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Bito T.,Kobe University | Nishikawa R.,Kobe University | Hatakeyama M.,Kobe University | Kikusawa A.,Kobe University | And 10 more authors.
British Journal of Dermatology | Year: 2014

Background Current treatment with biologics has produced dramatic therapeutic effects in patients with psoriasis, although these agents occasionally decrease in efficacy. One of the main factors responsible for this attenuation is attributed to the development of antidrug antibodies (ADAs). Objectives To analyse the relationship between serum drug concentrations, the presence of ADAs and treatment efficacy of adalimumab and infliximab, and to determine the optimal use of these biologics. Methods This was a 1-year prospective study in the dermatology departments of Kobe University Hospital and collaborating hospitals. All patients starting a regimen of adalimumab and infliximab for psoriasis were included. We measured the serum concentration of the drugs and titres of antibodies to adalimumab and infliximab, as well as the Psoriasis Area and Severity Index scores at weeks 0, 4, 12, 24 and 48 during the first year of treatment. Results We observed a 50% positive rate of ADAs to adalimumab, and a 41% positive rate of ADAs to infliximab. The titres of ADAs showed a wide range from low to high titres. In the high-titre groups, the patients exhibited a decreased clinical response, and demonstrated a negative correlation between titre and clinical response. However, an equivalent therapeutic effect was observed between the low-titre group and the group with no antibodies detected for adalimumab. For infliximab, the patients with ADAs showed decreased clinical response. An apparent negative correlation between antibody production and reduced clinical response was observed. Conclusions Two biologics, adalimumab and infliximab, showed different therapeutic behaviour. The measurement of ADAs and drug concentrations has important implications for treatment with biologics. What's already known about this topic? High frequent production of antidrug antibodies (ADAs) has been observed in patients treated with biologics, and the production has caused impairment of treatment efficacy. What does this study add? The optimal use of the biologics should be determined by the measurement of ADAs and each drug concentration in each patient because the standard protocol may not uniformly fit all patients. © 2013 British Association of Dermatologists.


Origasa H.,University of Toyama | Yokoyama M.,Hyogo Prefectural Awaji Hospital | Matsuzaki M.,Yamaguchi University | Saito Y.,Chiba University | Matsuzawa Y.,Sumitomo Hospital
Circulation Journal | Year: 2010

Background: Despite the risk of critical heart disease, poor adherence to treatment is common in patients with lifestyle-related diseases such as hypercholesterolemia. The association between adherence to treatment and clinical outcome was examined in JELIS (Japan EPA Lipid Intervention Study) and strategies for avoiding poor adherence were explored. Methods and Results: Patients taking 80% or more of the study medications were considered to exhibit good adherence. The primary endpoint was either sudden cardiac death or myocardial infarction. Adherence was lower in the eicosapentaenoic acid (EPA) + statin group (66.5%) than in the statin alone group (72.5%). In good adherers with previous coronary artery disease, EPA substantially reduced the risk compared with statin alone (hazard ratio 0.55, 95% confidence intervals 0.34-0.88, P<0.014). Furthermore, the clinical benefit of EPA + statin was significantly larger in patients with good adherence than in those with poor adherence (P=0.041). Finally, a 5-year risk prediction model constructed from the data indicated that complete adherence would lead to 51% reduction of risk compared with non-adherence. Conclusions: Good adherence to medication was associated with a lower cardiovascular risk than with poor adherence, and the assistance of a pharmacist is of great importance in achieving persistent adherence during treatment.


Mizoguchi T.,Hyogo Prefectural Awaji Hospital | Sawada T.,Hyogo Prefectural Awaji Hospital | Shinke T.,Kobe University | Yamada S.,Hyogo Brain and Heart Center | And 4 more authors.
International Journal of Cardiology | Year: 2014

