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ObjectivesTo investigate the clinical impact of 1-year certolizumab pegol (CZP) therapy added to the first year of 2-year methotrexate (MTX) therapy, compared with 2-year therapy with MTX alone.MethodsMTX-naïve patients with early rheumatoid arthritis (RA) with poor prognostic factors were eligible to enter Certolizumab-Optimal Prevention of joint damage for Early RA (C-OPERA), a multicentre, randomised, controlled study, which consisted of a 52-week double-blind (DB) period and subsequent 52-week post treatment (PT) period. Patients were randomised to optimised MTX+CZP (n=159) or optimised MTX+placebo (PBO; n=157). Following the DB period, patients entered the PT period, receiving MTX alone (CZP+MTX→MTX; n=108, PBO+MTX→MTX; n=71). Patients who flared could receive rescue treatment with open-label CZP.Results34 CZP+MTX→MTX patients and 14 PBO+MTX→MTX patients discontinued during the PT period. From week 52 through week 104, significant inhibition of total modified total Sharp score progression was observed for CZP+MTX versus PBO+MTX (week 104: 84.2% vs 67.5% (pConclusionsIn MTX-naïve patients with early RA with poor prognostic factors, an initial 1 year of add-on CZP to 2-year optimised MTX therapy brings radiographic and clinical benefit through 2 years, even after stopping CZP.Trial registration numberNCT01451203.

Background We previously reported that pulmonary capillary wedge pressure (PCWP) was noninvasively evaluated by 2D speckle tracking echocardiography (STE). Recently, novel software was introduced to examine volume and function of left ventricular and left atrium (LA) by 3D-STE automatically. Purpose We sought to compare the PCWP estimated by conventional 2D-STE (2D-ePCWP) and by novel 3D-STE (3D-ePCWP), and validate those values by cardiac catheterization. Methods Echocardiography and catheterization were performed in 29 patients (age 72±2) (7 ischemic heart disease, 2 hypertensive heart disease, 5 dilated cardiomyopathy, 12 valvular heart disease and 3 primary pulmonary hypertension).The ePCWP (mmHg) is noninvasively obtained as 10.8 − 12.4 x Log (left atrial active emptying function/minimum volume) as we previously reported. Echocardiography was performed just before the catheterization and we analyzed the 2D and 3D data by novel off-line software. 3D data was automatically analyzed and the border settings were fixed at default (ES60, ED30) (Figure). Results 2D-ePCWP and 3D-ePCWP had a good correlation with PCWP invasively obtained by catheterization (r=0.87 and 0.83, respectively, both p Conclusion This study demonstrated that PCWP might be noninvasively assessed by not only 2D-STE but also 3D-STE with reasonable accuracy and 3D-STE might have utility and value in the routine clinical practice.

Background Left ventricular (LV) diastolic function is mainly composed of LV relaxation and LV stiffness. We reported that pulmonary capillary wedge pressure (ePCWP) and LV relaxation assessed by Tau (eTau) are noninvasively evaluated by speckle tracking echocardiography (STE). The minimum LV diastolic pressure (mLVP) was reported to have a strong correlation with Tau. Therefore, LV chamber stiffness (c-stiffness) may be assessed with the use of two LV diastolic pressure-volume coordinates: the mLVP and volume and the end-diastolic pressure (EDP) and volume. Purpose We sought to noninvasively assess LV stiffness using STE and validate the value by cardiac catheterization. Methods Echocardiography and catheterization were performed in 124 patients (age 72±8) (70 angina pectoris, 20 prior myocardial infarction, 19 hypertensive heart disease, 11 congestive heart failure and 4 paroxysmal atrial fibrillation). The ePCWP (mmHg) is noninvasively obtained as 10.8 − 12.4 × Log (left atrial active emptying function/minimum volume) and the eTau (ms) is obtained as isovolumic relaxation time/(ln 0.9 × systolic blood pressure − ln ePCWP) as previously reported. The mLVP (e-mLVP) was estimate using Tau. The estimated EDP (e-EDP) was calculated as 12.3 − 10.1 × Log (left atrial active emptying function / minimum volume). LV c-stiffness (mmHg/ml) was calculated as LV pressure change (from mLVP to EDP) obtained by catheterization divided by LV volume change during diastole which equals to stroke volume by echocardiography. Estimated c-stiffness (e-c-stiffness) was noninvasively obtained using e-mLVP and e-EDP. Furthermore, LV myocardial stiffness (m-stiffness) was calculated by LVED stress / LV longitudinal strain by STE, where LV stress (kdynes/cm2) was calculated as 0.334 × pressure × dimension / [thickness (1 + thickness/dimension)]. The estimated m-stiffness (e-m-stiffness) was calculated using e-EDP. Results The eTau and e-EDP estimated by STE had a good correlation with Tau and EDP invasively obtained by catheterization (r=0.75 and 0.63, respectively, both p Conclusion This study demonstrated that LV stiffness may be noninvasively assessed by STE with reasonable accuracy and may have utility and value in the routine clinical practice for the diagnosis and treatment in patients with diastolic dysfunction.

