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Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism, either symptomatic or not. The occlusion of proximal pulmonary arteries by fibrotic intravascular material, in combination with a secondary microvasculopathy of vessels < 500 μm, leads to increased pulmonary vascular resistance and progressive right heart failure. The mechanism responsible for the transformation of red clots into fibrotic material remnants has not yet been elucidated. In patients with pulmonary hypertension, the diagnosis is suspected when a ventilation/ perfusion lung scan shows mismatched perfusion defects, and confirmed by right heart catheterisation and vascular imaging. Today, in addition to lifelong anticoagulation, treatment modalities include surgery, angioplasty and medical treatment according to the localisation and characteristics of the lesions. This statement outlines a review of the literature and current practice concerning diagnosis and management of CTEPH. It covers the definitions, diagnosis, epidemiology, follow-up after acute pulmonary embolism, pathophysiology, treatment by pulmonary endarterectomy, balloon pulmonary angioplasty, drugs and their combination, rehabilitation and new lines of research in CTEPH. It represents the first collaboration of the European Respiratory Society, the International CTEPH Association and the European Reference Network-Lung in the pulmonary hypertension domain. The statement summarises current knowledge, but does not make formal recommendations for clinical practice.

Background Balloon pulmonary angioplasty (BPA) has been accepted as an alternative for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Although BPA improves most of the hemodynamic parameters, the improvement of cardiac output (CO) after BPA cannot be obtained in all the patients. Purpose This study was aimed to clarify whether BPA could improve CO or not. We also investigated the determinants for the improvement of CO after BPA. Methods We enrolled in consecutive 317 CTEPH patients treated with BPA in our hospital. All the patients were divided into three groups by generations (Younger group; age Results Baseline mean pulmonary arterial pressure and six minutes-walk distance in the elderly group were lower than those in the younger group. Baseline CO was almost similar among the three groups. All the hemodynamic parameters, excluding CO, were improved after BPA in overall patients' analyses. The significant improvement in CO after BPA was identified only in the younger patients. Whereas HR decreased after BPA in all age groups, the improvement of CO and SV depended on each patient's generation, as shown in Figure 1. Conclusions It would be challenging to improve CO after BPA in all the populations, especially in elderly CTEPH patients. Adjuvant medical treatment in addition to BPA would be required in elderly patients. Funding Acknowledgement Type of funding sources: None.

Background Balloon pulmonary angioplasty (BPA) improves hemodynamics and exercise capacity in inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, some symptoms, such as dyspnea on exertion, had remained in more than half of the patients even after BPA could decrease mean pulmonary artery pressure (PAP) Purpose The purpose of this study was to elucidate the determinants of residual symptom in patients who had achieved mean PAP Methods Among 310 CTEPH patients who received BPA in our center, 217 patients (70.0%) could achieve mean PAP Results Additional BPA had been underwent in 67 patients (30.9%). No significant differences in mean PAP were identified between the additional and non-additional BPA groups (20.4±2.5 mmHg vs. 19.7±2.7 mmHg, p=0.106). In additional BPA group, cardiac index (CI), heart rate (HR) and percutaneous oxygen saturation (SpO2) was lower than non-additional BPA group, and pulmonary vascular resistance (PVR) was higher than non-additional BPA group (CI, 2.51±0.41 L/min/m2 vs. 2.72±0.56 L/min/m2, p=0.016, HR, 62.9±9.7 bpm vs. 67.8±10.8 bpm, p=0.003, SpO2, 94.3±3.7% vs. 95.9±3.5%, p Conclusion Low CI and SpO2 and High PVR were determinants for residual symptoms in CTEPH patients who could achieve mean PAP Funding Acknowledgement Type of funding sources: None.

Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

AIM: Evaluation of the therapeutic efficacy of carbon-ion radiation therapy for isolated lymph node recurrence following curative resection of esophageal cancer. MATERIALS AND METHODS: Ten cases with lymph node recurrence after esophageal cancer surgery were treated with carbon-ion radiation therapy. A total of 48.0 Gy [relative biologic effectiveness (RBE)] was delivered over 3 weeks with a daily dose of 4.0 Gy (RBE). RESULTS: The median follow-up duration was 27.1 months (range=3-92.0 months) after carbon-ion radiation therapy. The local control rates at 2, 3 and 5 years were 92.4%. The overall survival rates at 2, 3 and 5 years were 70.0%, 58.3% and 21.9%. The median survival period was 45.3 months after carbon-ion radiation therapy. There were no toxicities of grade 3 or higher. CONCLUSION: Carbon-ion radiation therapy may be a safe and effective treatment option for isolated lymph node recurrence after radical surgery for esophageal cancer.

