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Hereditary angioedema (HAE) is characterized by unpredictable, recurring and painful swelling episodes that can be disabling or even life-threatening. Awareness of HAE has progressively grown worldwide, and options for treatment of acute attacks and prevention of future attacks continue to expand; however, unmet needs in diagnosis and treatment remain. In Japan, recognition of HAE within the medical community remains low, and numerous obstacles complicate diagnosis and access to treatment. Importance of timely treatment of HAE attacks with on-demand therapies is continually demonstrated; recommended agents per the WAO/EAACI treatment guidelines published in 2018 include C1 inhibitor (C1-INH) concentrate, ecallantide, and icatibant. In Japan, multiple factors contribute to delayed HAE treatment (potentially leading to life-threatening consequences), including difficulties in finding facilities at which C1-INH agents are readily available. Recognition of challenges faced in Japan can help promote efforts to address current needs and expand access to effective therapies. Icatibant, a potent, selective bradykinin B2 receptor antagonist, has demonstrated inhibition of various bradykinin-induced biological effects in preclinical studies and has shown efficacy in treating attacks in various clinical settings (e.g. clinical trials, real-world studies), and HAE patient populations (e.g. with C1-INH deficiency, normal C1-INH). Icatibant was approved in Japan for the treatment of HAE attacks in September 2018; its addition to the HAE treatment armamentarium contributes to improved patient care. In Japan, disease awareness and education campaigns are warranted to further advance the management of HAE patients in light of the unmet needs and the emerging availability of modern diagnostic approaches and therapies.

Pathogens including autoantigens all failed to induce systemic lupus erythematosus (SLE). We studied, instead of pathogen, the integrity of host’s immune response that recognized pathogen. By stimulating TCR with an antigen repeatedly to levels that surpass host’s steady-state response, self-organized criticality, SLE was induced in mice normally not prone to autoimmunity, wherein T follicular helper (Tfh) cells expressing guanine nucleotide exchange factor DOCK8 on the cell surface were newly generated. DOCK8+Tfh cells passed through TCR re-revision and induced varieties of autoantibody and lupus lesions. They existed in splenic red pulp and peripheral blood of active lupus patients, which subsequently declined after therapy. Autoantibodies and lupus lesions were healed by anti-DOCK8 antibody in the mice including (NZBxNZW)F1 and not raised in DOCK8-/- mice. Thus, DOCK8+Tfh cells, generated after repeated TCR stimulation by pathogen, either exogenous or endogenous, in combination with HLA to levels that surpass system’s self-organized criticality, cause SLE.

Tumor necrosis factor (TNF)-α is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-α therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-α full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab' fragment of anti-TNF-α antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-α agents on neutralization of soluble TNF-α, each anti-TNF-α agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-α agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-α and lymphotoxin, (2) effects toward transmembrane TNF-α-expressing cells, (3) effects toward Fcγ receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-α agents to enhance the clinical efficacy in inflammatory diseases.

Efficacy of B-cell depletion therapy highlights the antibody-independent effector functions of B cells in rheumatoid arthritis (RA). Given type 1 helper T (Th1) cells abundant in synovial fluid (SF) of RA, we have determined whether Th1 cells could generate novel effector B cells. Microarray and qPCR analysis identified CXCL9/10 transcripts as highly expressed genes upon BCR/CD40/IFN-γ stimulation. Activated Th1 cells promoted the generation of CXCL9/10-producing T-bet+ B cells. Expression of CXCL9/10 was most pronounced in CXCR3+ switched memory B cells. Compared with peripheral blood, SFRA enriched highly activated Th1 cells that coexisted with abundant CXCL9/10-producing T-bet+ B cells. Intriguingly, anti-IFN-γ antibody and JAK inhibitors significantly abrogated the generation of CXCL9/10-producing T-bet+ B cells. B cell derived CXCL9/10 significantly facilitated the migration of CD4+ T cells. These findings suggest that Th1 cells generate the novel CXCL9/10-producing T-bet+ effector B cells that could be an ideal pathogenic B cell target for RA therapy.