Background Left ventricular (LV) pressure-strain and pressure-volume (P-V) loop area reflect global myocardial work (MW) and stroke work (SW), but clinical use of these indexes is limited by the need of invasive pressure measurement. A noninvasive method to obtain LV pressure-strain loop area was recently introduced to examine MW by speckle tracking echocardiography (STE). Purpose We sought to evaluate the impact of preload change on MW and SW obtained using this novel method and to examine the utility to assess LV contractile performance by the SW and end-diastolic volume (EDV) relation (SW-VED) in patient with hemodialysis (HD). Methods LV pressure in a cardiac cycle was estimated using systolic blood pressure (SBP), LV minimum diastolic pressure (mDP) and end-diastolic pressure (EDP) in 20 HD patients (age 67±9)and 25 controls (age 67±9) by utilizing the profile of an empiric, normalized reference curve adjusted according to the duration of LV isovolumic and ejection phases as defined by timing of aortic and mitral valve events by echocardiography. Pulmonary capillary wedge pressure (ePCWP) is estimated as 10.8 – 12.4 × Log (left atrial active emptying function/minimum volume): KT index as previously reported. LVEDP were estimated as 12.3 – 10.1 × KT index. We examined the relation between LV pressure decline (Tau) and mDP by catheterization in 126 patients. Tau is estimated as isovolumic relaxation time/(ln 0.9 × systolic BP − ln ePCWP) as previously reported. SW was obtained by P-V loop area using the combination of pressure (SBP, mDP and EDP) and LV volume by 3D-STE. Echo parameters and BP were measured before and after HD and before and after leg up in controls. Results The mDP obtained by catheterization had a good correlation with Tau (Tau = 33.7 + 2.06 × mDP, r=0.70, p Conclusion LVSW noninvasively obtained by P-V loop area was increased in controls associated with increased preload and decreased in HD with decreased preload and SW-VED was deceased in HD. This novel and noninvasive method may be of potential utility to assess LV contractility and have a clinical interest and value to assess LV function.

Introduction Left ventricular (LV) pressure-volume (P-V) loop area reflects stroke work (SW), but clinical use of this index is limited by the need of invasive pressure measurement. A noninvasive method to obtain LV pressure-strain loop was recently introduced to assess myocardial work (MW). The minimum LV diastolic pressure (mLVP) was reported to have a strong correlation with Tau and we reported that Tau was noninvasively evaluated by speckle tracking echocardiography (STE). Purpose We sought to evaluate the impact of preload change by leg lifts on LV SW noninvasively obtained by the novel method and to examine the utility to assess LV contractility by SW and end-diastolic (ED) volume relation (SW-VED). Methods Thirty six controls (age 71±10) and 30 patients with heart failure with reduced ejection fraction (EF) Results LVEF and longitudinal strain in HF before leg up by 3D-STE were lower compared to normal (LVEF; normal: 58±5 vs HF: 39±10*% and strain; −12±3 vs −8±3%*, *p Conclusion LV SW noninvasively obtained by P-V loop area was increased after leg up in both normal and HF but SW-VED in HF was smaller than normal, indicating reduced contractility in HF. This noninvasive method may be a new echocardiographic approach for quantification of LV SW and contractility.

Aim The Certolizumab–Optimal Prevention of joint damage for Early Rheumatoid Arthritis (C‐OPERA) study demonstrated that in methotrexate (MTX)‐naïve early RA patients with poor prognostic factors, 1‐year certolizumab pegol (CZP) therapy added to the first year of 2‐year optimized MTX therapy brings radiographic and clinical benefits through 2 years even after stopping CZP. This exploratory analysis aimed to identify factors at baseline and at CZP discontinuation associated with successful CZP discontinuation. Methods MTX‐naïve early RA patients with poor prognostic factors entered C‐OPERA (NCT01451203), a multicenter, randomized controlled trial. Patients were randomized to CZP + MTX (n = 159) or PBO + MTX (n = 157); those who completed the 1‐year, double‐blind period received MTX alone in Year 2 (CZP + MTX→MTX, n = 108; PBO + MTX→MTX, n = 71). Association between factors at baseline or at discontinuation of CZP and clinical/radiographic outcomes were evaluated by multiple logistic regression analysis. Predictive value cut‐offs were calculated using receiver operating characteristic analysis. Results Sex (male) and low baseline Disease Activity Score of 28 joints – erythrocyte sedimentation rate (DAS28‐ESR) were associated with simple disease activity index (SDAI) remission (≤3.3), whereas high baseline DAS28‐ESR and modified total Sharp score (mTSS) were associated with clinically relevant radiographic progression (yearly progression mTSS > 3) at Week 104 (across both treatment arms). Low DAS28‐ESR (