Background Few studies have been conducted on patterns of recurrence after resection for distal cholangiocarcinoma (DCC). The aim of this study was to investigate the incidence and pattern of recurrence after resection of DCC, and to evaluate prognostic factors for time to recurrence and recurrence-free survival (RFS). Methods Patients who underwent pancreatoduodenectomy with curative intent for DCC between 2001 and 2010 at one of 30 hospitals in Japan were reviewed retrospectively, with special attention to recurrence patterns. The Cox proportional hazards model was used for multivariable analysis. Results In the study interval, 389 patients underwent pancreatoduodenectomy for DCC with R0/M0 status. Recurrence developed in 213 patients (54·8 per cent). The estimated cumulative probability of recurrence was 54·3 per cent at 5 years. An initial locoregional recurrence occurred in 55 patients (14·1 per cent) and initial distant recurrence in 168 (43·2 per cent), most commonly in the liver. Isolated initial locoregional recurrence occurred in 45 patients (11·6 per cent). Independent prognostic factors for time to recurrence and RFS were perineural invasion (P = 0·001 and P = 0·009 respectively), pancreatic invasion (both P < 0·001) and lymph node metastasis (both P < 0·001). RFS worsened as the number of risk factors increased: the 5-year RFS rate was 70·6 per cent for patients without any risk factors, 50·3 per cent for patients with one factor, 31·8 per cent for those with two factors, and 13·4 per cent when three factors were present. Conclusion More than half of patients with DCC experienced recurrence after R0 resection, usually within 5 years. Perineural invasion, pancreatic invasion and positive nodal involvement are risk factors for recurrence.

Recent studies have shown that the combination of a NOx storage reduction catalyst (NSR) and a passive selective catalytic reduction catalyst (pSCR) would be a technical solution to meet post EU6 emission legislation for small passenger cars. In this case, NH3 formed during rich NSR regeneration is used to reduce remaining NOx on a SCR catalyst which is located downstream of the NSR. In this study, first, the NH3 formation mechanism of NSR under different emission λs, rich durations, and stored NOx values are clarified using a diesel engine operating under steady-state operation. Finally, NOx conversion and the associated fuel consumption penalty are clarified under the Worldwide harmonized light vehicle test cycle (WLTC). It was identified that NH3 starts to be produced by the NSR after oxygen storage capacity depletion. Next, a NH3 peak occurs as a result of the converted pre-stored and engine out NOx. If the rich operation is long enough, the pre-stored NOx contribution fades and NH3 concentration lowers to an equivalent level as the engine out NOx. From this understanding, several WLTC patterns were measured varying the number of rich operations and their duration in order to identify best regeneration strategy with a minimum fuel consumption penalty. The optimal pSCR benefit, in terms of fuel penalty, is achieved when the rich operation duration is (1) longer than the breakthrough time, (2) includes the initial NH3 peak resulting from the conversion of the pre-stored NOx.

The (^{12}N, ^{12}C) charge-exchange reaction at 175 MeV/u was developed as a novel probe for studying the isovector spin giant monopole resonance (IVSMR), whose properties are important for better understanding the bulk properties of nuclei and asymmetric nuclear matter. This probe, now available through the production of ^{12}N as a secondary rare-isotope beam, is exothermic, is strongly absorbed at the surface of the target nucleus, and provides selectivity for spin-transfer excitations. All three properties enhance the excitation of the IVSMR compared to other, primarily light-ion, probes, which have been used to study the IVSMR thus far. The ^{90}Zr(^{12}N,^{12}C) reaction was measured and the excitation energy spectra up to about 70 MeV for both the spin-transfer and non-spin-transfer channels were deduced separately by tagging the decay by γ emission from the ^{12}C ejectile. Besides the well-known Gamow-Teller and isobaric analog transitions, a clear signature of the IVSMR was identified. By comparing with the results from light-ion reactions on the same target nucleus and theoretical predictions, the suitability of this new probe for studying the IVSMR was confirmed.

We observed the atomic 1s and 2p states of π^{-} bound to ^{121}Sn nuclei as distinct peak structures in the missing mass spectra of the ^{122}Sn(d,^{3}He) nuclear reaction. A very intense deuteron beam and a spectrometer with a large angular acceptance let us achieve a potential of discovery, which includes the capability of determining the angle-dependent cross sections with high statistics. The 2p state in a Sn nucleus was observed for the first time. The binding energies and widths of the pionic states are determined and found to be consistent with previous experimental results of other Sn isotopes. The spectrum is measured at finite reaction angles for the first time. The formation cross sections at the reaction angles between 0° and 2° are determined. The observed reaction-angle dependence of each state is reproduced by theoretical calculations. However, the quantitative comparison with our high-precision data reveals a significant discrepancy between the measured and calculated formation cross sections of the pionic 1s state.

