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Black carbon aerosol (BCA) in the Arctic has profound impacts on the global climate system through radiation processes. Despite its enormous impacts, current global scale models, powerful tools for estimating overall impact, tend to underestimate the levels of BCA in the Arctic over several seasons. Using a global aerosol transport simulation with a horizontal grid resolution of 3.5 km, we determined that a higher resolution significantly reduced the underestimation of BCA levels in the Arctic, mainly due to an enhancement of the representation of low-pressure and frontal systems. The BCA mass loading in the Arctic simulated with 3.5-km grid resolution was 4.2-times larger than that simulated with coarse (56-km) grid resolution. Our results also indicated that grid convergence had not occurred on both the contrast between the cloud/cloud free areas and the poleward BCA mass flux, despite the use of the 3.5-km grid resolution. These results suggest that a global aerosol transport simulation using kilometre-order or finer grid resolution is required for more accurate estimation of the distribution of pollutants in the Arctic.

Diel vertical migration (DVM) of some zooplankters in eutrophic lakes is often com- pressed during peak hypoxia. To better understand the indirect consequences of seasonal hypolimnetic hypoxia, we integrated laboratory-based experimental and field-based observa- tional approaches to quantify how compressed DVM can affect growth of a cladoceran, Daphnia mendotae, in central Lake Erie, North America. To evaluate hypoxia tolerance of D. mendotae, we conducted a survivorship experiment with varying dissolved oxygen concentrations, which demonstrated high sensitivity of D. mendotae to hypoxia (≤2 mg O2 l �1 ), supporting the field obser- vations of their behavioral avoidance of the hypoxic hypolimnion. To investigate the effect of tem- porary changes in habitat conditions associated with the compressed DVM, we quantified the growth of D. mendotae, using a 3 (food quantity) × 2 (temperature) factorial design laboratory experiment. Neither food quantity nor temperature affected short-term growth in body length of D. mendotae. However, D. mendotae RNA content (an index of short-term condition) decreased under starvation, indicating an immediate response of short-term feeding on condition. We further evaluated the effect of hypoxia-induced upward shifts in vertical distribution by quantifying the RNA content of D. mendotae from central Lake Erie before and during peak hypoxia. Despite high temperature and food quantity in the upper water column, RNA content in field-collected D. men- dotae remained low during peak hypoxia. Furthermore, D. mendotae collected during peak hypoxia consisted of only small-bodied (

Background: The mode of death has not been investigated in the registry data of patients with heart failure and reduced ejection fraction (HFREF) vs. preserved ejection fraction (HFPEF). The aim of the present study was therefore to carry out this comparison. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied the characteristics and treatments in a broad sample of 2,675 patients hospitalized with worsening HF, and followed them for an average of 2.1 years. This study included 323 patients in whom information on both the mode of death and left ventricular EF on echocardiography could be obtained. The mode of death was cardiovascular (CV) in 63% (including 17% sudden, 36% HF, 3% myocardial infarction, and 3% stroke), non-CV in 23%, and unknown in 14%. The prevalence of CV death including sudden death was high in patients with HFREF compared to HFPEF (68% vs. 58%, P=0.020). HF death, the most common mode of death, was similar between groups (37% vs. 35%, P=0.694). In contrast, non-CV mortality was significantly higher in HFPEF than those with HFREF (28% vs. 18%, P=0.021). Conclusions: In 60-70% of deaths the mode was CV, and HF death was the most common mode of death in either HFREF or HFPEF. The prevalence of sudden death was lower, and that of non-CV death higher, in HFPEF compared with HFREF. (Circ J 2012; 76: 1662–1669)

Background: Loop diuretics are commonly used in patients with heart failure (HF) to remove retained fluid and improve symptoms. However, they may potentially worsen outcomes in HF. It remains unknown whether the use of loop diuretics is associated with adverse HF outcomes in routine clinical practice. We thus determined the effects of loop diuretic use at discharge on long-term mortality and rehospitalization among patients hospitalized with HF. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) prospectively studied the characteristics and treatments of a broad sample of patients hospitalized with worsening HF and followed for 2.1 years. Among a total of 2,549 HF patients, loop diuretics were used by 2,015 patients (79%), but not 534 patients (21%). The mean age was 70.7 years and 60% were male. Etiology was ischemic in 32% and mean left ventricular ejection fraction was 42%. After adjustment for covariates, discharge use of loop diuretics was associated with significant adverse risks of cardiac death (adjusted hazard ratio [HR] 2.348, 95% confidence interval [CI] 1.246-4.423, P=0.008) and rehospitalization (adjusted HR 1.427, 95% CI 1.040-1.959, P=0.027). Conclusions: Among patients hospitalized with worsening HF, loop diuretic use at discharge was associated with long-term adverse outcomes, which suggests that routine chronic use of loop diuretics may be harmful for patients with HF. (Circ J 2012; 76: 1920–1927)

Objective. To clarify the clinical course of SSc in Japanese patients with early-onset disease. It is well known that ethnic variations exist in the clinical features and severity of SSc. However, neither the clinical course nor prognostic factors have been thoroughly investigated in the Japanese population. Methods. Ninety-three Japanese patients of early-onset SSc (disease duration

Interstitial lung disease (ILD) is induced by various factors in humans. However, the exact mechanism of ILD remains elusive. This study sought to determine the role of natural killer (NK) 1.1(+) γδT cells in ILD. The injection of IL-18 plus IL-2 (IL-18/IL-2) into C57BL6 (B6) mice induced acute ILD that resembled early-stage human ILD. An accumulation of NK1.1(+) γδT cells similar to NK cells was evident in the lungs. The T Cell Receptor (TCR) Vγ and Vδ repertoires of NK1.1(+) γδT cells indicated polyclonal expansion. The expression of IL-2 receptor β (Rβ) and IL-18Rβ in NK1.1(+) γδT cells was higher than in NK1.1(-) γδT cells. IL-18/IL-2 stimulated the proliferation of NK1.1(+) γδT cells, but not NK1.1(-) γδT cells. The IL-18/IL-2-stimulated NK1.1(+) γδT cells produced higher concentrations of IFN-γ than did NK1.1(-) γδT cells. Moreover, NK1.1(+) γδT and NK1.1(-) γδT cells constituted completely different cell populations. The IL-18/IL-2-induced ILD was milder in TCRδ(-/-) and IFN-γ(-/-) mice, compared with B6 mice. Furthermore, cell-transfer experiments demonstrated that NK1.1(+) γδT cells could induce the expansion of NK cells and IFN-γ mRNA in the lung by IL-18/IL-2. Our results suggest that NK1.1(+) γδT cells function as inflammatory mediators in the early phase of IL-18/IL-2-induced ILD.