Background:Pulmonary hypertension (PH) is prominent as a vascular involvement of systemic sclerosis (SSc), which remains a leading cause of death in spite of current best treatments. Recently, hemodynamic definition of PH was updated from mPAP≥25mmHg to mPAP>20mmHg and PVR≥3WU. Although new definition may improve the prognosis of PH associated with SSc by giving a chance to start management early, it may be insufficient as more than 2/3 of the pulmonary circulation is already impaired by the time of meeting the definition. Therefore, the ideal therapeutic intervention should be started at the subclinical stage of PH in SSc patients, but little is known about underlying pathological mechanisms at the stage. In this study, we investigate progression to exercise-induced PH (exPH)1), which is considered subclinical PH, in the prospective registry of high-risk population for developing PH associated with SSc.Objectives:To detect the gene expressions in peripheral blood involved in the progression of pulmonary vessel disease (PVD) at the subclinical stage of PH associated with SSc.Methods:Total of 180 patients who had not met PH criteria with Raynaud phenomenon, skin sclerosis or SSc-related autoantibody was registered. To detect the early PVD, exercise Doppler echocardiography (exDE) was carried out every 6 or 12 months for up to 6 years. The definition of exPH was maximum sPAP>40mmHg or increase in sPAP>20mmHg estimated by exDE during exercise. For gene expression analysis, total RNAs from whole peripheral blood cells were extracted by PAXgene system, and then multiplex sequencing was done. To identify candidate genes involved in the progression to exPH, random forest machine learning method was employed. Volcano plots, a scatter plots to visualize fold-changes and p-values of differentially expressed genes (DEGs) between exPH and others (exN), were also used for seeking the important genes for disease progression.Results:At the time of registration, 34.4% of patients met exPH criteria, and 15.6% of patients developed exPH during follow-up period (35.0±18.1 months). Expression of TNF gene was selected as the most useful genes to predict progression to exPH by random forest, and the accuracy of the model was about 87%. Volcano plots indicated that expressions of TMEM176A and TMEM176B were prominent (fold-change >2.4 and -log10 p-value >3.5) in exPH patients. The accuracy was improved to 90% if the expression of TNF and TMEMA/B were used for the prediction of progression to exPH. We found that statistically significant increase in the expression of TNF was eliminated at the time of fulfilling the exPH criteria, while increase in expressions of TMEM A/B were still kept.Conclusion:It was reported that TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling2). Our findings suggest that TNFα plays important role only in the period of pre-exPH. On the other hand, increase in expressions of TMEM A/B were observed through the period of pre-exPH to post-exPH. It suggests that there are multiple phases before developing PH associated with SSc. It is very important to understand the phases for the precise treatment to arrest the progression of PVD.References:[1]R. Naeije et al., Am J resp and critical care med 187, 576-583 (2013). 2) LA. Hurst et al., Nat Commun. 13;8:14079 (2017).Disclosure of Interests:Yoshinobu Koyama Speakers bureau: Asahikasei, Ayumi, BMS, Mitsubishi Tanabe, Shin-nihon, Paid instructor for: Asahikasei, Asteras, BMS, Grant/research support from: Eli-Lilly, Yoshiharu Sato: None declared, Tatsuma Shoji: None declared, Soichiro Fuke: None declared, Takatsune Umayahara: None declared, Moe Sakamoto: None declared

Objectives: To compare the efficacy and safety of certolizumab pegol (CZP) with and without loading dose (LD) in a post-hoc analysis of two Japanese clinical studies. Methods: Data from the double-blind trials (DBT) J-RAPID and HIKARI, and their open-label extension (OLE) studies, were used. Patients randomized to CZP 200 mg every 2 weeks (Q2W) groups starting with LD (400 mg Weeks 0/2/4; LD group; J-RAPID: n = 82, HIKARI: n = 116) and patients randomized to placebo groups who subsequently started CZP Q2W without LD in the OLEs (No-LD group; J-RAPID: n = 61, HIKARI: n = 99) were analyzed. Efficacy and pharmacokinetics were assessed during 24 weeks. Adverse events were reported from all studies. Results: In both trials, the LD groups showed more rapid initial ACR20/50/70 kinetics, and maintained higher ACR50/70 responses until 24 weeks, compared with the No-LD groups. Anti-CZP antibody development was less frequent in the LD groups (J-RAPID: 1.2% versus 4.9%; HIKARI: 17.2% versus 27.3%). Similar safety profiles were reported between LD and No-LD groups (any AEs: 281.8 versus 315.7 [J-RAPID], 282.6 versus 321.3 [HIKARI] [incidence rate/100 patient-years]). Conclusions: Despite limitations, including comparing DBT and OLE studies, these results suggest that a CZP LD improves clinical response in active rheumatoid arthritis without altering the safety profile.

Objectives To evaluate efficacy and safety of combination therapy using certolizumab pegol (CZP) and methotrexate (MTX) as first-line treatment for MTX-naive, early rheumatoid arthritis (RA) with poor prognostic factors, compared with MTX alone. Methods MTX-naive, early RA patients with ≤12 months persistent disease, high anti-cyclic citrullinated peptide, and either rheumatoid factor positive and/or presence of bone erosions were enrolled in this multicentre, double-blind, randomised placebo (PBO)-controlled study. Patients were randomised 1:1 to CZP+MTX or PBO+MTX for 52 weeks. Primary endpoint was inhibition of radiographic progression (change from baseline in modified Total Sharp Score (mTSS CFB)) at week 52. Secondary endpoints were mTSS CFB at week 24, and clinical remission rates at weeks 24 and 52. Results 316 patients randomised to CZP+MTX (n=159) or PBO+MTX (n=157) had comparable baseline characteristics reflecting features of early RA (mean disease duration: 4.0 vs 4.3 months; Disease Activity Score 28-joint assessment (DAS28)) (erythrocyte sedimentation rate (ESR)): 5.4 vs 5.5; mTSS: 5.2 vs 6.0). CZP+MTX group showed significantly greater inhibition of radiographic progression relative to PBO+MTX at week 52 (mTSS CFB=0.36 vs 1.58; p