Probiotics are live microorganisms that confer benefits to the host health. The infection rate of potentially pathogenic organisms such as Candida albicans, the most common agent associated with mucosal candidiasis, can be reduced by probiotics. However, the mechanisms by which the probiotics interfere with the immune system are largely unknown. We evaluated the effect of probiotic bacteria on C. albicans challenged human macrophages. Macrophages were pretreated with lactobacilli alone (Lactobacillus rhamnosus LR32, Lactobacillus casei L324m, or Lactobacillus acidophilus NCFM) or associated with Escherichia coli lipopolysaccharide (LPS), followed by the challenge with C. albicans or LPS in a co-culture assay. The expression of pattern-recognition receptors genes (CLE7A, TLR2, and TLR4) was determined by RT-qPCR, and dectin-1 reduced levels were confirmed by flow cytometry. The cytokine profile was determined by ELISA using the macrophage cell supernatant. Overall probiotic lactobacilli down-regulated the transcription of CLEC7A (p < 0.05), resulting in the decreased expression of dectin-1 on probiotic pretreated macrophages. The tested Lactobacillus species down-regulated TLR4, and increased TLR2 mRNA levels in macrophages challenged with C. albicans. The cytokines profile of macrophages challenged with C. albicans or LPS were altered by the probiotics, which generally led to increased levels of IL-10 and IL-1β, and reduction of IL-12 production by macrophages (p < 0.05). Our data suggest that probiotic lactobacilli impair the recognition of PAMPs by macrophages, and alter the production of pro/anti-inflammatory cytokines, thus modulating inflammation.

Objective: This study aimed to investigate predictors of biologic discontinuation due to insufficient response as a surrogate for relapse in patients with rheumatoid arthritis (RA) who achieved clinical remission with biologic treatment. Methods: This study was performed based on data from a multicenter registry, and included 404 patients who achieved clinical remission within the first year of treatment with their first biologic. Cumulative retention rate of the first biologic was estimated using Kaplan–Meier curves, and the impact of patient characteristics on biologic discontinuation was assessed with Cox proportional hazards models. Results: During follow-up, 50 patients discontinued their first biologic due to insufficient response. Overall discontinuation rates due to insufficient response after achieving remission were 6%, 11%, and 19% at 1, 2, and 5 years, respectively. Multivariate analysis revealed that concomitant glucocorticoids at achieving remission [hazard ratio (HR): 3.80, 95% confidence interval (CI): 1.89–7.64)] and a higher level of C-reactive protein (CRP) at achieving remission (HR: 1.47 per 1 mg/dL, 95% CI: 1.09–1.99) independently predict discontinuation due to insufficient response after achieving remission. Conclusion: Patients with RA who achieved remission with concomitant glucocorticoid treatment and a higher level of CRP are at high risk of subsequent biologic discontinuation due to insufficient response., Published online: 13 Jul 2017

Background Little is known about the value of portal vein (PV) resection in distal cholangiocarcinoma. The aim of this study was to evaluate the clinical significance of PV resection in distal cholangiocarcinoma. Methods Patients who underwent pancreatoduodenectomy (PD) for distal cholangiocarcinoma between 2001 and 2010 at one of 31 hospitals in Japan were reviewed retrospectively with special attention to PV resection. Short- and long-term outcomes were evaluated. Results In the study interval, 453 consecutive patients with distal cholangiocarcinoma underwent PD, of whom 31 (6·8 per cent) had combined PV resection. The duration of surgery (510 versus 427 min; P = 0·005) and incidence of blood transfusion (48 versus 30·7 per cent; P = 0·042) were greater in patients who had PV resection than in those who did not. Postoperative morbidity and mortality were no different in the two groups. Several indices of tumour progression, including high T classification, lymphatic invasion, perineural invasion, pancreatic invasion and lymph node metastasis, were more common in patients who had PV resection. Consequently, the incidence of R1/2 resection was higher in this group (32 versus 11·8 per cent; P = 0·004). Survival among the 31 patients with PV resection was worse than that for the 422 patients without PV resection (15 versus 42·4 per cent at 5 years; P < 0·001). Multivariable analyses revealed that age, blood loss, histological grade, perineural invasion, pancreatic invasion, lymph node metastasis and surgical margin were independent risk factors for overall survival. PV resection was not an independent risk factor. Conclusion PV invasion in distal cholangiocarcinoma is associated with locally advanced disease and several negative prognostic factors. Survival for patients who have PV resection is poor even after curative resection.