Black carbon (BC) aerosols through their light-absorbing properties create strong perturbation in the atmosphere by heating the atmosphere. BC mass concentration and single scattering albedo (SSA) are important parameters to investigate atmospheric heating. In the present study, measurements of BC and SSA over Indian region from the literature are summarized and compared with simulations by a global aerosol model SPRINTARS. It has been observed that BC emission inventory widely used in the world is underestimating and the model simulated SSA tends to be higher than observed-SSA. In addition to the inventory, we have run the global model using the different BC emission inventory interpolated by Streets et al. (2003) over Asia. The model runs with this inventory was found to provide comparable results with ground observations for BC and SSA. Aerosol radiative forcing due to direct effect (ADRF) over Indian region estimated to be −2.76 W m −2 at the surface and −1.91 W m −2 at the atmosphere using the modified emission inventory in the global aerosol model. The atmospheric heating is estimated to be +0.85 W m −2 , which is three times higher than the original emission inventory estimated value of +0.25 W m −2 . Results of the study suggest that the differences in various BC emission inventories widely used in the world’s research community should be studied for proper estimation of the aerosol radiative forcing over the Indian region.

Imatinib and nilotinib are inhibitors that selectively target a set of protein tyrosine kinases, including abelson kinase (Abl), together with the chimeric oncoprotein, breakpoint cluster region-abelson kinase (Bcr-Abl), as well as stem cell factor receptor (KIT), platelet-derived growth factor receptor (PDGFR), discoidin domain receptor (DDR), and colony stimulating factor-1 receptor (CSF-1R). The aim of the present study was to investigate whether imatinib or nilotinib was effective against arthritis in the glucose-6-phosphate isomerase (GPI)-induced arthritis mouse model. Imatinib or nilotinib was administered orally to the arthritic mice at different time points. Efficacy was evaluated by visual scoring and by determining the production of anti-GPI antibody. Splenocytes from the arthritic mice were cultured with GPI in the presence of imatinib or nilotinib in vitro, and cytokine levels in the culture supernatants were analyzed. To investigate the effects of imatinib and nilotinib on T-cell proliferation, lymph node cells from the arthritic mice were cultured with GPI in the presence of imatinib or nilotinib in vitro. Interleukin (IL)-17 mRNA expression in the arthritic ankle joints from the onset of arthritis was analyzed by real-time polymerase chain reaction (PCR). The administration of imatinib from day 0 showed suppression of arthritis (P < 0.05), the administration of nilotinib from day 0 resulted in pronounced suppression of arthritis (P < 0.01), and that from day 7 showed significant inhibition of the progression of arthritis (P < 0.05). A reduction in anti-GPI antibodies was correlated with the therapeutic efficacy of imatinib, but not with that of nilotinib. Imatinib dose-dependently inhibited tumor necrosis factor (TNF)-α, IL-6, interferon (IFN)-γ, and IL-17 production by splenocytes in vitro, while nilotinib inhibited only IL-17 and IFN-γ production in a dose-dependent fashion. Imatinib at 3 μM exerted a mild antiproliferative effect on CD4+ T cells (P < 0.05), whereas imatinib at 10 μM and nilotinib at 3 and 10 μM demonstrated a marked antiproliferative effect (P < 0.01). The IL17 gene expression level on day 7 tended to be higher than that on day 14. These findings suggest that imatinib and nilotinib could prevent autoimmune arthritis, essentially via distinct mechanisms, in that imatinib inhibits both inflammatory and T-cell-derived cytokine production, whereas nilotinib suppresses T-cell-derived cytokine production. Imatinib and nilotinib could have therapeutic potential for rheumatoid arthritis (RA) and other inflammatory diseases.

Aerosols have great impacts on atmospheric environment, human health, and earth's climate. Therefore, information on their spatial and temporal distribution is of paramount importance. Despite numerous studies have examined the variation and trends of BC and AOD over India, only very few have focused on their spatial distribution or even correlating the observations with model simulations. In the present study, a three-dimensional aerosol transport-radiation model coupled with a general circulation model. SPRINTARS, simulated atmospheric aerosol distributions including BC and aerosol optical properties, i.e., aerosol optical thickness (AOT), Ångström Exponent (AE), and single scattering albedo (SSA). The simulated results are compared with both BC measurements by aethalometer and aerosol optical properties measured by ground-based skyradiometer and by satellite sensor, MODIS/Terra over Hyderabad, which is a tropical urban area of India, for the year 2008. The simulated AOT and AE in Hyderabad are found to be comparable to ground-based measured ones. The simulated SSA tends to be higher than the ground-based measurements. Both these comparisons of aerosol optical properties between the simulations with different emission inventories and the measurements indicate that, firstly the model uncertainties derived from aerosol emission inventory cannot explain the gaps between the simulations and the measurements and secondly the vertical transport of BC and the treatment of BC-containing particles can be the main issue in the global model to solve the gap.

Atmospheric aerosols are important aspects of climate research due to their impact on radiative forcing. In the present study, the aerosol optical depth (AOD), the Angstrom exponent (α) and the single scattering albedo (SSA) over the urban region of Hyderabad, India, were examined using Sun/Sky radiometer measurements during January–December, 2008. AOD showed higher values on certain Julian days coinciding with the occurrence of wintertime dust storm events in the Gulf Region and biomass burning due to forest fires over Indian Region. The AOD values during wintertime dust event are about ~ 55% higher than those on normal days. The SSAs show positive and negative trends in α (R 2 = 0.71) and black carbon (BC) aerosols (R 2 = 0.44), respectively. The aerosol size distribution shows a bimodal pattern with fine (~ 0.15 μm) and coarse (~>7 μm) mode during January–December, 2008. The MODIS AOD showed positive correlation with sky radiometer-derived AOD values (R 2 = 0.68).