Objectives. A post-hoc analysis was performed to determine the relationship between the timing and magnitude of DAS28(ESR) response and long term outcomes in Japanese patients after 1 year of CZP treatment. Methods. Our analysis included 82 J-RAPID trial patients treated with CZP 200 mg and methotrexate, and 116 HIKARI trial patients treated with CZP 200 mg alone or with disease-modifying agents other than methotrexate. Remission rates and changes in mTSS at year 1 were compared to the DAS28(ESR) response at week 12 of CZP treatment. Results. After 1 year of treatment, remission was achieved in 41.3% of the J-RAPID and 34.9% of the HIKARI patients with a week 12 DAS28(ESR) response of ≥ 1.2. In comparison, patients with a DAS28(ESR) response of < 1.2 at week 12 only had a < 7% probability of achieving remission and displayed higher change in mTSS after 1-year treatment. Conclusions. The likelihood of remission and extent of radiographic progression after 1 year was associated with the week 12 DAS28(ESR) response. The DAS28(ESR) response at 12 weeks could be beneficial for identifying patients that are unlikely to respond to prolonged CZP treatment.

A 4.36-mm-thick pixelated thallium bromide (TlBr) detector with Tl electrodes was fabricated from a crystal grown by the traveling molten zone method using zone-purified material. The detector had four 1×1 mm2 pixelated anodes. The detector performance was characterized at room temperature. The mobility-lifetime products of electrons for each pixel of the TlBr detector were measured to be >2.8×10−3 cm2/V. The four pixelated anodes of the detector exhibited energy resolutions of 1.5–1.8% full width at half maximum (FWHM) for 662-keV gamma rays for single-pixel events with the depth correction method. An energy resolution of 4.5% FWHM for 662-keV gamma rays was obtained from a reconstructed energy spectrum using two-pixel events from the two pixelated anodes on the detector.

Objectives. This 24-week, multicenter, double-blind, randomized, placebo-controlled study (NCT00791999) compared efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) vs placebo plus MTX in Japanese rheumatoid arthritis (RA) patients with inadequate response to MTX. Methods. In total, 316 patients were randomized 1:1:1:1 to subcutaneous CZP 100, 200, or 400 mg (induction dose: 200 mg or 400 mg CZP at Weeks 0, 2, and 4) plus MTX or placebo plus MTX every 2 weeks. Primary endpoint was ACR20 response at Week 12. Results. ACR20 response rates were 62.5%, 76.8%, 77.6%, and 28.6% at Week 12, and 61.1%, 73.2%, 71.8%, and 24.7% at Week 24 for CZP 100, 200, and 400 mg, and placebo groups, respectively, with statistical significance between each CZP group and placebo. Change in Total Sharp Score over 24 weeks was significantly smaller in CZP 200 and 400 mg groups vs placebo. Improvements in health-related quality of life (HRQoL) were observed in all three CZP groups vs placebo. Incidence of adverse events was similar between CZP groups. Conclusions. CZP plus MTX resulted in rapid, sustained reductions in RA signs and symptoms in Japanese patients with inadequate response to MTX, with significant inhibition of radiographic progression and improved HRQoL.

Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) plus methotrexate treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients with an inadequate response to methotrexate. Methods. J-RAPID double-blind patients were entered into an open-label extension (OLE) study. Patients withdrawn due to lack of efficacy at 16 weeks and double-blind completers without a week-24 American College of Rheumatology (ACR) 20 response received CZP 200 mg every other week (Q2W) plus methotrexate. Double-blind completers with week-24 ACR20 responses were randomized to CZP 200 mg Q2W plus methotrexate or CZP 400 mg every 4 weeks plus methotrexate. Results. The ACR20/ACR50/ACR70 response rates of double-blind completers (n = 204) were 89.7%/67.2%/36.3% at OLE entry and 95.6%/84.8%/58.3% at 52 weeks, respectively. Other clinical, functional and radiographic outcomes were sustained with long-term CZP plus methotrexate. Long-term treatment with CZP was well-tolerated with no new unexpected adverse events observed. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Conclusions. Continued CZP administration with methotrexate maintained efficacy over 52 weeks and was well-tolerated for Japanese RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules, giving flexibility in maintenance administration schedules.

Thallium bromide (TlBr) is a promising compound semiconductor for fabrication of gamma-ray detectors. The attractive physical properties of TlBr lie in its high photon stopping power, high resistivity and good charge transport properties. Gamma-ray detectors fabricated from TlBr crystals have exhibited excellent spectroscopic performance. In this paper, advances in TlBr radiation detector development are reviewed with emphasis on crystal growth, detector fabrication, physical properties and detector performance.