The electric dipole strength distribution in ^{48}Ca between 5 and 25 MeV has been determined at RCNP, Osaka from proton inelastic scattering experiments at forward angles. Combined with photoabsorption data at higher excitation energy, this enables the first extraction of the electric dipole polarizability α_{D}(^{48}Ca)=2.07(22) fm^{3}. Remarkably, the dipole response of ^{48}Ca is found to be very similar to that of ^{40}Ca, consistent with a small neutron skin in ^{48}Ca. The experimental results are in good agreement with ab initio calculations based on chiral effective field theory interactions and with state-of-the-art density-functional calculations, implying a neutron skin in ^{48}Ca of 0.14-0.20 fm.

Loxosceles intermedia venom comprises a complex mixture of proteins, glycoproteins and low molecular mass peptides that act synergistically to immobilize envenomed prey. Analysis of a venom-gland transcriptome from L. intermedia revealed that knottins, also known as inhibitor cystine knot peptides, are the most abundant class of toxins expressed in this species. Knottin peptides contain a particular arrangement of intramolecular disulphide bonds, and these peptides typically act upon ion channels or receptors in the insect nervous system, triggering paralysis or other lethal effects. Herein, we focused on a knottin peptide with 53 amino acid residues from L. intermedia venom. The recombinant peptide, named U

Background Previous studies have reported that patients undergoing oesophagectomy in high-volume hospitals experience lower mortality rates. However, there has been ongoing discussion regarding the validity of evidence for this association. The purpose of this study was to investigate the relationship between hospital volume and risk-adjusted mortality following oesophagectomy in Japan, using a nationwide web-based database. Methods The study included patients registered in the database as having undergone oesophagectomy with reconstruction between 2011 and 2013. Outcome measures were 30-day and operative mortality rates. Logistic regression analysis was used to adjust for hospital volume, surgeon volume and risk factors for mortality after oesophagectomy. Results A total of 16 556 oesophagectomies at 988 hospitals were included; the overall unadjusted 30-day and operative mortality rates were 1·1 and 3·0 per cent respectively. The unadjusted operative mortality rate in hospitals performing fewer than ten procedures per year (5·1 per cent) was more than three times higher than that in hospitals conducting 30 or more procedures annually (1·5 per cent). Multivariable models indicated that hospital volume had a significant effect on 30-day (odds ratio 0·88 per 10-patient increase; P = 0·012) and operative (odds ratio 0·86 per 10-patient increase; P < 0·001) mortality. Conclusion In Japan, high-volume hospitals had lower risk-adjusted 30-day and operative mortality rates following oesophagectomy compared with low-volume hospitals.

The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C-reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks.One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels.Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks.Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice.

The goal of treating rheumatoid arthritis (RA) should be remission, for which a new definition was proposed in 2011. To determine which patients can achieve the new Boolean-based definition of remission in clinical practice, we analyzed factors associated with remission in 123 patients who received tocilizumab for 52 weeks. We found that patients with short disease duration (

Tumor necrosis factor α (TNF-α) is a pleiotropic cytokine mediating inflammatory as well as cell death activities, and is thought to induce chondrocytic chondrolysis in inflammatory and degenerative joint diseases. Selective estrogen receptor modulators (SERMs), such as raloxifene, which are commonly used in clinical settings act as estrogen agonists or antagonists. It is assumed that estrogens have a potential role in cartilage protection; however, the precise molecular mechanism for the protective effects of estrogens is unclear. This study was designed to examine whether raloxifene inhibits TNF-α-induced apoptosis in human chondrocytes and to clarify the mechanisms involved. We also investigated the signaling pathways responsible for the anti-apoptotic effect of raloxifene. Apoptosis in chondrocytes was determined by DNA fragmentation assay and caspase-3 activation. Raloxifene significantly inhibited TNF-α-induced caspase-3 activation and cell DNA fragmentation levels in chondrocytes. The inhibitory effect of raloxifene was abolished by the estrogen receptor antagonist ICI 182,780. Extracellular signal-regulated kinase 1/2 (ERK1/2) regulates apoptosis, acting as an apoptotic or anti-apoptotic signal. TNF-α-induced apoptosis was significantly enhanced by the ERK1/2 pathway inhibitor PD98059. Raloxifene stimulated a further increase in ERK1/2 phosphorylation in TNF-α-treated chondrocytes. Furthermore, the anti-apoptotic effects of raloxifene were inhibited by PD98059. In addition, the anti-apoptotic effects of raloxifene were completely abolished in ERK1/2 siRNA-treated chondrocytes. These results suggest that raloxifene prevents caspase-3-dependent apoptosis induced by TNF-α in human chondrocytes by activating estrogen receptors and the ERK1/2 signaling pathway.