In cross-spectral iris recognition, different spectral bands are used to obtain rich information of the human iris. Previous studies on cross-spectral iris recognition are based primarily on feature-based approaches, which are prone to the changes in parameters in the feature extraction process, such as spatial position and iris image acquisition conditions. These parameters can degrade iris recognition performance. In this paper, we present a phase-based approach for cross-spectral iris recognition using phase-only correlation (POC) and band-limited phase-only correlation (BLPOC). A phase-based iris recognition system recognizes an iris using the phase information contained in the iris image; therefore, its performance is not affected by feature extraction parameters. However, the performance of a phase-based cross-spectral iris recognition is strongly influenced by specular reflection. Different illumination conditions may produce different iris images from the same subject. To overcome this challenge, we integrate a photometric normalization technique –homomorphic filtering– with phase-based cross-spectral iris recognition. The experimental results reveal that the proposed technique achieved an excellent matching performance with an equal error rate of 0.59% and a genuine acceptance rate of 95%., Biomedical engineering; Computer science; Electrical engineering; Medical imaging; Computer engineering; Signal processing; Image processing; Signal processing; Cross-spectral matching; Phase-based iris recognition; Band-limited phase-only correlation (BLPOC); Phase-only correlation (POC); Iris recognition

Recent experimental evidence supports the idea that human observers are good at recognizing and categorizing materials. Fleming et al. reported that perceptual qualities and material classes are closely related using projected images (Journal of Vision 13(8) (2013) 9). In this paper, we further investigated their findings using real materials and degraded image versions of the same materials. We constructed a real material dataset, as well as four image datasets by varying chromaticity (color vs. gray) and resolution (high vs. low) of the material images. To investigate the fundamental properties of materials’ static surface appearance, we used stimuli that lacked shape and saturated color information. We then investigated the relationship between these perceptual qualities and the various types of image representation through psychophysical experiments. Our results showed that the representation method of some materials affected their perceptual qualities. These cases could be classified into the following three types: (1) perceptual qualities decreased by reproducing the materials as images, (2) perceptual qualities decreased by creating gray images, and (3) perceptual qualities such as “Hardness” and “Coldness” tended to increase when the materials were reproduced as low-quality images. Through methods such as principal component analysis and k-means clustering, we found that material categories are more likely to be confused when materials are represented as images, especially gray images.

Evidence is accumulating that chronic inflammation may have an important mechanism for the development and progression of lung cancer. Therefore, genetic polymorphisms in genes that involved in the inflammatory response may be associated with lung cancer risk. We evaluated the role of tumor necrosis factor α (TNFA) rs1799724, interleukin 1β (IL1B) rs16944, IL6 rs1800796, myeloperoxidase (MPO) rs2333227 and C-reactive protein (CRP) rs2794520 in a case-control study comprised of 462 lung cancer cases and 379 controls in a Japanese population. Unconditional logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). CRP rs2794520 (OR=1.64, 95% CI=1.19-2.26) and IL6 rs1800796 (OR=1.41, 95% CI=1.02-1.96) were associated with lung cancer risk. In addition, we assessed interactions between the polymorphisms and smoking. The polymorphisms did not significantly modify the association between smoking and lung cancer. As TNFA triggers a cytokine cascade, the modifying effect of the TNFA rs1799724 genotypes on the association of any of the remaining polymorphisms with lung cancer risk was also examined. There was a significant interaction between TNFA rs1799724 and MPO rs2333227 (Pinteraction=0.058). Future studies involving larger control and case populations will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the inflammation pathway in lung cancer.

Background Several components of overall lung carcinogenesis, carcinogen metabolic and DNA repair pathways may be involved in individual genetic susceptibility to lung cancer. Methods We evaluated the role of cytochrome P450 ( CYP) 1A1 rs4646903 and rs104894, glutathione S-transferase ( GST ) M1 and GSTT1 deletion polymorphisms, GSTP1 rs1695, x-ray repair, excision repair cross-complementing group 2 ( ERCC2 ) rs13181, complementing defective in Chinese hamster 1 rs25487, and XRCC3 rs861539 in a case-control study comprising 462 lung cancer cases and 379 controls in a Japanese population. Unconditional logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Results CYP1A1 rs4646903 (OR = 1.72, 95% CI=1.25–2.38), rs1048943 (OR = 1.40, 95% CI=1.02–1.92), the GSTM1 deletion polymorphism (OR = 1.38, 95% CI=1.01–1.89), GSTP1 rs1695 (OR =1.48, 95% CI=1.04–2.11), ERCC2 rs13181 (OR = 1.89, 95% CI=1.28–2.78), and Chinese hamster 1 rs25487 (OR = 1.54, 95% CI=1.12–2.13) were associated with lung cancer risk whereas the GSTT1 deletion polymorphism and XRCC3 rs861539 were not. A pertinent combination of multiple "at-risk" genotypes of CYP1A1 rs4646903, the GSTM1 deletion polymorphism and ERCC2 rs13181 was at a 5.94-fold (95% CI=2.77–12.7) increased risk of lung cancer. Conclusions A pertinent combination of multiple at-risk genotypes may detect a high-risk group. Further studies are warranted to verify our findings.