The timing performance of TlBr detectors was evaluated at room temperature (22 °C). 0.5-mm-thick planar TlBr detectors with Tl circular electrodes with a diameter of 3 mm were fabricated from TlBr crystals grown by the traveling molten zone method using a zone-purified material. The pulse rise time of the TlBr detector was measured using a digital oscilloscope as the cathode surface of the device was irradiated with a 22Na gamma-ray source. Coincidence timing spectra were obtained between the TlBr detector and a BaF2 scintillation detector when both detectors were irradiated with 511 keV positron annihilation gamma-rays. The timing resolution of the TlBr detector was found to be inversely proportional to the applied bias voltage. The TlBr detector, in coincidence with the BaF2 detector, exhibited timing resolutions characterized by a 6.5 ns full width at half maximum (FWHM) and an 8.5 ns FWHM with and without an energy window of 350 keV-560 keV, respectively.

Capacitive Frisch grid detectors with the dimensions of 2 mm × 2 mm × 4.4 mm were fabricated from TlBr crystals grown by the travelling molten zone method using zone-purified materials. Spectroscopic performance of the detectors was evaluated at room temperature (24°C), - 5°C and - 20°C. The TlBr detector exhibited an energy resolution of 1.6% FWHM at 662 keV with a peak-to-Compton ratio of 8.7 with the depth correction at room temperature. Improvement of the detector performance was achieved by cooling the detector-preamplifier system. The energy resolutions of 3.4%, 1.5%, 1.0% and 0.9% FWHM at 122 keV, 356 keV, 662 keV and 1332 keV, respectively, were recorded with the TlBr detector without the depth correction at - 5°C. An energy resolution of 0.9% FWHM at 662 keV with a peak-to-Compton ratio of 18.2 was obtained from the TlBr detector with the depth correction at -20°C. An upper limit for the Fano factor of TlBr was estimated to be 0.43 at -20°C.

We demonstrate the first phase-stabilized, fully monolithic mode-locked solid-state laser operating at 1 GHz fundamental repetition rate. The offset frequency is stabilized to an RF reference with a residual integrated phase noise of < 50 mrad.

Background: The effects of anti-hypertensive drugs on survival have not been examined in a large cohort of hemodialysis (HD) patients. Methods: We examined the relationship between blood pressure, anti-hypertensive drug therapy, and survival using the nationwide HD registry of the Japanese Society for Dialysis Therapy. Outcomes were confirmed using the coded ID numbers of the 2005 and 2006 registries. Logistic analyses were performed to determine the effect of anti-hypertensive drug therapy on survival. Results: A total of 163,668 patients (50.6% men; 31.5% with diabetes mellitus; mean age 63.6 years) on HD 3 times a week in 2005 were studied. Mean (SD) levels of systolic and diastolic blood pressure were 153.4 (24.1) and 78.7 (13.7) mm Hg, respectively, before the HD session. Two-thirds of the HD patients were prescribed anti-hypertensive drugs and the numbers of anti-hypertensive medications were: 1 in 26.8%, 2 in 24.4%, and 3 or more in 14.5% of the total patients. The 1-year mortality rate was 6.6% overall: 8.5% in patients not prescribed anti-hypertensive drugs and 5.6% among those prescribed anti-hypertensive drugs. The odds ratio (95% confidence interval) for the 1-year mortality rate was 0.724 (0.681–0.770, p < 0.0001) for patients prescribed anti-hypertensive drugs, after adjusting for age, sex, diabetes mellitus, body mass index, HD duration, serum albumin, and systolic blood pressure. Conclusion: Survival was better in patients prescribed anti-hypertensive drugs, particularly renin-angiotensin system inhibitors, than in those not prescribed anti-hypertensive drugs. The causality on this association remained to be determined and prospective studies on blood pressure target levels and the effects of anti-hypertensive drug class in HD patients are warranted.

A comparison of long-term stabilities of TlBr detectors with Au and Tl electrodes was performed in this study, in order to reveal polarization phenomena in TlBr detectors. Au/TlBr/Au detectors exhibited polarization phenomena at room temperature, observed as degradation of spectral performance and reduction of leakage current with elapsed time. Applying reverse bias voltage to the detectors recovered the detector performance temporarily. No polarization phenomena were observed in Tl/TlBr/Tl detectors at room temperature. The detector exhibited stable spectral performance for 24 hours.

A rare case of mucinous adenocarcinoma of the cecum in a pregnant woman is described. A 32-year-old Korean woman was diagnosed as having an abdominal tumor immediately after giving birth. Abdominal computed tomography demonstrated a smooth mass measuring 10 cm in diameter on the right side of the abdomen. Acute abdomen developed 3 days after birth. At emergency surgery, volvulus of a polypoid tumor was detected at the cecum apart from the normal appendix. We successfully performed a tumorectomy; however, histopathological examination demonstrated mucinous adenocarcinoma with a massive blood clot.