A new circuit construction technique that actively utilises second harmonics injection (HI) to realise fifth-order predistortion (PD) for power amplifiers (PAs) with memoryless AM/AM and AM/PM conversions is proposed. Applying a combination of the proposed technique and cuber predistortion (CPD) to third-order distortion yields the simultaneous compensation of both third- and fifth-order intermodulation distortion (IM3 and IM5); capabilities are not possible with the conventional third-order PD approach. Since the proposed method can be implemented as a simple analogue circuit, it betters compactness and lowers cost. In order to derive the PA bias condition at which second HI works most effectively, a complex power series nonlinear model that allows both amplitude and phase nonlinearities to be dealt with simultaneously is used. To confirm the author's compensation theory, a 2'GHz band PA and a hybrid lineariser that employs second HI and CPD are fabricated and experiments are performed. About a 20'dB simultaneous reduction in IM3 and IM5 is achieved with the two-tone test. A W-CDMA one-carrier test is also conducted to verify the improvement in adjacent channel leakage power ratio compared with CPD only.

It remains to be determined whether the evidence in Western countries for blockade of the renin-angiotensin System in cardiovascular diseases could be directly applied to East Asian races including the Japanese population as a long-term strategy. The KYOTO HEART Study (KHS) is designed to investigate the add-on effect of valsartan versus conventional anti-hypertensive treatment on cardiovascular morbidity and mortality in Japanese hypertensive patients with uncontrolled blood pressure and with high cardiovascular risk. Over 3000 high-risk Japanese patients with uncontrolled hypertension were randomised to receive either additional treatment with valsartan or conventional non-angiotensin receptor blocker therapies, and the follow-up period will be at least 3 years. The primary end point is a composite of defined cardio- or cerebro-vascular events. Secondary end points include all causes of mortality, worsening of cardiac function, new onset or worsening of arrhythmias or diabetes mellitus. The KHS will provide new evidence for the management of blood pressure in hypertensive patients with high risk.

We have characterized the performance of soft-X-ray detectors fabricated with high-quality chemical-vapor-deposition (CVD) diamond layers which were homoepitaxially grown on high-pressure/high-temperature-synthesized Ib-type (100) substrates by means of a high-power microwave plasma CVD method. The soft-X-ray detectors with thin (≈ 15 nm) titanium-nitride interdigitated electrodes were fabricated using a standard photolithography process. We have found that the signal currents significantly increased at sufficiently higher voltages which were applied to the electrodes. The apparent room-temperature quantum efficiencies estimated at the applied voltage of 100 V from the signal currents attained by the diamond-based detector for a photon irradiation rate of ≈ 4 × 10 6 photons/s ranged from 3.2 × 10 5 to 3.1 × 10 6 with photon energies ranging from 400 to 1800 eV. In addition, the diamond detector had signal-to-noise ratios larger than 6 orders of magnitudes. Thus, the present diamond detector has been verified to have excellently high sensitivities to soft-X-ray photons. The internally amplifying function of the diamond detector is discussed.

We previously established a highly metastatic subline, LNM35, from the NCI-H460 lung cancer cell line, and demonstrated upregulation of a novel gene, CLCP1 (CUB, LCCL-homology, coagulation factor V/VIII homology domains protein), in LNM35 and lung cancer specimens. In this study, we focused on the potential roles of that gene in cancer metastasis. First, we established stable LNM35 RNAi clones, in which CLCP1 expression was suppressed by RNAi, and found that their motility was significantly reduced, although growth rates were not changed. Next, in vitro selection of a phage display library demonstrated that a phage clone displaying a peptide similar to a sequence within the Sema domain of semaphorin 4B (SEMA4B) interacted with LNM35. Immunoprecipitation experiments confirmed interaction of CLCP1 with SEMA4B, regulation of CLCP1 protein by ubiquitination and proteasome degradation enhanced in the presence of SEMA4B. These results are the first to indicate that CLCP1 plays a role in cell motility, whereas they also showed that at least one of its ligands is SEMA4B and that their interaction mediates proteasome degradation by CLCP1. Although the physiological role of the interaction between CLCP1 and SEMA4B remains to be investigated, this novel gene may become a target of therapy to inhibit metastasis of lung cancers.

