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There is a growing demand for skillful prediction systems in the Arctic. Using the Norwegian Climate Prediction Model that combines the fully coupled Norwegian Earth System Model and the Ensemble Kalman filter, we present a system that performs both, weakly coupled data assimilation (wCDA) when assimilating ocean hydrography (by updating the ocean alone) and strongly coupled data assimilation when assimilating sea ice concentration (SIC) (by jointly updating the sea ice and ocean). We assess the seasonal prediction skill of this version of the Norwegian Climate Prediction Model, the first climate prediction system using strongly coupled data assimilation, by performing retrospective predictions (hindcasts) for the period 1985 to 2010. To better understand the origins of the prediction skill of Arctic sea ice, we compare this version with a version that solely performs wCDA of ocean hydrography. The reanalysis that assimilates just ocean data exhibits skillful hydrography in the upper Arctic Ocean and features an improved sea ice state, such as improved summer SIC in the Barents Sea, or reduced biases in sea ice thickness. Skillful prediction of SIE up to 10–12 lead months are only found during winter in regions of a relatively deep ocean mixed layer outside the Arctic basin. Additional DA of SIC data notably further corrects the initial seaice state, confirming the applicability of the results of Kimmritz et al. (2018) in a historical setting. The resulting prediction skill of SIE is widely enhanced compared to predictions initialized through wCDA of only ocean data. Particularly high skill is found for July‐initialized autumn SIE predictions. Plain Language Summary: The declining Arctic sea ice entails both risks and opportunities for the Arctic ecosystem, communities, and economic activities. Reliable seasonal predictions of the Arctic sea ice could help to guide decisionmakers to benefit from arising opportunities and to mitigate increased risks in the Arctic. However, despite some success, seasonal prediction systems in the Arctic have not exploited their full potential yet. For instance, so far only a single model component, for example, the ocean, has been updated in isolation to derive a skillful initial state, though joint updates across model components, for example, the ocean and the sea ice, are expected to perform better. Here, we introduce a system that, for the first time, deploys joint updates of the ocean and the sea ice state, using data of the ocean hydrography and sea ice concentration, for seasonal prediction in the Arctic. By comparing this setup with a system that updates only the ocean in isolation, we assess the added skill of facilitating sea ice concentration data to jointly update the ocean and the sea ice. While the update of the ocean alone leads to skillful winter predictions only in the North Atlantic, the joint update strongly enhances the overall skill. Key Points: We developed strongly coupled assimilation of the ocean and sea ice for seasonal prediction of sea iceAssimilating ocean data affects ice thickness, but the prediction skill relies on mixed layer depthWith joint updates of the ocean and sea ice, we achieve highly skillful predictions of sea ice extent in the Arctic basin and the North Atlantic [ABSTRACT FROM AUTHOR]

We examined the preventive and therapeutic effects of fusion cells prepared from spleen-derived dendritic cells (DCs) transduced with the interleukin-2 (IL-2) gene and QRsP fibrosarcoma cells in a mouse lung metastasis model. The IL-2 or LacZ gene was introduced into spleen-derived DCs using an adenoviral vector. Irradiated QRsP tumour cells were fused with IL-2 gene-transduced DCs (fusion/IL-2) or LacZ gene-transduced DCs (fusion/LacZ) by polyethylene glycol. These fusion cells expressed major histocompatibility complexes (MHC) class I and II, CD86, CD11c and CD80α. Splenocytes from mice vaccinated with fusion cells showed increased production of interferon-γ (IFN-γ) and cytotoxic T-lymphocyte (CTL) activity as compared with those vaccinated with DCs or tumour cells alone, and CTL levels were higher in fusion/IL-2-vaccinated mice than in fusion/LacZ-vaccinated mice. In our experiments on the protective and therapeutic effects on lung metastasis, mice vaccinated with fusion/IL-2 fusion/ LacZ or fusion showed a significant reduction in pulmonary metastasis compared with those given DCs, tumour or phosphate-buffered saline. The introduction of the IL-2 gene into fusion cells produced more potent preventive and therapeutic effects. These results suggest that immunization with fusion cells prepared from spleen-derived DCs and tumour cells is capable of inducing preventive and therapeutic anti-tumour immunity against lung metastasis, and modification by the IL-2 gene may increase anti-tumour efficacy. [ABSTRACT FROM AUTHOR]