The molecular bases and clinical features of hereditary angioedema (HAE) have not been systematically documented in Japan or in other Asian countries. Thus, the authors researched the genetic and clinical characteristics of Japanese patients with HAE.The authors analyzed the CIINH gene for mutations in 13 unrelated Japanese patients with HAE by means of the polymerase chain reaction and nucleotide sequencing. In addition, the authors searched the literature from January 1969 to October 2010 on Japanese patients with HAE.Seven of the mutations found were novel, including 4 missense mutations (8728TG, 8831CA, 16661TG and 16885CA), 2 frameshift mutations (2281_2350del70, 14158delT) and 1 large deletion (at least 1 kb-length deletion including exon 4), whereas 6 mutations had previously been reported in European populations.The genetic and clinical characteristics in Japanese patients with HAE may be similar to those in Western patients although our sample size is small and the authors identified 7 novel mutations.

This paper proposes an accurate reversible algorithm without any distortion conditions such as a print-san process for converting full color images to gray images while preserving the chroma and spatial resolution of the images. In our previous study, we proposed a reversible color-to-gray algorithm using a second-level Haar wavelet transform with a packet assignment technique. We have improved this algorithm by devising a color embedding technique. The proposed algorithm distributes color information effectively in the one-level wavelet subbands for preserving the chroma and spatial resolution. Experimental results show that the proposed algorithm can achieve a higher accuracy of recovering color images from the textured gray images of the original color images. We also present a practical application of the proposed algorithm to a color-hiding image transmission; this application permits color recovery only to a specific user with a key.

Pseudomonas aeruginosa is a pathogen which is known to be responsible for nosocomial infection. The appropriate use of antibiotics has become important for preventing the spread of drug-resistant P. aeruginosa. In Hara-doi Hospital, two carbapenem antibiotics, imipenem (IPM) and meropenem (MEPM), are used for patients aged 65 years or older at a daily dosage of 1.0 g and 0.5 g, respectively. Of P. aeruginosa samples isolated in 2003, the sensitivity to IPM was 54% and to MEPM it was 58%. In 2004, the sensitivity to IPM was 55%, i.e., not significantly different from 2003. In 2004, the daily dosage of MEPM was increased to 1.0 g/day, and the sensitivity to MEPM increased to 71%. Based on the Pharmacokinetics/Pharmacodynamics (PK/PD) theory, even though the patients were elderly, a sufficient dosage of antibiotics given over a shorter period of time was effective against MEPM-resistant P. aeruginosa in a hospital ward, and there were no side effects.

A case of inherited homozygous complement C3 deficiency (C3D) in a patient with systemic lupus erythematosus (SLE) and the molecular basis for this deficiency are reported. A 22-year-old Japanese male was diagnosed as having SLE and his medical history revealed recurrent tonsillitis and pneumonia. He was diagnosed as having C3D because of undetectable serum C3 level. His parents were consanguineous. Sequence analysis of C3D cDNA revealed a homozygous deletion of exon 39 (84bp). A single base substitution (AG to GG) in the 3'-splice acceptor site of intron 38 was identified by sequencing the genomic DNA. Expression of C3Delta(ex39) cDNA, the C3cDNA lacking exon 39, in COS-7 cells revealed that C3Delta(ex39) was retained in endoplasmic reticulum-Golgi intermediate compartment because of defective secretion. These data indicate that a novel AG-->GG 3'-splice acceptor site mutation in intron 38 caused aberrant splicing of exon 39, resulting in defective secretion of C3.

Background & Aims: Both infliximab (chimeric anti-tumor necrosis factor [TNF]-α antibody) and etanercept (p75 TNF-α receptor/immunoglobulin G fusion protein) are effective against rheumatoid arthritis, but only infliximab induces clinical remission in Crohn's disease. To clarify this difference in clinical efficacy, we investigated reverse signaling through transmembrane TNF-α (mTNF) by these 2 anti-TNF agents. Methods: We stably transfected wild-type and cytoplasmic serine-replaced mutant forms of mTNF in human Jurkat T cells. Cells were stimulated with infliximab and etanercept and then analyzed for E-selectin expression, reactive oxygen species accumulation, apoptosis, and cell cycle distribution by flow cytometry. Interleukin-10 and interferon-γ were measured by enzyme-linked immunosorbent assay. Phospho-c-Jun NH2-terminal kinase, Bax, Bak, p21 WAF1/CIP1 , caspase-8, and caspase-3 were examined by immunoblotting. Results: Both anti-TNF agents induced E-selectin expression, but only infliximab induced interleukin-10 production, apoptosis, and G0/G1 cell cycle arrest. Apoptosis and cell cycle arrest were abolished by substitution of all 3 cytoplasmic serine residues of mTNF by alanine residues. Infliximab induced accumulation of reactive oxygen species and up-regulation of Bax, Bak, and p21 WAF1/CIP1 proteins, suggesting the involvement of p53 activation. Moreover, phosphorylation of c-Jun NH2-terminal kinase was necessary for infliximab-induced apoptosis and cell cycle arrest. Conclusions: We revealed the mTNF motifs and the downstream intracellular molecular events essential for reverse signaling through mTNF. The biologic effects of mTNF elicited by infliximab should be important action mechanisms of this potent anti-inflammatory agent in addition to the neutralization of soluble TNF-α. These observations will provide insight into the novel role of mTNF in inflammation.