Skin toxicity caused by radiotherapy has been visually classified into discrete grades. The present study proposes an objective and continuous assessment method of skin erythema in digital images taken under arbitrary lighting conditions, which is the case for most clinical environments. The purpose of this paper is to show the feasibility of the proposed method.Clinical data were gathered from six patients who received carbon beam therapy for lung cancer. Skin condition was recorded using an ordinary compact digital camera under unfixed lighting conditions; a laser Doppler flowmeter was used to measure blood flow in the skin. The photos and measurements were taken at 3 h, 30, and 90 days after irradiation. Images were decomposed into hemoglobin and melanin colors using independent component analysis. Pixel values in hemoglobin color images were compared with skin dose and skin blood flow. The uncertainty of the practical photographic method was also studied in nonclinical experiments.The clinical data showed good linearity between skin dose, skin blood flow, and pixel value in the hemoglobin color images; their correlation coefficients were larger than 0.7. It was deduced from the nonclinical that the uncertainty due to the proposed method with photography was 15%; such an uncertainty was not critical for assessment of skin erythema in practical use.Feasibility of the proposed method for assessment of skin erythema using digital images was demonstrated. The numerical relationship obtained helped to predict skin erythema by artificial processing of skin images. Although the proposed method using photographs taken under unfixed lighting conditions increased the uncertainty of skin information in the images, it was shown to be powerful for the assessment of skin conditions because of its flexibility and adaptability.

A candidate resonant tetraneutron state is found in the missing-mass spectrum obtained in the double-charge-exchange reaction ^{4}He(^{8}He,^{8}Be) at 186 MeV/u. The energy of the state is 0.83±0.65(stat)±1.25(syst) MeV above the threshold of four-neutron decay with a significance level of 4.9σ. Utilizing the large positive Q value of the (^{8}He,^{8}Be) reaction, an almost recoilless condition of the four-neutron system was achieved so as to obtain a weakly interacting four-neutron system efficiently.

Since 2000, new hand and environmental hygiene guidelines have been published by the Center for Disease Control and Prevention (CDC) based on scientific evidence. Accordingly, we expected that the use of disinfectants in clinical settings had been changed. To compare the use and amount of disinfectants before and after the publication of these guidelines, we conducted a questionnaire-based survey on the use of antiseptic agents in operating rooms (ORs) in 6 key hospitals over a period of a month in 2000 and 2004. As a result, the amount of disinfectants used in ORs was reduced in all hospitals in 2004. Especially, amphoteric detergents and glutaral products showed significant reductions in the total amount used in the 6 hospitals, by 94.8 and 96.8%, respectively. The use of povidone-iodine (PVP-I) was decreased by 23.4% overall, although it was increased in 3 hospitals by 11.0–58.6%. The number of applications of PVP-I on the surgical site did not change; however, the site was left to dry without wiping after PVP-I application more frequently in 2004 than in 2000. The time for surgical scrubbing was shortened in 2004, but brush scrubbing was still used as often as in 2000. Many of the hospitals used brush scrubbing in conjunction with alcohol-based rubs. These results indicated changes in infection control measures in hospital settings after publication of the new CDC guidelines; environmental disinfection had been limited and excessive use of disinfectants reevaluated.

Differential cross sections of isoscalar and isovector spin-M1 (0(+)→1(+)) transitions are measured using high-energy-resolution proton inelastic scattering at E(p)=295 MeV on (24)Mg, (28)Si, (32)S, and (36)Ar at 0°-14°. The squared spin-M1 nuclear transition matrix elements are deduced from the measured differential cross sections by applying empirically determined unit cross sections based on the assumption of isospin symmetry. The ratios of the squared nuclear matrix elements accumulated up to E(x)=16 MeV compared to a shell-model prediction are 1.01(9) for isoscalar and 0.61(6) for isovector spin-M1 transitions, respectively. Thus, no quenching is observed for isoscalar spin-M1 transitions, while the matrix elements for isovector spin-M1 transitions are quenched by an amount comparable with the analogous Gamow-Teller transitions on those target nuclei.

People with incomplete spinal cord injury (iSCI) expend considerable energy to walk, which can lead to rapid fatigue and limit community ambulation. Selecting locomotor patterns that enhance lateral stability may contribute to this population’s elevated cost of transport. The goal of the current study was to quantify the metabolic energy demands of maintaining lateral stability during gait in people with iSCI. To quantify this metabolic cost, we observed ten individuals with iSCI walking with and without external lateral stabilization. We hypothesized that with external lateral stabilization, people with iSCI would adapt their gait by decreasing step width, which would correspond with a substantial decrease in cost of transport. Our findings support this hypothesis. Subjects significantly (p < 0.05) decreased step width by 22%, step width variability by 18%, and minimum lateral margin of stability by 25% when they walked with external lateral stabilization compared to unassisted walking. Metabolic cost of transport also decreased significantly (p < 0.05) by 10% with external lateral stabilization. These findings suggest that this population is capable of adapting their gait to meet changing demands placed on balance. The percent reduction in cost of transport when walking with external lateral stabilization was strongly correlated with functional impairment level as assessed by subjects’ scores on the Berg Balance Scale (R = 0.778) and Lower Extremity Motor Score (R = 0.728). These relationships suggest that as functional balance and strength decrease, the amount of metabolic energy used to maintain lateral stability during gait will increase.