Burns are a common type of skin injury encountered at all levels of medical facilities from private clinics to core hospitals. Minor burns heal by topical treatment alone, but moderate to severe burns require systemic management, and skin grafting is often necessary also for topical treatment. Inappropriate initial treatment or delay of initial treatment may exert adverse effects on the subsequent treatment and course. Therefore, accurate evaluation of the severity and initiation of appropriate treatment are necessary. The Guidelines for the Management of Burn Injuries were issued in March 2009 from the Japanese Society for Burn Injuries as guidelines concerning burns, but they were focused on the treatment for extensive and severe burns in the acute period. Therefore, we prepared guidelines intended to support the appropriate diagnosis and initial treatment for patients with burns that are commonly encountered including minor as well as moderate and severe cases. Because of this intention of the present guidelines, there is no recommendation of individual surgical procedures., (© 2016 Japanese Dermatological Association.)

Varicose veins are treated at multiple clinical departments, but as patients often visit the dermatology clinic first due to leg ulcers, the present Guidelines for the Management of Lower Leg Ulcers/Varicose Veins were prepared in consideration of the importance of the dermatologist's role. Also, the disease concept of chronic venous insufficiency or chronic venous disorders and the CEAP classification of these disorders are presented. The objective of the present guidelines is to properly guide the diagnosis and treatment of lower leg ulcers/varicose veins by systematically presenting evidence-based recommendations that support clinical decisions., (© 2016 Japanese Dermatological Association.)

The Japanese Dermatological Association prepared guidelines focused on the treatment of skin ulcers associated with connective tissue disease/vasculitis practical in clinical settings of dermatological care. Skin ulcers associated with connective tissue diseases or vasculitis occur on the background of a wide variety of diseases including, typically, systemic sclerosis but also systemic lupus erythematosus (SLE), dermatomyositis, rheumatoid arthritis (RA), various vasculitides and antiphospholipid antibody syndrome (APS). Therefore, in preparing the present guidelines, we considered diagnostic/therapeutic approaches appropriate for each of these disorders to be necessary and developed algorithms and clinical questions for systemic sclerosis, SLE, dermatomyositis, RA, vasculitis and APS., (© 2016 Japanese Dermatological Association.)

We aimed to prepare guidelines for the management of diabetic ulcer/gangrene with emphasis on the diagnosis and treatment of skin symptoms. They serve as a tool to improve the quality of the diagnosis and treatment in each patient and, further, to improve the level of the care for diabetic ulcer in Japan by systematically presenting evidence-based recommendations for clinical judgments by incorporating various viewpoints., (© 2016 Japanese Dermatological Association.)

The Wound/Burn Guidelines Committee consists of members commissioned by the Board of Directors of the Japanese Dermatological Association (JDA). It held several meetings and evaluations in writing since October 2008, and drafted five guidelines for the diagnosis and treatment including commentaries on wounds in general and the Guidelines for the Diagnosis and Treatment for Pressure Ulcers by taking opinions of the Scientific Committee and Board of Directors of JDA into consideration., (© 2016 Japanese Dermatological Association.)

The Japanese Dermatological Association determined to prepare the Wound/Burn Guidelines focusing on treatments, catering to needs for the clinical practice of dermatology. Among these guidelines, "Wounds in General" was intended to explain knowledge necessary "to heal wounds" without specifying particular disorders., (© 2016 Japanese Dermatological Association.)

Objective: To identify the 140-kd autoantigen recognized by anti-155/140 autoantibodies that are associated with adult cancer-associated dermatomyositis (DM) and juvenile DM and to determine the clinical relevance of anti-155/140 antibodies in a large cohort., Methods: Sera from 456 DM patients were assessed for the presence of anti-155/140 antibodies by immunoprecipitation using K562 cell extracts as substrate. Using immunoprecipitation and Western blotting, we then examined whether anti-155/140-positive sera recognized transcription intermediary factor 1α (TIF-1α), TIF-1β, and TIF-1γ. The clinical associations of antigen reactivity were also evaluated., Results: Anti-155/140-positive sera reacted with 140-kd TIF-1α in addition to 155-kd TIF-1γ. Among sera from 456 DM patients, 52 were reactive with both TIF-1α and TIF-1γ, while another 25 were reactive with TIF-1γ alone. Additionally, 7 were reactive with TIF-1β. Malignancy was more frequently found in adult patients with both anti-TIF-1α and anti-TIF-1γ antibodies than in those with anti-TIF-1γ antibodies alone (73% versus 50%; P < 0.05). In addition to juvenile DM patients and middle-aged and older DM patients with high percentages of malignancy, 8 "young adult" DM patients without malignancy had these autoantibodies., Conclusion: Anti-155/140 antibodies target TIF-1 family proteins, TIF-1α and TIF-1β, in addition to TIF-1γ. Since TIF-1 proteins have significant roles in oncogenesis, these antibodies may be produced during misdirected antitumor immunity., (Copyright © 2012 by the American College of Rheumatology.)