Background The differences in lesion morphology between ST-segment elevation myocardial infarction (STEMI) and stable angina (SAP) significantly influence chronic intra-stent conditions after first-generation drug-eluting stent implantation. The study aimed to compare the intra-stent conditions 12 months after implantation of a second-generation everolimus-eluting stent (EES) in patients with STEMI or SAP. Methods and results We examined the lesion morphology before EES implantation in 53 patients (23 STEMI, 30 SAP) using virtual histology intravascular ultrasound. We maintained dual anti-platelet therapy for 12 months and subsequently analyzed intra-stent conditions using optical coherence tomography and angioscopy. Pre-intervention plaque and necrotic core volume/length, remodeling index, and the incidence of thin-cap fibroatheroma and thrombus were significantly greater in STEMI than in SAP. After 12 months, the median neointimal thickness (117.6 μm vs. 126.0 μm), frequency of uncovered struts (1.2% ± 2.3% vs. 1.0% ± 2.3%), and percentage of stents fully covered with neointima (60.9% vs. 61.1%) were similar between the 2 groups. Meanwhile, the frequency of malapposed struts (0.4% ± 0.6% vs. 0.1% ± 0.4%, p = 0.04) and neointimal unevenness score (1.74 ± 0.21 vs. 1.64 ± 0.16, p = 0.04) were significantly higher in STEMI than in SAP. The neointimal color grade was more xanthochromatic in STEMI than in SAP. However, the differences were not associated with the incidence of clinical events and intra-stent thrombus (21.7% vs. 16.7%, p = 0.89). Conclusions Although a small degree of delayed healing still persists with second-generation EES, EES promotes a favorable arterial healing response in patients with STEMI, as well as those with SAP. © 2013 Published by Elsevier Ireland Ltd.


Tanaka S.-I.,Toyooka Hospital Hidaka Medical Center | Miki T.,Toyooka Hospital Hidaka Medical Center | Sha S.,Toyooka Hospital Hidaka Medical Center | Hirata K.-I.,Kobe University | And 2 more authors.
Journal of Atherosclerosis and Thrombosis | Year: 2011

Aim: Evidence of relationships between lipid peroxidation and the incidence of coronary heart disease is limited. We therefore investigated this association in a Japanese general population. Methods: We prospectively studied 1945 individuals who were apparently healthy at the baseline. Cox proportional-hazards models were used to investigate the relationship between serum levels of thiobarbituric acid-reactive substances (TBARS) as a marker of lipid peroxidation and the incidence of coronary heart disease, adjusted for established risk factors including age, sex, current smoking, body mass index, systolic blood pressure, glycohemoglobin A1c, serum total cholesterol, and serum high-density lipoprotein cholesterol levels. Results: During 20,226 person-years of follow-up (median follow-up, 10.9 years), 44 coronary events were documented. The risk of coronary heart disease increased in consecutive tertiles of the TBARS level. On age-and sex-adjusted analysis, the level of TBARS was significantly associated with the incidence of coronary heart disease. The hazard ratio in the highest tertile compared with the lowest tertile was 3.22 (95% confidence interval, 1.38 to 7.53; p = 0.007). On multivariate analysis adjusted for age, sex, and other established risk factors, this association remained significant (hazard ratio, 3.23; 95% confidence interval, 1.28 to 8.16; p = 0.01). Conclusions: Serum levels of TBARS are a strong and independent predictor of coronary heart disease. These findings support the hypothesis that lipid peroxidation is an important risk factor for coronary heart disease.


Horiguchi H.,Tokushima University | Yamagata S.,Hyogo Prefectural Awaji Hospital | Qian Z.R.,Tokushima University | Kagawa S.,Tokushima University | Sakashita N.,Tokushima University
Journal of Medical Investigation | Year: 2013

Desmoplastic (scirrhous) invasion and lymph node metastasis are critical for the treatment and prognosis of invasive ductal carcinoma of the breast. Despite being an anti-angiogenic therapeutic candidate, Thrombospondin-1 (TSP-1) promotes invasion and metastasis of some carcinomas. To clarify the effect of TSP-1 on invasion and metastasis, we obtained 101 invasive ductal carcinomas of the breast with axillary lymph node resection. All tumors were histologically divided into two categories, carcinomas with, and those with non- /minimal desmoplastic component. Immunohistochemistry for TSP-1 was performed on all primary tumors and axillary lymph nodes with tumor metastasis. Fifty-four (53.5%) of 101 tumors were recognized as positive for TSP-1 in the cytoplasm of tumor cells. Histological study showed that significantly more cancers with desmoplastic components (46/69, 66.7%) manifested TSP-1 expression than did cancers with no- or minimal (less than 20%) desmoplasia (8/32, 25.0%; p 0.001). Axillary lymph node metastasis was significantly higher in TSP-1-positive- (28/54, 51.9%) than TSP-1- negative cancers (11/47, 23.4%; p 0.005). The present study indicates that tumor cells in the desmoplastic component strongly expressed TSP-1 in invasive ductal carcinoma of the breast and TSP-1 participates in invasion of these tumors. Our findings also suggest that TSP-1 promotes lymph node metastasis and TSP-1 potentially could be a predictive marker for metastasis.