The aim of this study was to assess a method for measuring epicardial fat volume (EFV) by means of a single-slice area measurement. We investigated the relation between a single-slice fat area measurement and total EFV.A series of 72 consecutive patients (ages 65 ± 11 years; 36 men) who had undergone cardiac computed tomography (CT) on a 64-slice multidetector scanner with prospective electrocardiographic triggering were retrospectively reviewed. Pixels in the pericardium with a density range from -230 to -30 Hounsfield units were considered fat, giving the per-slice epicardial fat area (EFA). The EFV was estimated by the summation of EFAs multiplied by the slice thickness. We investigated the relation between total EFV and each EFA.EFAs measured at several anatomical landmarks-right pulmonary artery, origins of the left main coronary artery, right coronary artery, coronary sinus-all correlated with the EFV (r = 0.77-0.92). The EFA at the LMCA level was highly reproducible and showed an excellent correlation with the EFV (r = 0.92).The EFA is significantly correlated with the EFV. The EFA is a simple, quick method for representing the time-consuming EFV, which has been used as a predictive indicator of cardiovascular diseases.

Background and Objectives: Biliary drainage (BD) under EUS guidance is usually indicated for malignant biliary obstruction. Recently, EUS-guided transluminal treatment has been applied to benign biliary disease (BBD). This multicenter retrospective study evaluated the clinical impact of EUS-guided transluminal stent deployment for BBD with long-term follow-up. Patients and Methods: This retrospective study investigated patients treated between September 2015 and October 2016 at participating hospitals in the therapeutic endoscopic group. The inclusion criteria comprised complications with BBD obstructive jaundice or cholangitis and failed endoscopic retrograde cholangiopancreatography or inaccessible ampulla of Vater. Results: Twenty-six patients underwent EUS-guided transluminal stent deployment. Indications for EUS-guided transluminal stent deployment comprised anastomotic biliary stricture (n = 17), bile duct stones (n = 5), inflammatory biliary stricture (n = 3), and acute pancreatitis prevention (n = 1). Thirteen of these 26 patients underwent scheduled reintervention, with technical success achieved in all 13 patients. None of the deployed stents became dysfunctional. Among the 13 patients who underwent reintervention on demand, stents had become dysfunctional in six patients (stent patency: 48, 90, 172, 288, 289, and 608 days). Reintervention was successfully performed in all patients. During follow-up (median, 749 days), severe adverse events were not seen in any patients. Conclusion: We concluded that EUS-guided transluminal stent deployment for BBD is feasible and safe. Because metal stent dysfunction was more frequent when deployed on demand, such stents should be exchanged for plastic stents in a scheduled manner if a metal stent is used.

症例は68歳男性．病歴，血液検査，画像検査，肝組織像，遺伝子解析などから，TFR2ヘモクロマトーシス（1861_1872del 12）と診断した．診断時，すでに肝硬変であったが，瀉血による治療を継続し，診断後20年経過しているが，糖尿病や心不全の発症なく，良好な経過をえている．19年目に施行した肝生検でも，初回肝生検に比べ，肝内の鉄沈着は消失し，明らかに線維は細くなり，膠原線維のみならず，弾力線維，好銀線維の改善が確認された．ヘモクロマトーシスにおいては，診断と瀉血治療の継続が重要であると考えられた．

The burning behavior for non-charring fuels is modeled to predict the fire behavior in a compartment. This modeling considers the following phenomena: (i) the reduction of heat transfer from flames due to lack of oxygen mass fraction; and (ii) the thermal feedback from the smoke layer and walls. In addition, a compartment integrated zone model is developed to obtain the parameters which are necessary for the prediction of fuel burning behavior. Namely, this approach applies a two-zone model for the growth or preflashover stage and a one-zone model for the fully-developed or post-flashover stage which also incorporates the fuel burning behavior. Fire experiments in a cubic compartment are conducted to validate this model. Overall, calculations of this integrated compartment model give good agreement with the experiments of mass loss rate and temperature in the compartment.

Background: Aging is associated with adverse outcomes in patients with cardiac diseases. Whether elderly patients hospitalized with heart failure (HF) had increased risks for mortality and rehospitalization compared with younger patients during the long-term follow-up was examined. The predictors of these adverse outcomes were also identified. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of 2,675 patients hospitalized with worsening HF and the outcomes were followed up. The majority of elderly patients were female, had lower body mass index (BMI), a higher rate of ischemic, valvular, and hypertensive heart disease as etiologies of HF, a lower estimated glomerular filtration rate (eGFR), lower hemoglobin, and higher left ventricular ejection fraction values. Even after adjustment for covariates, the elderly patients were associated with higher risks of adverse outcomes. The predictors for all-cause death were: lower eGFR, lower BMI, male sex, sustained ventricular tachycardia or fibrillation (VT/VF), and the use of diuretics at discharge. Conclusions: Among patients hospitalized with HF, elderly patients had a worse prognosis than younger patients. Lower eGFR, lower BMI, male sex, sustained VT/VF, and diuretic use were independent predictors for all-cause death in these patients with higher risk. (Circ J 2011; 75: 2403-2410)

The RALES trial demonstrated that spironolactone improved the prognosis of patients with heart failure (HF). However, it is unknown whether the discharge use of spironolactone is associated with better long-term outcomes among hospitalized systolic HF patients in routine clinical practice. We examined the effects of spironolactone use at discharge on mortality and rehospitalization by comparing with outcomes in patients who did not receive spironolactone.The JCARE-CARD studied prospectively the characteristics and treatments in a broad sample of patients hospitalized with worsening HF and the outcomes were followed with an average of 2.2 years of follow-up.A total of 946 patients had HF with reduced left ventricular ejection fraction (LVEF) (40%), among whom spironolactone was prescribed at discharge in 435 patients (46%), but not in 511 patients (54%). The mean age was 66.3 years and 72.2% were male. Etiology was ischemic in 39.7% and mean LVEF was 27.1%. After adjustment for covariates, discharge use of spironolactone was associated with a significant reduction in all-cause death (adjusted hazard ratio 0.612, P=.020) and cardiac death (adjusted hazard ratio 0.524, P=.013).Among patients with HF hospitalized for systolic dysfunction, spironolactone use at the time of discharge was associated with long-term survival benefit. These findings provide further support for the idea that spironolactone may be useful in patients hospitalized with HF and reduced LVEF.

