy performed according to our institutional procedure.

Polyvinyl alcohol (PVA) has been used to prevent flaking of paint pigments on traditional Japanese Shohekiga painted screens and panels. However, over time these PVA coatings whiten. To date, the mechanism of this whitening has not been studied from the point of view of polymer degradation. In this study, a piece of whitened PVA was obtained from a painted wooden panel. The PVA whitening mechanism was studied in this piece using scanning electron microscopy (SEM) and functional group analysis by Fourier transform-infrared spectroscopy (FT-IR) and X-ray photoelectron spectroscopy (XPS). SEM showed that the surface of the whitened PVA thin film was irregular and rugged, and many micrometer-sized cracks were observed. This suggests that efficient scattering of all visible light from the cracks causes whitening. FT-IR and XPS measurements revealed that inter- and intra-chain dehydration and chemical crosslinking (C–O ether linkage) occur on the surface of the whitened PVA. Polyvinyl alcohol (PVA), which has been used to prevent flaking of paint pigments on traditional Japanese Shohekiga, became white and we investigated its phenomenon. The surface of whitened PVA was irregular and rugged, and many micrometer size cracks were observed. This suggests that efficient scattering of all visible region light from the cracks causes whitening. Fourier transform-infrared spectroscopy and X-ray photoelectron spectroscopy measurements revealed that interchain dehydration and chemical crosslinking (C–O ether linkage) occurred on the surface of whitened PVA.

This study aims to discuss role-play activity in oral proficiency interviews (OPIs) in terms of its construct validity; that is, whether it correlates with what it is supposed to measure. The data for the analysis were obtained from 71 role-play activities conducted during an OPI. The analysis is based on conversation analytic (CA) methodology and invokes the analytic frameworks of interactive footing and interactional competencies. Conversational analyses performed on the data revealed that candidates executed not only the role-play instructions but also the interviewers’ explicit and implicit requirements of the next desirable action. In doing so, candidates employed and displayed their interactional competencies in role-play interactions. The role-play activity in the OPI being managed by the interviewer created an asymmetrical relationship between the interviewers and the candidates in terms of speaking rights (i.e., turn-taking and topical organization). Nevertheless, competencies that candidates displayed in performing a role-play activity did not seem different from those employed in ordinary conversations. Thus, role-play activity in OPIs, if recognized as an interactional phenomenon co-constructed by participants’ display of their turn-by-turn practical evaluation of each other's actions, seems to be a valid instrument for assessing the candidates’ performance of the given tasks.

Purpose: The Biopharmaceutics Classification System (BCS) based biowaiver is a scientific model which enables the substitution of in vivo bioequivalence studies with in vitro data as evidence of therapeutic equivalence subject to certain conditions. Despite being based on the same principles, BCS-based biowaivers are interpreted and regulated differently among international regulatory agencies. In this survey, the Bioequivalence Working Group (BEWG) of the International Generic Drug Regulators Programme (IGDRP) compared the criteria for BCS-based biowaivers applied by the participating regulators and organisations. Methods: Differences and similarities regarding solubility, permeability, dissolution, excipients and fixed-dose combination products, were identified and compared in a detailed survey of each participant’s criteria for BCS-based biowaivers. These criteria were determined based upon the participants’ respective regulatory guidance documents, policies and practices. Results: This review has, with the exception of two participants who do not accept BCS-based biowaivers, revealed that most IGDRP participants interpret the BCS principles and conditions similarly but notable differences exist in the application of these principles. Conclusion: Although many similarities exist, this review identifies several opportunities for greater convergence of regulatory requirements amongst the surveyed jurisdictions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page

The surfaces of core histones in nucleosome are exposed as required for factor recognition, or buried for histone-DNA and histone-histone interactions. To understand the mechanisms by which nucleosome structure and function are coordinately altered in DNA-mediated reactions, it is essential to define the roles of both exposed and buried residues and their functional relationships. For this purpose, we developed GLASP (GLobal Analysis of Surfaces by Point mutation) and GLAMP (GLobal Analysis of Mutual interaction surfaces of multi-subunit protein complex by Point mutation) strategies, both of which are comprehensive analyses by point mutagenesis of exposed and buried residues in nucleosome, respectively. Four distinct DNA-mediated reactions evaluated by Ty suppression (the Spt(-) phenotype), and sensitivities to 6-azauracil (6AU), hydroxyurea (HU), and methyl methanesulfonate (MMS), require common and different GLAMP residues. Mutated GLAMP residues at the interface between histones H2A and H2B mainly affect the Spt(-) phenotype but not HU and MMS sensitivities. Interestingly, among the mutated GLAMP residues surrounding the histone H3-H3' interface, some equally affect the Spt(-) phenotype, and HU and MMS sensitivities, whereas others differentially affect the Spt(-) phenotype, and HU and MMS sensitivities. Based on these and other results, the functional relationships among chromatin factors and GLASP and GLAMP residues provide insights into nucleosome disassembly/assembly processes in DNA-mediated reactions.