We present a case of pulmonary metastasis from pancreatic cancer with biphasic radiological patterns: demarcated nodules, irregularly shaped opacities showing the so-called ‘air-space pattern’, and both typical and atypical radiological findings. The histology of the demarcated nodules was poorly differentiated adenocarcinoma identical to the pancreatic tumor, while that of the irregularly shaped opacities was well-differentiated adenocarcinoma showing a lepidic growth pattern. Pulmonary metastasis from pancreatic cancer may contain components of various differentiations showing different radiological findings.

This paper presents a method of colorizing a black and white imagery based on the probabilistic relaxation algorithm. Since the colorization is an ill-posed problem, a user specifies a suitable color on each isolated pixel of an image as prior information in this paper. Then other pixels in the image are colorized automatically. The colorizing process is done by assuming local Markov property on the images. By minimizing a total of RGB pixel-wise differences, the problem can be considered as a combinatorial optimization problem and it is solved by using the probabilistic relaxation. The proposed algorithm works very well when a few percent color pixels are known with confidence.

Class-selective rejection scheme assigns to an input pattern a subset of classes that are most likely to identify the pattern, and not simply reject it. Conventional class-selective rejection rules can minimize the error rate for a given average number of classes. In this paper, an example of unnatural classification is shown by using conventional rules and a new optimum criterion for establishing a class-selective rejection rule is proposed. Its optimality and upper-bound of error rate are proven. Finally, two examples are provided to illustrate various aspects of this optimum decision rule.

The fourth component of complement (C4) in urine was measured in 19 patients with systemic lupus erythematosus (SLE). Urinary C4 was detectable in all SLE patients using an enzyme linked immunosorbent assay. In 11 of 13 patients whose urinary C4 was serially measured, a decrease of urinary C4 was found in parallel with a decrease of disease activity of SLE. In the remaining 2 patients, the amount of C4 increased preceding a flare-up of the disease. The measurement of urinary C4 may be useful in evaluating the disease activity of SLE in individual patients and sometimes in predicting the flare-up of the disease. The specific hemolytic activity of excreted C4 and Western blotting analysis showed that urinary C4 consisted mainly of degraded fragments of C4. In two cases, camostat, a serine protease inhibitor, rapidly decreased the urinary C4 excretion, suggesting that the complement activation occurred in the glomerulus in lupus nephritis.

Neurofibromatosis 1 (NF1) is an autosomal dominant disease characterized by abnormalities in multiple tissues derived from the neural crest. We analysed 50 unrelated Japanese patients for NF1 mutations by using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis for exons 28 to 36. Here, we demonstrate a single base pair (bp) insertional mutations in exon 31 in one patient (5843insA/5844insA/5845insA/5846insA) and a single adenine to guanine transitional mutation 4 bp upstream from the 3' end of intron 31 in two unrelated cases. The insertional mutation in exon 31 was novel and resulted in premature termination of the transcript. The other intron 31 mutations resulted in 4 bp insertions of cDNA between exon 31 and exon 32 with premature termination of the transcript, indicating that those transitions of intron 31 caused aberrant splice acceptor sites upstream from the 5' end of exon 32. However, as the same mutation of intron 31 has been reported previously in two cases of unrelated Caucasians, the splice junction mutation of intron 31 is thought to be common among different ethnic groups.