The aim of this study was to clarify the role of the immune response to muscarinic type 3 receptor (M3R) in the pathogenesis of Sjögren's syndrome (SS). M3R(-/-) mice were immunized with murine M3R peptides and their splenocytes were inoculated into Rag1(-/-) (M3R(-/-)→Rag1(-/-)) mice. M3R(-/-)→Rag1(-/-) mice had high serum levels of anti-M3R antibodies and low saliva volume. Histological examination showed marked infiltration of mononuclear cells in the salivary glands and immunohistochemistry demonstrated that the majority of these cells were CD4(+) T cells with a few B cells and several IFN-γ- and IL-17-producing cells. Apoptotic cells were present in the salivary glands of M3R(-/-)→Rag1(-/-) mice. Moreover, transfer of only CD3(+) T cells from M3R(-/-) immunized with M3R peptides into Rag1(-/-) mice resulted in cell infiltration and destruction of epithelial cells in the salivary glands, suggesting that M3R reactive CD3(+) T cells play a pathogenic role in the development of autoimmune sialoadenitis. Our findings support the notion that the immune response to M3R plays a crucial role in the pathogenesis of SS-like autoimmune sialoadenitis.

Aim: It is reported that in salivary glands of Sjogren’s syndrome (SS), interferon gamma (IFNγ) and IFNγ-inducible genes containing signal transducers and activators of transcription 1 (STAT1) are upregulated and play a crucial role in the pathogenesis of SS. The aim of this study is to clarify which phosphorylation of STAT1, serine727 (Ser727) or tyrosine701 (Tyr701) of STAT1, is important for IFNγ signaling and IFNγ-induced apoptosis in salivary gland cells. Methods: We established STAT1 Tyr701 variant (tyrosine to phenylalanine; Y701F) and STAT1 Ser727 variant (serine to alanine; S727A), which were transfected into human salivary gland (HSG) cells. HSG cells transfected with these mutant-STAT1 were analyzed on the expression of IFNγ-inducible genes and apoptosis after stimulation with IFNγ. Results: In Y701F mutant-STAT1 transfected HSG cells (Ser727-dominant HSG cells), IFNγ-inducible genes such as IP10, IRF1, and Fas expression were increased after stimulation with IFNγ. In Ser727-dominant HSG cells, the induction of apoptosis after stimulation with IFNγ was also increased compared with S727A mutant-STAT1 transfected HSG cells (Tyr701-dominant HSG cells). Conclusion: Phosphorylation of Ser727 in STAT1 might be more important in IFNγ signaling and the induction of apoptosis in HSG cells than phosphorylation of Tyr701. Accordingly, we propose that phosphorylation of Ser727 in STAT1 could be a potentially suitable new therapeutic target for SS patients to prevent the destruction of salivary glands.

In this study, we examined bioenergetic responses of age-2+ and age-3+ mummichogs ( Fundulus heteroclitus ) to degraded habitat condition and impoverished benthic prey community in polluted salt marshes by incorporating in situ food consumption rates with the mercury mass balance model technique. In general, bioenergetic responses of mummichogs appeared to be more related to benthic prey community than habitat condition. Fish from prey-impoverished marsh (PIM) sites generally had significantly elevated total metabolic costs compared with those from non-prey-impoverished marsh (NPIM) sites. However, the PIM populations also had ~two- to three-fold higher consumption rates than the NPIM populations, suggesting that the PIM populations may be capable of adjusting food consumption to offset elevated metabolic costs. Furthermore, only age-2+ females of the PIM populations had significantly reduced growth rates, whereas there was little among-site differences for age-2+ males and age-3+ fish, indicating that an increased consumption by the PIM populations may also have been a compensatory mechanism to maintain growth. Most of the PIM populations, however, had substantially (up to 80%) lower growth conversion efficiency relative to the NPIM populations. These findings suggest that pollution-tolerant fishes such as mummichogs may have energetic costs of living in chronically degraded habitats.

Low-field extremity magnetic resonance imaging (lfMRI) is currently commercially available and has been used clinically to evaluate rheumatoid arthritis (RA). However, one disadvantage of this new modality is that the field of view (FOV) is too small to assess hand and wrist joints simultaneously. Thus, we have developed a new lfMRI system, compacTscan, with a FOV that is large enough to simultaneously assess the entire wrist to proximal interphalangeal joint area. In this work, we examined its clinical value compared to conventional 1.5 tesla (T) MRI. The comparison involved evaluating three RA patients by both 0.3 T compacTscan and 1.5 T MRI on the same day. Bone erosion, bone edema, and synovitis were estimated by our new compact MRI scoring system (cMRIS) and the kappa coefficient was calculated on a joint-by-joint basis. We evaluated a total of 69 regions. Bone erosion was detected in 49 regions by compacTscan and in 48 regions by 1.5 T MRI, while the total erosion score was 77 for compacTscan and 76.5 for 1.5 T MRI. These findings point to excellent agreement between the two techniques (kappa = 0.833). Bone edema was detected in 14 regions by compacTscan and in 19 by 1.5 T MRI, and the total edema score was 36.25 by compacTscan and 47.5 by 1.5 T MRI. Pseudo-negative findings were noted in 5 regions. However, there was still good agreement between the techniques (kappa = 0.640). Total number of evaluated joints was 33. Synovitis was detected in 13 joints by compacTscan and 14 joints by 1.5 T MRI, while the total synovitis score was 30 by compacTscan and 32 by 1.5 T MRI. Thus, although 1 pseudo-positive and 2 pseudo-negative findings resulted from the joint evaluations, there was again excellent agreement between the techniques (kappa = 0.827). Overall, the data obtained by our compacTscan system showed high agreement with those obtained by conventional 1.5 T MRI with regard to diagnosis and the scoring of bone erosion, edema, and synovitis. We conclude that compacTscan is useful for diagnosis and estimation of disease activity in patients with RA.