Sawada T.,Himeji Brain and Heart Center | Shiotani H.,Kobe University | Terashita D.,Hyogo Prefectural Awaji Hospital | Nagasawa Y.,Hyogo Prefectural Awaji Hospital | And 3 more authors.
Circulation Journal | Year: 2014

Background: Studies have shown that repeated post-prandial hyperglycemia may play an important role in the development of atherosclerosis by suppressing endothelial function. α-Glucosidase inhibitors (α-GIs), which reduce postprandial hyperglycemia without stimulating insulin secretion, significantly reduce the risk of coronary artery disease (CAD), whereas glinides, which improve post-prandial hyperglycemia through post-prandial insulin secretion, do not appear to affect CAD. Methods and Results: A total of 104 diabetic patients with CAD were randomly divided into 2 groups: those treated with miglitol (M-group; n=52) and those treated with nateglinide (N-group; n=52). After 4 months' treatment, although hemoglobin A1c and 1,5-anhydroglucitol were significantly improved in both groups, only the M-group had significant reductions in insulin resistance index and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C; a beneficial index for assessing the presence of small dense low-density lipoprotein, and a marker of atherogenic dyslipidemia). Furthermore, only the M-group had improvement in percentage flow-mediated dilatation (%FMD) and reactive oxygen metabolites. In the M-group, multiple regression analysis showed that improvement in TG/HDL-C, in addition to 1,5-anhydroglucitol, was an independent predictor of improvement in %FMD. Conclusions: The ameliorating effect of α-GI on post-prandial hyperglycemia without stimulating insulin secretion may improve atherogenic dyslipidemia by reducing insulin resistance. These effects are associated with its beneficial impact on oxidative stress, consequently leading to an improvement in endothelial dysfunction.


Matsuo T.,Hyogo Prefectural Awaji Hospital | Wanaka K.,Kobe Research Projects on Thrombosis and Haemostasis | Walenga J.M.,Loyola University
Clinical and Applied Thrombosis/Hemostasis | Year: 2013

A retrospective study was performed to elucidate the characteristics of heparin-induced thrombocytopenia (HIT) in newly treated hemodialysis (HD) patients who essentially required anticoagulation with unfractionated heparin (UFH). Seventy-eight patients suspected of having HIT within 3 months of starting HD with UFH were selected for this study. Their platelet counts were routinely followed, and anti-PF4/heparin complex antibodies (HIT antibodies) were measured with enzyme-linked immunosorbent assay (ELISA) until the titer became negative. The characteristics of thrombocytopenia were a platelet count of ≤150 × 109/L and/or decrease of ≥30% and as caused by the intermittent use (3 times/a week) of UFH during HD. Fifty-five patients showed unexpected clotting in the extracorporeal circuit and/or arteriovenous fistula (AVF) thrombosis, while 23 patients had neither of these complications. The patients were classified into HD-related and non-HD-related thrombus groups. The impact of various combinations of the 3 clinical factors (thrombocytopenia, timing, and HD-related thrombus) and the results of ELISA as a laboratory factor were examined. A combination of 2 platelet factors (thrombocytopenia and timing) and ELISA positivity did not reveal the presence of HIT, while a combination of the 3 clinical factors and a positive ELISA improved the accuracy of HIT diagnosis. The findings on the 4-factor combination were supported by high rates of seroconversion in a serotonin release assay. Combining appropriate clinical factors and a positive ELISA may lead to the proper management of HD patients suspected of having HIT. In conclusion, while HD patients showed a drop of ≤150 × 109/L or ≥30% on days 7 to 30, unexpected clotting in the circuit and/or AVF thrombosis was considered as a sign of HIT development. © 2012 The Author(s).


Kario K.,Jichi Medical University | Yano Y.,Jichi Medical University | Yano Y.,University of Miyazaki | Matsuo T.,Hyogo Prefectural Awaji Hospital | And 3 more authors.
Journal of Hypertension | Year: 2011