Hirofumi Tsuzuki, Yojiro Arinobu, Kohta Miyawaki, Ayako Takaki, Shun-ichiro Ota, Naoko Ueki, Yuri Ota, Siamak Jabbarzadeh Tabrizi, Mitsuteru Akahoshi, Hiroaki Niiro, Hiroshi Tsukamoto, Takahiko Horiuchi, Shoichiro Ohta, Kenji Izuhara, MD, PhD, Hiroyuki Fukui, Koichi Akashi; Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka City, Japan, Clinical Education Center, Kyushu University Hospital, Fukuoka City, Japan, Department of Rheumatology, Internal medicine and connective tissue disorders, Shimonoseki City Hospital, Shimonoseki City, Japan, Division of Nephrology and Rheumatology, Fukuoka University Hospital, Fukuoka City, Japan, Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu City, Japan, Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical School, Saga City, Japan, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima City, Japan. RATIONALE: A dried root of Sophora flavescens (S. flavescens) is a traditional Chinese herbal medicine used for the treatment of allergic diseases. Previous studies have demonstrated that S. flavescens possesses antiinflammatory activities and suppresses allergic inflammation such as allergic rhinitis. However, the mechanism of anti-asthmatic effect of S. flavescens is not yet clarified. METHODS: To clarify the effect of S. flavescens on asthma, we analyzed OVA-induced asthma mice treated with S. flavescens extract. We also conducted flow cytometry, cell count assay and gene expression analysis to evaluate the effect of S. flavescens on eosinophil hematopoiesis. To reveal the effect of S. flavescens on eosinophil chemotaxis, we performed transwell migration assay. RESULTS: Lung eosinophilic inflammation inOVA-induced asthmamice was suppressed by the treatment of S. flavescens. In addition, S. flavescens inhibited allergen-induced increment of eosinophil progenitors (EoPs) in the bonemarrow. In vitro, S. flavescens suppressed IL-5-induced expansion of EoPs and eosinophil lineage specification directly. Moreover, IL-5 expression was suppressed in CD4 T cells isolated from asthmatic mice treatedwith Sophora flavescens. In terms of eosinophil migration, S. flavescens suppressed eosinophil chemotaxis for eotaxin-1, one of themajor chemokines for eosinophil migration. CONCLUSIONS: S. flavescens suppressed eosinophil accumulation in the lung of asthmatic mice by inhibiting both eosinophil hematopoiesis and migration. S. flavescens might be valuable for the treatment of eosinophil-related diseases such as asthma.

Neurofibromatosis type 1 (NF1) is one of the most common inherited disorders and is characterized by abnormalities in multiple tissues derived from the neural crest. Here, we report two novel deletion mutations of the NF1 gene from two out of 25 unrelated Japanese NF1 patients. These mutations were detected using polymerase chain reaction (PCR) / single-strand conformation polymorphism (SSCP) analysis. Sequencing analysis revealed a 4 base pair (bp) deletion at 5679 (5679delACTG) in exon 30 in one patient and a single bp deletion at 5949 (5949delA) in exon 32 in the other patient. Both of these mutations resulted in frameshifts, followed by premature terminations of the mutant allele. Because only a few large rearrangements of the NF1 gene have been reported in NF1 patients, it is likely that subtle mutations such as these are common.

Hyperphosphatasemia due to increased intestinal type serum alkaline phosphatase was noted in a 48-year-old male who had asymptomatic liver cirrhosis. The alkaline phosphatase activity in the serum was 828 U/l (our reference range in adults: 57–194 U/l), 94% of which was of the intestinal type as measured by an immunoprecipitation method. The intestinal component of alkaline phosphatase was separated into two major and some minor components using electrophoresis and isoelectrofocusing. One of the major components had similar mobility to that of a standard intestinal enzyme purified from adult intestine. The components were heat-labile and neuraminidase-resistant. Serial lectin affinity chromatography, however, indicated that sugar chain compositions of the alkaline phosphatase were different from those of the standard tissue intestinal enzyme. These results and further enzymological studies suggest that the patient's serum alkaline phophatase basically consisted of several intestine-like isoforms.

A calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), reduced the number of phorbol ester receptors in mouse skin in a dose- and time-dependent manner. The reduction occurred immediately after topical application of 30 μmoles of W-7, reaching a maximum of 86% after 5 min. Reduction in specific binding of 12-0-tetradecanoylphorbol-13-acetate can explain the antitumor promoting activity of W-7 in mouse skin.

Cellular retinol-binding protein, cellular retinoic acid-binding protein, and fetal cellular retinol-binding protein were purified to homogeneity and each polypeptide had a molecular weight of 16,000. Their apoproteins were not phosphorylated under the same conditions. Their holoproteins did not inhibit the phosphorylation of histone III-S by protein kinase C. Each of these observations is contrary to the results reported by Cope et al. (Biochem. Biophys. Res. Commun., 120 , 593–601, 1984).