A case of a 37-year-old pregnant patient with antiphospholipid syndrome (APS), who has a medical history of both thrombosis and recurrent fetal loss, is presented. She was treated with predonisolone and fixed-dose unfractionated heparin (UFH) infusion, followed by plasmaphereses and fixed-dose low-molecular-weight heparin infusion during her fourth pregnancy. Unfortunately, this treatment did not have beneficial effects, resulting in intrauterine growth restriction and finally neonatal death. Continuous intravenous UFH infusion and low-dose aspirin were administrated under the monitoring of the activated partial thromboplastin time to achieve a target level of 120 s during her fifth pregnancy. A healthy baby weighing 1818 g at birth was delivered by Cesarean section at the 34th week of pregnancy. High-dose UFH infusion may be considered to be one of the preferable options to manage pregnant patients with refractory APS.

Intracellular partitioning of trace metals is critical to metal detoxification in aquatic organisms. In the present study, we assessed metal (Cd, Cu, Pb, and Zn) handling capacities of mummichogs (Fundulus heteroclitus) in metal-polluted salt marshes in New York, USA by examining metal intracellular partitioning. Despite the lack of differences in the whole body burdens, partitioning patterns of metals in intracellular components (heat-stable proteins, heat-denaturable proteins, organelles, and metal-rich granules) revealed clear differential metal handling capacities among the populations of mummichogs. In general, mummichogs living in metal-polluted sites stored a large amount of metals in detoxifying cellular components, particularly metal-rich granules (MRG). Moreover, only metals associated with MRG were consistently correlated with variations in the whole body burdens. These findings suggest that metal detoxification through intracellular partitioning, particularly the sequestration to MRG, may have important implications for metal tolerance of mummichogs living in chronically metal-polluted habitats.

SummaryInterstitial lung disease (ILD) is an intractable disease induced by various factors in humans. However, there is no universally effective treatment for ILD. In this study, we investigated the role of transforming growth factor (TGF)-β signalling in the pathogenesis of ILD by using model mice. Injection of interleukin (IL)-18 plus IL-2 in C57BL6 (B6) mice resulted in acute ILD by infiltration of natural killer (NK) cells and a significant increase of TGF-β mRNA in the lung. To examine the pathogenetic role of TGF-β in ILD mice, we used SB-431542 (4-[4-(1,3-benzodioxol-5-yl)-5-(2-pyridinyl)-1H-imidazol-2-yl]-benzamide), which is a potent and selective inhibitor of TGF-β receptor I (TβRI), also known as activin receptor-like kinase 5 (ALK5). Treatment of B6-ILD mice with SB-431542 resulted in improvement of ILD, delay in mortality, reduction of the expression of interferon (IFN)-γ and IL-6 in the lungs. The same treatment also decreased significantly the percentage of natural killer (NK) cells in the lungs (P

Background: Obesity is a risk factor for cardiovascular disease (CVD) and is also associated with an increased risk of death in subjects without CVD. However, in heart failure (HF), elevated body mass index (BMI) has been shown to be associated with better prognosis, but it is unknown whether this is the case in unselected HF patients encountered in routine clinical practice in Japan. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of patients hospitalized with worsening HF and the outcomes were followed for 2.1 years. Study cohort (n=2,488) was classified into 3 groups according to baseline BMI

Background: Previous studies demonstrated that β-blocker use at the time of hospital discharge significantly increased postdischarge treatment rates, associated with an early (60- to 90-day) survival benefit in patients with heart failure (HF). However, it is unknown whether this therapeutic approach can also improve the long-term survival. We thus examined the long-term effects of β-blocker use at discharge on outcomes in patients hospitalized for HF and left ventricular systolic dysfunction (LVSD) (ejection fraction

Intracellular partitioning of trace metals is critical to metal tolerance in aquatic organisms and may also influence metal trophic transfer in ecosystems. In this study, we tested the relevance of metal (Cd, Cu, Pb, and Zn) intracellular partitioning in prey as an indicator of metal trophic availability to benthic forage fish, mummichogs (Fundulus heteroclitus), in chronically metal-polluted salt marshes in New York, USA. Two common prey of mummichogs in the study area, Palaemonetes pugio and Nereis acuminata, generally stored increasingly higher proportions of non-essential metals (particularly Pb) in insoluble (less trophically available) cellular components, as the whole body burdens increased. In contrast, intracellular partitioning of essential metals (Cu and Zn) in invertebrate prey varied relatively little among sites. Differential Cd and Pb intracellular partitioning patterns within P. pugio among sites were significantly associated with Cd and Pb whole body burdens in mummichogs, respectively (i.e., prey-driven bioreduction of metals), while bioaccumulation of Cu and Zn in mummichogs was similar among populations. The findings in this study suggest that metal intracellular partitioning within prey may be partially responsible for metal trophic availability to a predator in metal-polluted habitats, while there was also evidence that some predator-dependent processes may offset differential trophic availabilities from prey.

Organic mercury such as methylmercury is not only one of the most toxic substances found in coastal ecosystems but also has high trophic transfer efficiency. In this study, we examined implications of chronically altered benthic macroinfaunal assemblages for organic mercury trophic availability (based on organic mercury intracellular partitioning) to their predators in the Arthur Kill-AK (New York, USA). Despite low species diversity, both density and biomass of benthic macroinvertebrates in AK were significantly higher than those at the reference site. Disproportionately high biomass of benthic macroinvertebrates (mostly polychaetes) in the northern AK resulted in a more than twofold increase ('ecological enrichment') in the trophically available organic mercury pool. These results suggest that altered benthic macroinfaunal community structure in AK may play an important role in organic mercury trophic availability at the base of benthic food webs and potentially in mercury biogeochemical cycling in this severely urbanized coastal ecosystem.

Objective. To evaluate the clinical usefulness of measuring anti-RNA polymerase (RNAP) III antibody with a commercially available ELISA in Japanese patients with SSc. Methods. This multicentre study involved 354 patients with SSc, 245 with non-SSc CTDs and 102 healthy controls. ELISAs were used to detect anti-RNAP III antibody, anti-topo I antibody and ACA. The presence of anti-RNAP III antibody in selected serum samples was confirmed by immunoprecipitation (IP) assay. Results. By ELISA, anti-RNAP III antibody was detected in 38 (10.7%) patients with SSc, 3 (1.2%) with non-SSc CTD and no healthy controls. The clinical specificity for SSc was excellent (98.8%), although a small number of false positives occurred. The sensitivity of the antitopo I and ACA ELISAs for SSc was 59.9%, which increased to 68.2% without a reduction in specificity when the anti-RNAP III measurement was added. Clinical features associated with positivity for the anti-RNAP III antibody include dcSSc, a high total skin score and a trend towards high prevalence of renal crisis, consistent with previous studies that used an IP assay. Furthermore, on clinical severity scales, SSc patients with anti-RNAP III antibody scored highest for skin and renal involvement among patients subgrouped by the presence of individual SSc-related antibodies. Conclusions. The measurement of anti-RNAP III antibody by ELISA is useful in routine clinical practice, because it helps diagnose SSc and identify a disease subset with severe skin and renal involvement.