A diffraction system has been constructed at the Synchrotron Radiation Centre at Ritsumeikan University, in which a wide-band parallel X-ray beam is produced by reflection from the depth-graded multilayer monochromator. The band width is 600 eV and the monochromator is useful in the photon energy range from 6500 to 7700 eV. In diffraction patterns of an oscillating single crystal recorded using the beam, Bragg reflections appear in an elongated form on an imaging-plate detector and, if the absorption edge of an atom in the crystal is included in the band, a characteristic intensity profile is seen due to anomalous dispersion. As an application of the system, the absolute configuration was determined for a newly synthesized compound, 4-(1-hydroxyethyl)phenylferrocene, C18H18FeO, with an enantiomorphic structure, choosing the Fe atoms as anomalous scatterers. In the intensity profiles of the Friedel pairs of reflections, clear contrast between the pair was observed at the absorption edge, leading unequivocally to theSform. Further possible application of the wide-bandpass parallel beam is discussed.

In the future, every material will contain a computer and become smart. We call these materials sentient materials. Sentient materials can communicate with each other and change behavior according to their surrounding environments. However, current infrastructures such as the Internet are not suitable for building the infrastructure for supporting sentient materials. The paper especially describes two issues for building software infrastructures for supporting sentient materials.

X-ray absorption fine structure (XAFS) spectroscopy has been used to investigate the valence states and molecular structures of sulfur (S), chromium (Cr), arsenic (As), and zinc (Zn) in fine particulate matter (PM) separated from coal fly ash produced in a laboratory combustion system. A cyclone separator was used to separate the PM into fractions 2.5 μm in diameter (PM2.5+). Sulfate was the dominant form of S present. However, thiophene was present in many samples, and sulfite was significant in two of the PM2.5+ samples. For Cr and As, the valence states were of primary concern. Analysis of the X-ray absorption near-edge structure (XANES) regions of the spectra revealed that the toxic Cr6+ valence state accounted for approximately 10 to 30% of the Cr in PM derived from the fly ash of several coals from the western United States. However, only Cr3+ was observed in a number of PM samples from eastern U.S. bituminous coal fly ash. For As, only As5+ as arsenate was dete...

The paper deals with the coil power supplies for ITER-FEAT and focuses on the topics related to their interface with the HV grid, which provides the required pulsed electric power. The availability of a suitable HV grid is assumed. The technical solutions addressed to the limitation of the reactive power consumption are described along with the means for reactive power compensation and active power shedding. The adaptation of the power supply reference design to a site supplied by a HV grid, with capabilities lower than the site assumptions, is discussed.

A new X-ray diffraction system has been constructed at the SR Center at Ritsumeikan University, in which the wavelength of the incident synchrotron radiation is continually and repeatedly changed over a definite range by rocking a couple of monochromator crystals while rotating a sample crystal and recording the diffraction pattern on a moving imaging plate detector. Bragg reflections appear as elongated spots and, if the wavelength range is chosen in the immediate vicinity of the absorption edge of an atom in the crystal, direct information on the phase of Bragg reflections can be derived from the intensity gradient of the elongated spots with respect to the wavelength. This method of phase determination is simple and free from the problem of intensity scaling encountered in the multi-wavelength diffraction method. When both a sample crystal and the detector are kept stationary while changing the wavelength, a pattern is obtained which is similar to Laue pattern, but there is a definite difference. The wavelength of the radiation that has given rise to the diffraction spot can be uniquely known and the diffraction intensity can be measured from the spectrum of the incident radiation. This method of diffraction has a wide range of applicability.

A new ray-tracing simulation program, RIGTRACE, has been developed specifically for the X-ray optics range. It traces consecutively each ray, following its path from the source to the observation plane, and treats diffraction by a monochromator crystal by adopting the Darwin-Prins theory so that it may be seen how rays of slightly different energies and incident angles reach the plane. It is also possible to treat the case of the laboratory system, in which the optical elements are disposed close to each other. Examples of the application are provided.

Objectives. To evaluate the long-term efficacy and safety of certolizumab pegol (CZP) treatment and to assess the efficacy of two CZP maintenance dosing schedules in Japanese rheumatoid arthritis (RA) patients who could not receive methotrexate (MTX). Methods. HIKARI double-blind (DB) patients were entered into an open-label extension (OLE) study. Patients withdrawn at 16 weeks due to lack of efficacy and DB completers without a 24-week American College of Rheumatology (ACR)20 response received CZP 200 mg every 2 weeks (Q2W). DB completers with 24-week ACR20 responses were randomized to CZP 200 mg Q2W or CZP 400 mg every 4 weeks. Results. The ACR20/ACR50/ACR70 response rates of DB completers (n = 98) were 82.7%/56.1%/34.7% at OLE entry, and 83.7%/65.3%/48.0% at 52 weeks, respectively. Other clinical, functional, and radiographic outcomes were sustained during long-term administration of CZP, even without MTX. No new unexpected adverse events were observed during long-term CZP treatment. The efficacy and safety of CZP treatment were similar between the two dosing schedules. Conclusions. Long-term CZP administration is efficacious and safe for RA patients. No obvious differences in clinical efficacy and safety were observed between the two dosing schedules. The choice between two maintenace regimens adds flexibility in administration schedules for RA patients and physicians.