Objective: Patients with systemic sclerosis (SSc) exhibit enhanced production of free radicals due to ischemia and reperfusion injury following Raynaud's phenomenon, an initial clinical manifestation. Oxidative stress induces cytokine production, inflammatory cell recruitment, and tissue injury in several inflammatory diseases. The aim of this study was to examine the effect of edaravone, a free radical scavenger, on the development of fibrosis and autoimmunity in two different mouse models of SSc., Methods: The bleomycin-induced SSc model in mice and the tight skin mouse model were used to evaluate the effect of edaravone on fibrosis and immunologic abnormalities. To assess the reaction of fibroblasts to stimulation with free radicals, fibroblasts from these mice were cultured with NONOate, a nitric oxide-releasing agent, and hydrogen peroxide., Results: Treatment with edaravone reduced fibrosis in mice with bleomycin-induced SSc and in TSK/+ mice. The production of free radicals was also attenuated by edaravone in both models. In addition, production of fibrogenic cytokines such as interleukin-6 and transforming growth factor β1, production of anti-topoisomerase I antibody, and the degree of hypergammaglobulinemia were reduced by edaravone. Furthermore, bleomycin induced the production of H2O2 and nitric oxide from inflammatory cells, and collagen production was increased in fibroblasts cultured with H2O2 and NONOate., Conclusion: This study is the first to show that edaravone has a significant inhibitory effect on fibrosis both in the bleomycin-induced SSc model and in TSK/+ mice. These results indicate that edaravone should be further evaluated for potential use as an antifibrotic agent in SSc., (Copyright © 2011 by the American College of Rheumatology.)

Objective: Rapamycin, a novel macrolide immunosuppressive drug, is increasingly used as an agent for posttransplant immunosuppression and treatment of autoimmune disease. The molecular mechanism related to rapamycin-mediated immunosuppression is that rapamycin binds to FK-506 binding protein 12, and the formed complex inhibits the function of the mammalian target of rapamycin (mTOR), which in turn reduces protein phosphorylation, cell cycle progression, and cytokine production. The aim of this study was to examine the effect of rapamycin against the development of fibrosis and autoimmunity in 2 different types of systemic sclerosis (SSc) model mice., Methods: Tight skin (TSK/+) mice and bleomycin- induced SSc model mice were used to evaluate the effect of rapamycin on fibrosis and immunologic abnormalities. Furthermore, the antifibrotic effect of rapamycin was assessed using TSK/+ mouse fibroblasts., Results: Treatment with rapamycin reduced skin fibrosis of TSK/+ mice and skin and lung fibrosis of bleomycin-induced SSc model mice. The production of fibrogenic cytokines, such as interleukin-4 (IL-4), IL-6, IL-17, and transforming growth factor beta1, was attenuated by rapamycin. Hypergammaglobulinemia and anti-topoisomerase I antibody production were also reduced by rapamycin treatment in TSK/+ mice. In addition, mTOR expression levels were increased in TSK/+ mouse fibroblasts compared with those in wild-type mouse fibroblasts. Rapamycin treatment inhibited proliferation and collagen production of TSK/+ mouse fibroblasts in a dose-dependent manner., Conclusion: This study is the first to show that rapamycin has a significant inhibitory effect on fibrosis in both TSK/+ and bleomycin-induced SSc model mice. These results suggest that rapamycin might be an attractive candidate for clinical trials in SSc patients.

We report a 4-year-old girl presenting with progressive linear scleroderma affecting the right leg. Biopsy specimen disclosed typical histopathological findings of localized scleroderma. Right leg magnetic resonance imaging (MRI) showed high signal areas on T(2)-weighted images on the subcutaneous fatty tissue, muscles and bone marrow, suggesting that skin inflammation extended to the bone marrow. Oral corticosteroid therapy was instituted with improvement of both skin sclerosis and MRI findings. Our observations suggest that MRI examination should be considered in patients with localized scleroderma to evaluate the extension of the inflammation.