Factors affecting CH3Hg and Cd trophic transfer from six invertebrates and a juvenile fish prey to mummichogs ( Fundulus heteroclitus ) were investigated using prey-dependent and predator-dependent approaches. Prey-specific trophic availability of metals to mummichogs was estimated using a subcellular partitioning approach (i.e., trophically available metals (TAM), as originally proposed by Wallace and Luoma (2003) ). The proportions of CH3Hg partitioned to TAM (CH3Hg-TAM%) ranged from 39.7% to 82.7%, while the proportions of Cd partitioned to TAM (Cd-TAM%) ranged from 51.8% to 67.4%. CH3Hg-TAM% and Cd-TAM% were significantly correlated with the proportions of metals released from prey by in vitro solubilization with mummichog gut fluid (i.e., gut solubilizable metals (GSM)), CH3Hg-GSM% and Cd-GSM%, respectively. This relationship suggests that the majority of CH3Hg and Cd partitioned as TAM in prey were solubilized in the digestive tract of mummichogs. Mummichogs retained 52.7% to 73.7% of the ingested CH3Hg, which was comparable with prey-specific CH3Hg-TAM% and CH3Hg-GSM%. However, mummichogs retained only 3.2%–11.0% of ingested Cd, which was substantially lower than Cd-TAM% or Cd-GSM%. These results suggest that solubilizable, prey-associated CH3Hg was transported through the gut membrane of mummichogs, whereas the majority of prey-associated Cd was excluded and subsequently eliminated, regardless of its subcellular partitioning.

Magnetic resonance imaging (MRI) is a useful tool for evaluating disease activity and therapeutic efficacy in rheumatoid arthritis (RA). However, conventional whole-body MRI is inconvenient on several levels. We have therefore developed a new low-field extremity MRI (compact MRI, cMRI) and examined its clinical utility. Thirteen RA patients treated with anti-tumor necrosis factor (TNF) biologics were included in the study. The MRI was performed twice using a 0.21-T extremity MRI system. The MRI images were scored using our proposed cMRI scoring system, which we devised with reference to the Outcome Measures in Rheumatology Clinical Trials RA MRI score (OMERACT RAMRIS). In our cMRI scoring system, synovitis, bone edema, and bone erosion are separately graded on a scale from 0 to 3 by imaging over the whole hand, including the proximal interphalangeal joint. The total cMRI score (cMRIS) is then obtained by calculating the total bone erosion score x 1.5 + total bone edema score x 1.25 + total synovitis score. In this study, one patient showed a progression of bone destruction even under low clinical activity, as assessed by the disease activity score on 28 joints (DAS28); however, another patient's cMRIS decreased concurrently with the decrease in DAS28, with the positive correlation observed between DeltaDAS28 and DeltacMRIS (R = 0.055, P < 0.05). We conclude that cMRI and cMRIS are useful for assessing total disease activity and as a method linking MRI image evaluation to clinical evaluation.

Objective Recent genome-wide association studies identified an association between single-nucleotide polymorphisms (SNPs) in the C8orf13 region of BLK, the B lymphoid tyrosine kinase gene, with systemic lupus erythematosus (SLE) in Caucasians. The purpose of this study was to evaluate the significance of this region in the genetic background of Japanese patients with SLE. Methods Fourteen tag SNPs in the C8orf13–BLK region were genotyped in 327 Japanese patients with SLE and 322 healthy Japanese controls. The population-attributable risk percentage (PAR%) of rs13277113 in Japanese was compared with that in Caucasians as well as with that of other SLE susceptibility genes in Japanese. Results As in Caucasians, rs13277113A demonstrated the strongest association in Japanese (P = 1.73 × 10–6 for the genotype frequency, P = 4.75 × 10–7 for the allele frequency, odds ratio [OR] 2.44 [95% confidence interval (95% CI) 1.43–4.16]). The association in Japanese was consistent with a recessive model (P = 2.74 × 10–7, OR 2.27 [95% CI 1.66–3.11]). In contrast to the Caucasian population, this risk allele was the major allele in the Japanese population. Because both the risk allele frequency and the OR were higher in Japanese than in Caucasians, the PAR% of rs13277113 was estimated to be much higher in Japanese (35.4%) than in Caucasians (16.2%), and the second highest among the 6 confirmed SLE susceptibility genes in Japanese. Conclusion The association of the C8orf13–BLK region with SLE was replicated in a Japanese population. Contribution of this region to the genetic predisposition to SLE appeared to be greater in Japanese than in Caucasians.

OBJECTIVE: Mannose binding lectin (MBL) is a key molecule in first line defense against various microorganisms. Polymorphism of the MBL gene greatly affects serum MBL concentration, and is known to be associated with occurrence of infectious diseases. We aimed to determine whether there is a relationship between occurrence or severity of chronic periodontitis (CP) and polymorphism of the MBL gene. PATIENTS AND METHODS: Ninety-eight CP patients and 63 healthy subjects with no periodontitis were typed for the codon 54 polymorphism of the MBL gene by PCR-restriction fragment length polymorphism method. RESULTS: Genotype frequencies of the codon 54 polymorphism were similar between patients and control subjects. When patients were categorized to mild, moderate and severe periodontitis groups, possession of the low serum MBL concentration allele was a risk factor for having severe CP, as assessed by logistic regression analysis. CONCLUSION: Patients with MBL genotypes that cause lower serum MBL concentration may be at risk of having severe periodontitis. MBL gene typing may become useful to predict the prognosis of CP.