Background Pranlukast (8-[p-(4-phenylbutyloxy) benzol] amino-2-[tetrazol-5-yl]-4-oxo-4H-1-benzopyran hemihydrate), a selective cysteinyl leukotriene receptor antagonist, has been reported to exhibit not only antileukotrine activity but also pharmacological activity including antieosinophilic effects. Objective This study was designed to investigate whether the antiasthmatic activity of pranlukast is associated with a reduction in eosinophilic inflammation. Methods A double-blind, randomized, crossover design was used. Subjects received 225 mg of pranlukast or placebo orally twice daily for 4 weeks and then, after a washout period of at least 4 weeks, crossed over to receive the alternative treatment. We assessed the effects of pretreatment with pranlukast on bronchoconstriction precipitated by inhalation of methacholine in 32 adult patients with mild or moderate bronchial asthma; those who were in stable clinical condition were allocated to this study. Blood and sputum samples were taken the morning of the methacholine provocation test. Eosinophil counts and measurement of eosinophilic cationic protein (ECP) were performed. Results After the 4 weeks of treatment with pranlukast, patients' symptoms, blood eosinophils, serum ECP, sputum eosinophils, and sputum ECP were significantly decreased. Furthermore, values of PC20-methacholine significantly improved in the treatment with pranlukast. Conclusion Our results suggest that pranlukast has an anti-inflammatory effect on bronchial eosinophilic infiltration. This study raises further interesting therapeutic possibilities and argues for further trials of new approaches to the treatment of bronchial asthma.

Background Albeit its exact pathogenesis is still ambiguous; aspirin-intolerant asthma is one of several types of asthma for which antileukotriene therapy is useful, because it is widely accepted that bronchial over-production of leukotrienes may be involved in its pathogenesis. Pranlukast (8-[p-(4-phenylbutyloxy) benzol] amino-2-(tetrazol-5-yl)-4-oxo-4H-1-benzopyran hemihydrate), a selective cysteinyl leukotriene receptor antagonist, is now widely used in the treatment of asthma. Objective This study was designed to investigate the protective effect of pranlukast on airway sensitivity to sulpyrine provocation testing, bronchial responsiveness to methacholine provocation testing, and to investigate whether this protective activity is associated with a reduction in aspirin-induced excretion of urinary LTE4 (uLTE4), a marker of the cysteinyl leukotriene (LT) overproduction that participates in the pathogenesis of aspirin-induced asthma. Methods We assessed the effects of pretreatment with pranlukast on bronchoconstriction precipitated by inhalation of methacholine and sulpyrine in 16 adult patients with mild or moderate aspirin-intolerant asthma; those who were in stable clinical condition and were hypersensitive to sulpyrine provocation testing were allocated to this study. A double-blind, randomized, crossover design was used. uLTE4 was measured using combined reverse-phase high-performance liquid chromatography (rp-HPLC)/enzyme immunoassay. Results Pranlukast protected against analgesic-induced bronchoconstriction through mechanisms that were not related to the bronchodilator property, but were related to the improvement both of bronchial hyperresponsiveness and hypersensitivity to analgesic (P

We report here on the successful treatment for right ventricular outflow tract obstruction after bilateral lung transplantation in a patient with primary pulmonary hypertension. A 31-year-old female patient with primary pulmonary hypertension underwent successful bilateral lung transplantation. She had a pressure gradient of 30 mmHg through the right ventricular outflow tract one week after transplantation, but was successfully treated with atelenol and disopyramide. Long-term follow-up cardiac catheterization did not show any significant right ventricular outflow tract obstruction. The actual cause of the right ventricular outflow tract obstruction remained unknown, but longstanding pulmonary hypertension might have induced significant structural changes in the heart, such as right ventricular hypertrophy and enlargement.

The possibilities of pulsed laser single ablation (PLSA) from the frozen target materials, such as inert gases (Ar, Kr, Xe), N2 and CH4, using KrF excimer and YAG(SHG) lasers have been investigated. The single ablations were realized by the pulsed YAG(SHG) laser in a relatively short time, but the KrF excimer laser was unsuccessful. As an example of the application of pulsed laser co-ablation (PLCA) of the frozen target, polycrystalline hexagonal SiC films were formed without any post-thermal annealing by using frozen CH4 on Si targets. The films, however, contain splashing Si particles. On the other hand, the PLSA method, using a mixture of frozen N2 and CH4 targets, enabled the formation of amorphous C-N films without splashing particles.