Objective.Assessing retention rate and risk factor for drug discontinuation is important for drug evaluation. We examined a 3-year retention rate and the risk factor for discontinuation due to insufficient efficacy (IE) and adverse events (AE) in Japanese patients with rheumatoid arthritis (RA) who are receiving etanercept (ETN).Methods.Data were collected from 588 patients treated with ETN as a first biologic from the Tsurumai Biologics Communication Registry. Baseline characteristics for the incidence of both IE and AE were analyzed using the Cox proportional-hazards regression model. Patients were divided into groups based on age and concomitant methotrexate (MTX). Drug retention rates were calculated using the Kaplan-Meier method and compared among groups using the log-rank test.Results.ETN monotherapy without concomitant MTX [MTX(–)] was significantly related to a higher incidence of discontinuation due to IE [hazard ratio (HR) = 2.226, 95% CI 1.363–3.634]. Older age and MTX(–) were significantly related to a higher incidence of discontinuation due to AE [HR = 1.040, 1.746, 95% CI 1.020–1.060, 1.103–2.763, respectively]. The MTX(–)/≥ 65 years group had the lowest retention rate (p < 0.001). The discontinuation rate due to IE was lower in the MTX(+)/< 65 years group compared to < 65 years/MTX(–), ≥ 65 years/MTX(–) group (p = 0.006, p < 0.001, respectively). The discontinuation rate due to AE was highest in the MTX(–)/≥ 65 years group (p < 0.001).Conclusion.Our findings suggest that the risk of discontinuation due to IE was high in the patients who did not use concomitant MTX and that the risk of discontinuation due to AE was high in elderly patients who did not use concomitant MTX.

The prevalence of Candida infections has been rising with an increasingly aging population and a larger population of immunocompromised individuals. The use of probiotics may be an alternative approach to antifungal agents in the prevention and treatment of oral candidiasis. This study aimed to evaluate the short-term effect of probiotics in reducing the infection level of oral Candida in candidiasis-asymptomatic elderly denture wearers.In a double-blind randomized study, 59 denture wearers harboring Candida spp. in the oral cavity with no clinical symptoms were allocated into two groups: probiotic and placebo. All patients were instructed to clean the denture daily. The probiotic group poured a capsule containing lyophilized Lactobacillus rhamnosus HS111, Lactobacillus acidophillus HS101, and Bifidobacterium bifidum daily on the palatal surface of the maxillary denture, whereas the placebo group was submitted to the same regimen using placebo capsules. Candida spp. infection levels were evaluated in palate mucosa samples obtained before and after a 5-week experimental period.All patients harbored Candida in the palate mucosa at baseline. Fifty-five individuals completed the experimental period. The detection rate of Candida spp. was 92.0% in the placebo group after the experimental period, whereas it was reduced to 16.7% in the probiotic group. The reduction promoted by the probiotic regimen was independent of baseline characteristics such as Candida infection level and colonizing species, age of denture, and other variables.The probiotic product was effective in reducing the colonization of the oral cavity with Candida in candidiasis-asymptomatic elderly denture wearers, suggesting that this multispecies probiotic could be used to prevent oral candidiasis.Colonization of oral surfaces by Candida is considered a risk factor for invasive fungal infections. The use of a product with L. rhamnosus, L. acidophilus, and B. bifidum may represent an alternative treatment for reduction of Candida infections in elderly denture wearers.

SUMMARYRetroviral superantigens such as minor lymphocyte stimulating (Mls) antigen play an important role in the pathogenesis of acute graft-versus-host disease (GVHD). However, it remains unclear how exogenous bacterial superantigens modulate acute GVHD. In this study, we tested the effects of staphylococcal enterotoxin B (SEB) on the development of acute GVHD in a model involving the systemic transfer of parental C57Bl/6 spleen cells into BDF1 mice. SEB treatment suppressed the expansion of donor-derived T cells and blocked the decrease in the number of host cells. Impaired haematopoiesis was actually rescued by treatment with SEB. In SEB-treated mice, both spontaneous proliferation and IL-2 production in T cells were suppressed on day 2 after parental cell infusion. On day 21, the number of donor-derived CD4+ Vβ8+ T cells markedly decreased in the spleen of SEB-treated mice. Donor-derived CD4+ T cells failed to proliferate in response to host alloantigens, and both donor- and host-derived T cells were unable to produce IL-2 in response to concanavalin A stimulation, suggesting that SEB treatment induced a general immunosuppressive state. Our results indicate that SEB treatment prevents the development of acute GVHD by leading to unresponsiveness of donor-derived T cells against host alloantigens in a Vβ-restricted and unrestricted manner.