Objective: The contribution of CD19 and B lymphocytes to pulmonary fibrosis is controversial. The aim of this study was to address the role of CD19 during the development of pulmonary fibrosis., Methods: Mice lacking or overexpressing the B cell surface molecule CD19, which is known as a positive regulator of B cell activation, were used in a model of bleomycin-induced pulmonary fibrosis. Ten or sixteen days after intratracheal injection of bleomycin, lung sections from mice were evaluated by histologic analysis. Seven days after instillation, the total leukocyte count and the number of B cells in bronchoalveolar lavage fluid (BALF) were determined, using a hemocytometer and flow cytometry. Bleomycin was also administered into selectin-deficient or intercellular adhesion molecule 1-deficient mouse strains. The level of CXCR3 expression on B cells was determined by flow cytometry., Results: CD19 deficiency significantly reduced susceptibility to intratracheal bleomycin challenge on day 16, while CD19 overexpression augmented fibrosis even on day 10. Furthermore, the survival rate and number of B cells in BALF also correlated with CD19 expression levels. The accumulation of B cells in BALF was dependent on CD19 levels, whereas there was no association with the levels of selectins or intercellular adhesion molecule 1. Additionally, CXCR3 was up-regulated in BALF B cells, while it was rarely expressed on circulating B cells. Furthermore, CD19 signaling facilitated B cell CXCR3 up-regulation in response to stimulation in vitro., Conclusion: These results suggest that CD19 signaling is associated with the development of pulmonary fibrosis by controlling B cell infiltration into lung tissue, which may be associated with CXCR3 up-regulation.

Cutaneous extravascular papillary endothelial hyperplasia (PEH) is a rare lesion presenting as a cutaneous mass and histologically mimicking angiosarcoma. Herein, we describe a patient who presented with a palm tumor that had developed after trauma. Histologically, the lesion was ulcerated and showed proliferation of atypical epithelioid cells with nuclear enlargement and mitosis. Vascular proliferation was evident, and these were positive for CD31 and CD34, with approximately 20% positivity for MIB-1. We diagnosed this case as an extravascular papillary endothelial hyperplasia because there was no evidence of invasion into the surrounding tissue and elastica staining proved it did not have a vascular structure. To our knowledge, cutaneous extravascular PEH has not yet been reported in the published work.

We experienced a case of bullous pemphigoid (BP) arising in juvenile hyaline fibromatosis (JHF) associated with oral squamous cell carcinoma (SCC). JHF is a very rare disease inherited in an autosomal recessive fashion. Skin-colored, elastic hard nodules up to 10 cm in size were scattered mainly on the trunk and scalp. Gingival hypertrophy and an ill-defined mass with an irregular surface on the hard palate were noticed. A skin biopsy and a gingival biopsy confirmed the diagnosis of JFH and oral SCC, respectively. The patient was receiving anti-cancer drugs for the treatment of oral SCC and the treatment was successful. In the meantime, bean to nail sized bullas were noticed on the hands and feet. Histological examination, immunofluorescence method and ELISA confirmed the diagnosis of BP. The pathophysiological mechanisms are discussed in the present case.

Gaseous carbon monoxide (CO) has received attention as a neurotransmitter and as a material involved in persistent dilatation of vessels. CO is released by heme oxygenase (HO) during the process from heme to bilirubin or biliverdin. Many reports have revealed that exogenous nitric oxide (NO) can induce HO-1 in vitro, which is the induced isoform of HO. In the present study, we attempted an ex vivo system as an explant culture. A quantitative analysis was performed in combination with a reverse transcription-competitive polymerase chain reaction method, which proved to be very accurate, as well as a qualitative analysis with an immunohistochemistry. With this system we confirmed the induction of HO-1 mRNA and protein by exogenous NO in normal human skin. Our results concluded that this ex vivo system was very useful, because skin samples could be handled easily under conditions close to the in vivo situation.

We report here a homozygous variant case of antithrombin (AT) associated with arterial thrombosis and recurrent leg ulcers. The deep vein thrombosis was recognized by the venogram of his pelvic veins. His leg ulcers were scattered around his left ankle and accompanied by lipodermatosclerosis, which was evident in venous insufficiency. The propositus had developed cerebral infarction 12 years prior to his leg ulcers. Coagulation study showed low heparin cofactor activity of his AT with a normal level of immunoreactive AT. Nucleotide sequence analysis of the exon 2 of his AT gene showed Arg47-Cys mutation, leading to the lack of affinity of AT for heparin. The propositus is a homozygote for this abnormality., (Copyright 2001 Wiley-Liss, Inc.)