Background: Heart failure (HF) with preserved ejection fraction (EF) is common. We compared the characteristics, treatments, and outcomes in HF patients with reduced vs preserved EF by using the national registry database in Japan. Methods and Results: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) is a prospective observational study in a broad sample of patients hospitalized with worsening HF. The study enrolled 2,675 patients from 164 hospitals with an average of 2.4 years of follow-up. Patients with preserved EF (EF ≥50% by echocardiography; n=429) were more likely to be older, female, have hypertension and atrial fibrillation, and less likely to have ischemic etiology compared with those with reduced EF (EF

A model for predicting fire behavior in a compartment is formulated that considered the following two points regarding mass loss rate: (i) the heat transfer from flame to fuel is decreased with lack of oxygen concentration; and (ii) the heat transfer from walls, ceilings and smoke layer to fuel with development of compartment fire. In addition a computer simulation model based on zone concept is developed that considers conditions in a compartment from the initial period to the decay period of compartment fire. Namely, this approach applies a two-layer zone model for the growth or pre-flashover stage and a one-layer zone model for the fully developed or post-flashover fire. The compartment fire experiment is performed to validate this model. In general, good agreement between experimental and theoretical results about the mass loss rate and the temperature in the compartment is obtained.

Tristetraprolin (TTP) is an intracellular protein that modulates the production of cytokines, including TNFalpha, by binding to and destabilizing the mRNAs of these cytokines. Therefore, differences in TTP gene expression may affect the severity of inflammatory diseases, such as rheumatoid arthritis (RA). We searched for polymorphisms in the human TTP gene and for this purpose, we sequenced the entire TTP gene in 20 Japanese individuals (ten with RA and ten healthy volunteers) and found one single nucleotide polymorphism (SNP) in the promoter region. We analyzed this SNP (A/G) by restriction fragment length polymorphism method in 155 RA patients and 100 control subjects. While the frequency of A allele in this SNP was similar in RA patients (74.5%) and controls (76.0%), the disease duration in RA patients with genotype GG was shorter than that of patients with genotypes AA/AG and RA patients with genotype GG had a higher probability of being treated with infliximab. We studied the difference in promoter activity between the two alleles by luciferase assay and found that the promoter activity of TTP promoter region with allele A was around two-fold higher than that with allele G. We conclude that this SNP in the promoter region of the TTP gene mildly affects promoter activity, and thus, may influence the disease activity of inflammatory disorders including RA.

Objective To clarify the glucose-6-phosphate isomerase (GPI)–specific CD4+ T cell lineage involved in GPI-induced arthritis and to investigate their pathologic and regulatory roles in the induction of the disease. Methods DBA/1 mice were immunized with GPI to induce arthritis. CD4+ T cells and antigen-presenting cells were cocultured with GPI, and cytokines in the supernatant were analyzed by enzyme-linked immunosorbent assay. Anti–interferon-γ (anti-IFNγ) monoclonal antibody (mAb), anti–interleukin-17 (anti–IL-17) mAb, or the murine IL-6 receptor (IL-6R) mAb MR16-1 was injected at different time points, and arthritis development was monitored visually. After MR16-1 was injected, percentages of Th1, Th2, Th17, and Treg cells were analyzed by flow cytometry, and CD4+ T cell proliferation was analyzed using carboxyfluorescein diacetate succinimidyl ester. Results GPI-specific CD4+ T cells were found to be differentiated to Th1 and Th17 cells, but not Th2 cells. Administration of anti–IL-17 mAb on day 7 significantly ameliorated arthritis (P < 0.01), whereas administration of anti-IFNγ mAb exacerbated arthritis. Neither anti–IL-17 mAb nor anti-IFNγ mAb administration on day 14 ameliorated arthritis. Administration of MR16-1 on day 0 or day 3 protected against arthritis induction, and MR16-1 administration on day 8 significantly ameliorated existing arthritis (P < 0.05). After administration of MR16-1, there was marked suppression of Th17 differentiation, without an increase in Th1, Th2, or Treg cells, and CD4+ T cell proliferation was also suppressed. Conclusion IL-6 and Th17 play an essential role in GPI-induced arthritis. Since it has previously been shown that treatment with a humanized anti–IL-6R mAb has excellent effects in patients with rheumatoid arthritis (RA), we propose that the IL-6/IL-17 axis might also be involved in the generation of RA, especially in the early effector phase.

If a fire occurs and spreads in a building, fire plumes ejected from the openings may cause fire spread to upper floors and neighboring buildings. In particular, flames ejected from an opening were investigated by many researchers [1-5]. However, most of their works focused on temperature distribution of fire jet plume and heights of the flames issuing from the opening. Although some researchers examined heat transfer from ejected flames to facade wall [6], their studies did not cover situations where there was an opposite wall. In the present study, a series of small-scale experiments having a facade wall and an opposite parallel wall representing an adjacent buildings were carried out in order to investigate flame heights, heat flux to the facade wall and to the facing wall, and temperature distribution of ejected flame from an opening. The following phenomena were examined: 1) the heat release rate at which flames occurred from the opening and 2) the temperature distribution in ejected flames and the heat flux from ejected flames with and without an opposite wall [7].

We aimed to compare the efficacy and safety of mirabegron, a β3-adrenoceptor agonist, and imidafenacin, an anticholinergic agent, in overactive bladder patients.We conducted a multicenter, prospective randomized cross-over study at 5 hospitals in Japan from December 2012 to June 2015. We enrolled female patients with overactive bladder aged ≥50 years, who had never received treatment for the condition. The patients were assigned to Group A or B. Group A patients were administered mirabegron (50 mg per day) for 8 weeks, followed by a 2-week washout period, and then imidafenacin (0.2 mg per day) for 8 weeks. This order of drug administration was reversed in Group B.A total of 33 and 18 patients in Group A and 37 and 26 patients in Group B continued to receive treatment at weeks 8 and 18, respectively. Mirabegron administration significantly improved overactive bladder symptom score (OABSS), the urinary frequency per 24 hr, voided volume per micturition, and number of nocturia episodes per night at week 8. Moreover, imidafenacin administration improved all these variables, except for the number of nocturia episodes per night at week 8. No significant difference was observed in the drug effects between mirabegron and imidafenacin. Although imidafenacin administration significantly increased the scores for dry mouth, blurred vision, and constipation, mirabegron administration did not.Mirabegron and imidafenacin have the same efficacy. Imidafenacin administration is associated with a higher rate of dry mouth, blurred vision, and constipation as compared to mirabegron administration. Neurourol. Urodynam. 36:1097-1103, 2017. © 2016 Wiley Periodicals, Inc.