The signaling cascade elicited by angiotensin II (Ang II) resembles that characteristic of growth factor, and recent evidence indicates transactivation of epidermal growth factor receptor (EGF-R) by G protein-coupled receptors. Here, we report the involvement of EGF-R in Ang II-induced synthesis of fibronectin and TGF-beta in cardiac fibroblasts. Ang II stimulated fibronectin mRNA levels dose-dependently with a maximal increase (approximately 5-fold) observed after 12 h of incubation. Ang II-, or calcium ionophore-induced fibronectin synthesis was completely abolished by tyrosine kinase inhibitors and intracellular Ca2+ chelating agents. Ang II-induced fibronectin mRNA was not affected by PKC inhibitors or PKC depletion, whereas specific inhibition of EGF-R function by a dominant negative EGF-R mutant and tyrphostin AG1478 abolished induction of fibronectin mRNA. We isolated the rat fibronectin gene including the 5'-flanking region and found that the AP-1 binding site present in the promoter region was responsible for the Ang II responsiveness of this gene. Gel retardation assay revealed the binding of nuclear protein to the AP-1 site, which was supershifted with anti-c-fos and anti-c-jun but not anti-ATF-2 antibodies. Conditioned medium from Ang II-treated cells contained TGF-beta bioactivity and addition of neutralizing TGF-beta antibody modestly (46%) inhibited induction of fibronectin. Ang II-induced synthesis of TGF-beta was also abolished by inhibition of EGF-R function. The effect of TGF-beta was exerted by stabilizing fibronectin mRNA without affecting the promoter activity and required de novo protein synthesis. We concluded that Ang II-induced expression of fibronectin and TGF-beta is mediated by downstream signaling of EGF-R transactivated by Ca2+-dependent tyrosine kinase, and that Ang II-induced fibronectin mRNA expression is regulated by two different mechanisms; transcriptional control by binding of c-fos/c-jun complex to the AP-1 site, and post-transcriptional control by mRNA stabilization due to autocrine and/or paracrine effects of TGF-beta. Thus, this study suggested that the action of Ang II on extracellular matrix formation should be interpreted in association with the EGF-R signaling cascade.

Seismo-turbidite layers are deposited at the foot of the steep slope of the half graben in which Lake Biwa has accumulated. Sedimentary studies, especially of grain-size distribution of selected turbidites provide excellent information for clarifying the distinctive features of general seismo-turbidites. Development of the two constituent sublayers (lower sandy sublayer and upper silt sublayer), lack or limited appearances of traction-indicating structures and characteristic grain-size distribution in the two constituent sublayers are most remarkable and significant. The characteristic grain-size distribution features are coarse tail grading in a relatively thick sandy sublayer, exceptionally rapid distribution grading through the thin boundary interval between the two sublayers, height increase and fluctuation of the silt mode, and high clay content. Brief discussion was made on the causes of these sedimentary features. The need and importance of further comparative studies of various turbidites known triggering forces are emphasized.

We applied the high-field technique to study the magnetization process in model substances. Measurements have been performed on the powder samples under a pulsed magnetic field up to 50 T. A family of organic verdazyl radical is a candidate of an isotropic S = 1/2 antiferro-magnetic linear chain model. The observed magnetization is practically zero up to a certain critical field around 40 T and steeply increases to the saturation value of 1 μB/molecule. The feature cannot be explained by the uniform chain model but agrees with the alternation linear chain model closed to the dimer model in which the ground state is a nonmagnetic singlet with an energy gap between the excited triplet state. Metal-assembled tetranuclear complexes [Mn(MeOH)L(OH)M(bpy)]2 represent a prototype of geometrically frustrated spin systems. We observed a step-like magnetization process which clearly shows the successive transitions among quantum states with different total spins.

Spherical glass beads were coated with a copper oxide film prepared by electroless copper plating and chemical oxidation. A flow-through detector filled with the glass beads was fabricated. Sensitive detection of glucose was possible. The detector had a low resistance to flow and didn’t suffer from a large dead volume. The hydrodynamic current at constant potential was about 100 times larger than that for the conventional, plate-type detector. Although reproducibility was rather poor, current peaks corresponding to ca. 1 fmol could be detected.