Background Fourteen-membered macrolides, such as roxithromycin, have been reported to exhibit other pharmacological activity including anti-asthmatic effects, besides antibiotic activity. Objective This study was designed to investigate the protective effect of roxithromycin on airway responsiveness to the sulpyrine provocation test and to investigate whether this protective activity is associated with a reduction in aspirin-induced excretion of urinary leucotriene E 4 (u-LTE 4 ), a marker of cysteinyl leucotriene overproduction that participates in the pathogenesis of aspirin-intolerant asthma. Also, the present study was designed to examine whether or not its anti-asthmatic activity was associated with a reduction in eosinophilic inflammation. Methods For 8 weeks before analysis, subjects received 150 mg of roxithromycin or matching placebo twice daily. We assessed the effects of pretreatment with roxithromycin on bronchoconstriction precipitated by inhalation of sulpyrine in 14 adult patients with mild or moderate aspirin-intolerant asthma; those who were in stable clinical condition and were hyperresponsive to sulpyrine provocation test were allocated to this study. A double-blind, randomized, crossover design was used. Urinary LTE 4 was measured by a combined reverse-phase high-performance liquid chromatography (rp-HPLC) enzyme immunoassay on sulpyrine provocation testing day. Blood and sputum samples were taken in the morning on the sulpyrine provocation testing day. Eosinophil counting and measurement of eosinophilic cationic protein (ECP) were performed. Results After the 8 weeks of treatment with roxithromycin, patients' symptoms, blood eosinophils, serum ECP, sputum eosinophils, and sputum ECP were significantly decreased. On the other hand, values of PC 20 -sulpyrine did not improve after roxithromycin at all. Furthermore, although challenge with sulpyrine caused a significant increase in u-LTE 4 , pretreatment with roxithromycin or placebo did not affect excretion of u-LTE 4 . Conclusion Although roxithromycin does not have antileucotriene effects, it has an antibronchial inflammatory effect associated with eosinophilic infiltration. This study raises further interesting therapeutic possibilities and warrants further trials of new approaches to the treatment of aspirin-intolerant asthma.

No polarization phenomena were observed in TlBr detectors at room temperature for 30 h by applying Tl electrodes to the detectors.

This study was designed to investigate the protective effect of cromolyn sodium on airway sensitivity to sulpyrine, and bronchial responsiveness to methacholine, and to investigate whether this protective activity is associated with reduction in aspirin–induced excretion of urinary leukotriene E4 (u–LTE4), a marker of the cysteinyl LT overproduction that participates in the pathogenesis of aspirin–induced asthma. We assessed the effects of pretreatment with cromolyn sodium on bronchoconstriction precipitated by inhalation of methacholine and sulpyrine in 16 adult patients with mild or moderate aspirin–intolerant asthma; those who were in stable clinical condition and were hypersensitive to a sulpyrine provocation test were included in this study. A double–blind, randomized, crossover design was used. u–LTE4 was measured using combined reverse–phase high–performance liquid chromatography enzyme immunoassay. Cromolyn sodium protected against analgesic–induced bronchoconstriction through mechanisms that are not related to its bronchodilator property, but to the improvement of both bronchial hyperresponsiveness and hypersensitivity to analgesics (p4 did not increase after the methacholine provocation test, it significantly increased after sulpyrine provocation (p4 after the sulpyrine provocation test was significantly lower than in controls (p

Objectives The mechanisms and treatment of chronic rejection in pulmonary allotransplantation remain elusive. We have induced robust tolerance to class I-disparate lung allografts in miniature swine using an intensive 12-day course of tacrolimus. Here, we tested whether a tolerant state can be induced in swine receiving fully mismatched lung allografts. Methods Orthotopic left lung allografts were performed using MHC class I-disparate (group 1: n = 3) or fully disparate (group 2: n = 6) donors. The recipients received a 12-day postoperative course of tacrolimus (continuous intravenous infusion; target level = 35–50 ng/mL) as their only immunosuppression. Results All swine in group 1 maintained their grafts long term without developing any lesions of chronic rejection (>497, >432, >451 days). These recipients exhibited donor-specific hyporesponsiveness in cell-mediated lymphocytotoxity (CML) and mixed lymphocyte reaction (MLR) assays. In group 2, five of the six recipients maintained their grafts long term (sacrificed on postoperative days 515, 389, 429, 481, and 438 with viable grafts). Isolated lesions of obliterative bronchiolitis were occasionally seen on biopsy, and donor-specific hyporesponsiveness on assays was consistently observed. The remaining recipient rejected its graft on day 103 with histologic findings of obliterative bronchiolitis. Conclusions We report long-term graft acceptance without chronic immunosuppression in five of six recipients across a full MHC disparity, albeit with some evidence of obliterative bronchiolitis. These data suggest that the class II disparity inherent in a fully mismatched transplant increases the requirement for tolerance induction.

The axial profile of the axial component of the wave magnetic field has been measured for m = 0 helicon waves. A dip in is observed at cm from the antenna, and is explained as a result of the beat between the fundamental and the second-order radial modes of the m = 0 helicon wave. The measured imaginary part of , which consists only of the wave field, is compared with that of the calculated wave field using the theory of the uniform plasma case. It is found that % of the amplitude arises from the second-order mode and the axial damping length of the fundamental mode .

Radiation detectors have been fabricated from lead iodide (PbI/sub 2/) crystals grown by two methods; zone melting and the Bridgman methods. In the response characteristics of the detector fabricated from crystals grown by the zone melting method, a photopeak for /spl gamma/-rays from an /sup 241/Am source (59.5 keV) has been clearly observed with an applied detector bias of 500 V at room temperature. The hole drift mobility is estimated to be about 5.5 cm/sup 2//Vs from measurement of the pulse rise time for 5.48 MeV /spl alpha/-rays from /sup 241/Am. By comparing the detector bias versus the saturated peak position of the PbI/sub 2/ detector with that of the CdTe detector, the average energy of the PbI/sub 2/ crystal for producing electron-hole pairs is estimated to be about 8.4 eV. A radiation detector fabricated from PbI/sub 2/ crystals grown by the Bridgman method, however, exhibited no response for /spl gamma/-rays. >