Several studies report on the outcomes of self-expandable metallic stents (SEMSs) deployment for malignant gastric outlet obstruction (GOO). However, data was mostly based on the analysis of single-center studies including only a small number of patients. This study aimed to evaluate clinical outcomes after the deployment of SEMS in patients with malignant GOO and to compare the clinical outcomes of two metallic stents with different designs.Altogether 125 consecutive patients from five institutions were included. Clinical outcomes were evaluated according to technical success, clinical success, stent patency period, survival period and complications. A comparison of clinical outcomes between Niti-S pyloric/duodenal and WallFlex duodenal stents was also undertaken.Rates for clinical and technical success were 100% and 92.0%, respectively. The median stent patency and survival periods were 72.0 days (range 3-775 days) and 75.0 days (range 3-775 days), respectively. The rate of overall adverse events was 28.8%. The rate of stent dysfunction was 16.8%, and that of adverse events, except stent dysfunction was 12.0%. Massive bleeding occurred in two patients as a late complication. The clinical success rate for Niti-S stent was significantly higher than that for WallFlex stent (96.2% vs 84.8%, P = 0.023).We successfully deployed a SEMS in malignant GOO. The selection of a SEMS with a lower axial force may be important for patients to resume the oral food intake. Additionally, consideration must be given to the appropriate management of fatal bleeding as a late complication.

Interleukin-17 is a proinflammatory cytokine. Recent animal studies have shown that IL-17 plays a role in the initiation and progression of arthritis. However, whether IL-17 has a prominent role in human rheumatoid arthritis (RA) or not remains unclear. Here we investigated the role of IL-17 in patients with RA. cDNA was prepared from knee joint synovial tissues of RA (n = 11) and osteoarthritic (OA, n = 10) patients and PBMC of RA (n = 52) and healthy subjects (n = 34). IL-17 gene expression level was measured by real-time PCR, and was compared with various clinical parameters. IL-17 gene expression in synovial tissues of RA was similar to that in OA. IL-17 gene expression level in PBMC of RA patients was significantly higher than in the control. The response (changes in DAS) to two-week treatment with anti-TNF-alpha blockers (infliximab or etanercept) did not correlate with changes in IL-17 gene expression levels. The IL-17/TNF-alpha gene expression ratio at baseline (before treatment) tended to be lower in responders to the treatment. Expression of IL-17 gene in PBMC may be associated with the inflammatory process of RA. IL-17/TNF-alpha expression ratio is a potentially suitable marker of response to anti-TNF-alpha therapy.

A 54-year-old woman complaining of muscle weakness and weight loss was admitted to our hospital with suspected polymyositis. Muscle biopsy revealed Langhans-type giant cells and noncaseating granulomas. Therefore, sarcoid myositis was diagnosed. The patient was treated with prednisolone, and the symptoms improved gradually. Generally, sarcoidosis is identified clinically in patients with foggy vision or mediastinal lymphadenopathy, but muscular weakness may be an infrequently observed initial symptom. Sarcoidosis should be considered in the differential diagnosis of polymyositis.

Background The characteristics and outcomes of patients discharged from hospitals with a diagnosis of heart failure (HF) have been described by a number of previous epidemiological studies. However, very little information is available on this issue in general practice in Japan. Methods and Results The Japanese Cardiac Registry of Heart Failure in General Practice (JCARE-GENERAL) is designed to study the characteristics, treatment and outcomes prospectively in a broad sample of outpatients with HF who were managed by cardiologists in hospital (Hospital-HF) and primary care physicians in general practice (GP-HF). Out of 2,685 patients with HF, 1,280 patients were Hospital-HF and 1,405 GP-HF. Compared to the Hospital-HF patients, GP-HF patients were more likely to be elderly and female, and they had a higher prevalence of hypertensive heart disease as a cause of HF. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and β-blockers were more prescribed to Hospital-HF than GP-HF patients. At the follow-up of 1.2 year, after adjustment, the mortality was comparable between the Hospital-HF and GP-HF groups, whereas HF-related admission was higher in the Hospital-HF group than in in the GP-HF group. Conclusions Based on the JCARE-GENERAL, the characteristics, treatment and outcomes of GP-HF patients differed from those of Hospital-HFpatients in Japan. (Circ J 2007; 71: 449 - 454)

An 80-year-old woman with a history of chronic hepatitis B was referred to our hospital because of upper gastrointestinal bleeding of unknown origin. Dynamic computed tomography revealed liver cirrhosis and hepatofugal collateral vessels around the duodenum. Emergency esophagogastroduodenoscopy showed duodenal varices with an erosive spot, highly suggestive of a variceal rupture site. We immediately performed endoscopic clipping of the ruptured site to achieve temporary hemostasis. Ten days later, elective balloon-occluded retrograde transvenous obliteration (B-RTO) was performed to prevent recurrence. We describe a successfully treated case of duodenal variceal rupture managed by combination therapy with endoscopic clipping and B-RTO.

The Chaperonins comprise a family of molecular chaperones having a double-ring structure and similar sequence homology. These proteins play an essential role in biological reactions that mediate the folding of newly synthesized polypeptides and partially denatured proteins. In the prokaryotic group I chaperonins, structural and reaction cycle analyses of GroEL and its co-chaperone GroES have been performed in detail. While in eukaryotes, there have been limited reports analyzing the group I chaperonin HSP60 and its co-chaperone HSP10. In the present study, we purified the wild type HSP60 from porcine liver and investigated the interaction between HSP60 and HSP10, including conformation and physiological relationships. Based on the results of transmission electron microscopy, native PAGE, and gel filtration column chromatography, the wild type HSP60 displayed a heptameric single-ring structure in the absence of ATP. In contrast, HSP60 formed mainly a "football-type" complex with HSP10 in the presence of ATP and mediated the refolding of denatured substrate protein. The functional conformation cycle of the purified mammalian HSP60 is distinct from the cycle of the prokaryotic GroEL/GroES chaperonin.