OBJECTIVE: To examine whether or not the extent of morning blood pressure surge (MBPS), defined as a morning SBP increase from sleep SBP, is associated with that of platelet aggregation, coagulation/fibrinolytic activity, and silent cerebral infarction (SCI) in older hypertensive patients. METHODS: Sixty hypertensive patients aged at least 60 years (mean age 70.6 years; 40% men) underwent measurement of morning spontaneous small-sized platelet aggregation (SPA) detected by a light scattering intensity method, measurement of circulatory levels of von-Willebrand factor (vWF), noradrenalin, and plasma renin activity (PRA), and brain MRI. RESULTS: The extent of MBPS, but not 24-h SBP, was associated with circulatory levels of noradrenalin, PRA, vWF, and spontaneous SPA (all P < 0.05); the association between MBPS and spontaneous SPA remained significant even after adjustment for significant covariates (P < 0.001). The patients with multiple (more than three per person) SCIs had a significantly greater extent of MBPS (43.3 vs. 31.8 mmHg), morning spontaneous SPA (20 471.9 vs. 4850.9 × 10 × 2 mV counts 10 min), and higher circulatory vWF (196.6 vs. 150.1%) compared with those without it (all P < 0.01). On multiple regression analysis, the odds ratio for multiple SCIs with a +1 SD increase of MBPS was 2.0, that of morning spontaneous SPA was 3.0, and that of circulatory morning vWF level was 3.3 (all P < 0.05). When MBPS increase and either platelet aggregation or vWF increases were entered into the same model, the latter parameters, but not the MBPS, were associated with multiple SCIs (both P < 0.05). CONCLUSION: The extent of MBPS was associated with increased activity of morning platelet aggregation in older hypertensive patients. © 2011 Wolters Kluwer Health | Lippincott Williams and Wilkins.


Kario K.,Jichi Medical University | Yano Y.,Jichi Medical University | Matsuo T.,Hyogo Prefectural Awaji Hospital | Hoshide S.,Jichi Medical University | And 2 more authors.
European Heart Journal | Year: 2011

Aims Stroke events occur most frequently in the morning hours. Impaired haemostatic activity and morning blood pressure (BP) surge, defined as the morning BP increase from sleep, have individually been associated with stroke risk in general or hypertensive populations. However, their combined impact on the risk of a stroke remains unknown. Methods and results A total of 514 hypertensive patients aged >50 years (mean 72.3 years; 37men) underwent 24 h BP monitoring, measurement of haemostatic risk factors [plasma fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and prothrombin fragment 12(F12)], and brain MRI at baseline. The incidence of stroke was prospectively ascertained. During an average of 41 months (1751 person-years), there were 43 stroke events (ischaemic, 30; haemorrhagic, 5; undefined, 8). On multivariable analysis adjusted for confounding factors, the hazard ratio [HR (95 confidence interval (CI)] for stroke in the highest vs. lower quartiles of PAI-1 was 2.5 (1.34.6), that for F12 was 2.6 (1.45.0), and that for the morning BP surge was 1.2 (1.11.4; all P< 0.01). In particular, the ratio was substantially higher in cases with the highest quartile of both PAI-1 and F12 levels compared with those with the lower quartiles of both parameters (HR: 8.2; 95 CI: 3.718.2; P< 0.001). Among the patients with the highest quartile of the morning BP surge (n=128), the multivariable HR (95 CI) for the highest vs. lower quartiles of PAI-1 was 3.4 (1.39.1) and that for F12 was 3.3 (1.38.7) (both P< 0.05). Conclusion High levels of plasma PAI-1 and F12, as well as an excessive morning BP surge, are independently and additively associated with an increased risk of stroke in older hypertensive patients. © 2010 The Author.


Hanafusa T.,Okayama University | Mohamed A.E.A.,Alexandria University | Kitaoka K.,Hyogo Prefectural Awaji Hospital | Ohue Y.,Okayama University | And 2 more authors.
Cancer Letters | Year: 2011

Serological analysis of a recombinant cDNA expression library (SEREX) derived from two lung adenocarcinoma cancer cell lines using autologous sera led to the isolation of 41 positive cDNA clones comprising 28 different antigens. They coded for a variety of nuclear and cytoplasmic proteins. Among the antigens, nucleoporin 107 (NUP107) was isolated most frequently (5 of 41 clones). The second most frequently isolated antigen was coded for by C21orf58 (4 of 41 clones). During serological analysis of selected antigens based on their reactivity to sera from normal individuals and lung cancer patients, none of the antigens showed a cancer-restricted recognition pattern. However, five genes including NUP107 showed higher expression when we examined the changes in gene expression in five different adenocarcinoma cell lines, including those used in SEREX, compared with their levels in normal lung tissues by cDNA microarray analysis. On the other hand, the expression levels of five genes including C21orf58 were down regulated in all adenocarcinoma cell lines. This SEREX study combining comprehensive gene expression assays has added to the growing list of lung cancer antigens, which may aid the development of diagnostic and immunotherapeutic reagents for patients with lung cancer. © 2010 Elsevier Ireland Ltd.

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