Here, we demonstrated the one-step production of cadaverine from starch using a Corynebacterium glutamicum strain coexpressing Streptococcus bovis 148 alpha-amylase (AmyA) and Escherichia coli K-12 lysine decarboxylase (CadA). We constructed the E. coli-C. glutamicum shuttle vector, which produces CadA under the control of the high constitutive expression (HCE) promoter, and transformed this vector into C. glutamicum CSS secreting AmyA. The engineered C. glutamicum expressed both CadA and AmyA, which retained their activity. We performed cadaverine fermentation using 50 g/l soluble starch as the sole carbon source without pyridoxal-5'-phosphate, which is the coenzyme for CadA. C. glutamicum coexpressing AmyA and CadA successfully produced cadaverine from soluble starch and the yield of cadaverine was 23.4 mM after 21 h. CadA expression levels under the control of the HCE promoter were assumed to be sufficient to convert L-lysine to cadaverine, as there was no accumulation of L-lysine in the culture medium during fermentation. Thus, we demonstrated that C. glutamicum has great potential to produce cadaverine from biomass resources.

We aimed to evaluate the effects of cytochrome P450 (CYP) 2C19 and CYP3A5 polymorphisms on zonisamide (ZNS) clearance. The pharmacokinetics of the 282 ZNS concentrations at a steady state obtained from 99 Japanese epileptic patients was performed with a nonlinear mixed-effect modeling program, using a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight, gender, ZNS daily dose, CYP2C19 and CYP3A5 genotypes, and the coadministered antiepileptic drugs. The final model of ZNS apparent clearance was as follows: CL = 1.22 x (BW/44)0.77 x DOSE(-0.17 x 0.84CYP2C19 hetero EM x 0.70CYP2C19 PM x 1.24CBZ x 1.28PHT x 1.29PB x eetaCL where CL is the apparent oral clearance of ZNS, DOSE is ZNS daily dose, and CYP2C19 heterozygous extensive metabolizer (EM) or CYP2C19 poor metabolizer (PM) is equal to 1 if one or two CYP2C19-defective alleles are carried, respectively; otherwise, it is 0. Carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB) is equal to 1 if carbamazepine, phenytoin, or phenobarbital is coadministered, respectively; otherwise, it is 0. etaCL is the independent random error distributed normally with the mean zero and variance equal to omegaCL. The CL of ZNS was lower in the CYP2C19 heterozygous extensive metabolizers and poor metabolizers than in the homozygous extensive metabolizers by 16% and 30%, respectively (P < 0.001). An effect of CYP3A5 polymorphisms was not identified. The coadministration of carbamazepine, phenytoin, or phenobarbital increased the CL of ZNS by 24% to 29%. This report demonstrates that the CYP2C19 genotype affects the ZNS metabolism in Japanese epileptic subjects. The clinical relevance of these changes remains to be explored in future studies.

Haplotype frequencies of the beta-globin gene cluster of Han Chinese at Beijing, Xi'an, and Kunming were estimated, and their mutual genetic relationships were examined and compared to those of Buryats, Khalkhs, Evenkis, Oroqens, Koreans, and Colombian Amerindians. A major 5' subhaplotype (5' to the delta-globin gene), a major 3' subhaplotype (in and 3' to the beta-globin gene), and a major haplotype (combination of 5' and 3' subhaplotypes) are represented as + - - - -, - +, and + - - - - - +, respectively, and found in all three Han Chinese. A rare 5' subhaplotype, - - - - -, which is one of the possible ancestral types, was found only in Han Chinese at Kunming at low frequency (0.013), and a rare 3' subhaplotype, - -, was also observed in all three Han Chinese at low frequencies (0.009-0.014). The present haplotype frequency study suggested that the highest genetic affinity was found between Han Chinese at Beijing and those at Xi'an; the next highest was between Han Chinese at Beijing and Koreans, followed by that between Han Chinese at Beijing and Khalkhs, then that between Han Chinese at Xi'an and those at Kunming or Khalkhs, and finally that between Han Chinese at Beijing and those at Kunming. A genetic boundary between northern and southern Han Chinese was not evident in the present study.