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Acute exacerbation (AE) is a life-threatening clinical event that occurs during the clinical course of idiopathic pulmonary fibrosis (IPF). Several studies have reported that AE also occurs in interstitial lung disease (ILD) other than IPF. However, the incidence, clinical features, risk factors for AE, and major causes of death in antineutrophil cytoplasmic antibody (ANCA)-associated ILD (ANCA-ILD) patients have not been well established.We retrospectively reviewed the data of 54 ANCA-ILD patients and 304 IPF patients. We investigated the frequency of AE, post-AE prognoses, risk factors for AE, and major causes of death in ANCA-ILD patients. We also compared the data of ANCA-ILD with that of IPF.Fourteen (25.9%) ANCA-ILD patients and 84 (27.6%) IPF patients developed AE. The median survival times (MSTs) after AE in ANCA-ILD and IPF patients were 35.5 and 60 days, respectively (p = 0.588, log-rank test). In a multivariate analysis, the percentage of predicted forced vital capacity (%FVC) [O.R. 0.750 (95% CI 0.570, 0.986), p 0.01] and serum C-reactive protein (CRP) [O.R. 2.202 (95% CI 1.037, 4.674), p 0.01] were independent risk factors for AE. AE was the most frequent cause of death in ANCA-ILD and IPF patients.ANCA-ILD patients could develop AE, and the frequency of AE in ANCA-ILD is similar to that in IPF. AE is the most frequent cause of death in ANCA-ILD patients. A low %FVC and a high serum CRP level were independent predictive factors for AE in ANCA-ILD. The prognosis after AE in ANCA-ILD was poor, as it was in IPF.

Several studies have reported that acute exacerbation (AE), which occurs during the clinical course of idiopathic pulmonary fibrosis (IPF), also occurs in rheumatoid arthritis-associated interstitial lung disease (RA-ILD). However, the incidence, clinical features, and risk factors for AE, a major cause of death of RA-ILD patients, and the differences in clinical aspects of AE between RA-ILD and IPF have yet to be fully understood.We retrospectively reviewed data on 149 RA-ILD patients and 305 IPF patients. We investigated the frequency of AE and compared the clinical data between RA-ILD with and without AE to clarify the risk factor for AE. We also compared the post-AE prognosis and cause of death between RA-ILD and IPF patients.Twenty-seven (18.1%) RA-ILD patients and 84 (27.5%) IPF patients developed AE. The median survival time (MST) after AE of RA-ILD and IPF was 277 days and 60 days, respectively (log rank, p = 0.038). In a multivariate analysis, hypoalbuminemia [odds ratio (O.R.) 0.090 (95%CI 0.011-0.733), p = 0.012] and % carbon monoxide diffusion capacity (%DLRA-ILD patients could develop AE, and AE was not uncommon in RA-ILD or IPF. %DL

Objective A previously developed sputum antigen detection kit for Streptococcus pneumoniae enabled the early diagnosis of pneumococcal pneumonia using sputum samples. We conducted a prospective study to compare the sensitivity of the sputum and urinary antigen kits. Methods Pneumonia patients who were treated from April 2014 to September 2015 were recruited for the present study. Patients with pneumococcal pneumonia who could not participate in the prospective arm of the study were analyzed in the retrospective arm. Results Nine of the 69 participants in the prospective study had pneumococcal pneumonia. The sputum antigen kit results correlated well with the sputum culture results. The sensitivity of the sputum antigen kit was 88.9% (8/9), which was higher than that of the urinary antigen kit (5/9; 55.6%). When patients from the retrospective arm of the study were included, the sensitivity of the sputum culture was 93.5% (29/31), which was significantly higher than that of the urinary antigen kit (19/31; 60.6%). False positives were obtained using the sputum antigen kit in four cases. Three of the four false positives were suspected to have resulted from the administration of antibiotics prior to the use of the kit; the remaining case likely occurred due to a false reaction to S. milleri-induced pyothorax. Conclusion Collectively, our findings suggest that the sputum antigen kit has a higher sensitivity for detecting S. pneumoniae than the urinary antigen kit. However, the prior administration of antibiotics can render the sputum culture results negative or lead to a false-positive result.

The construction of image transformation manually requires large amounts of effort, and thus several methods of automating it with machine learning, such as neural networks or genetic programming, have been proposed. Most of these methods are just constructed image filters that calculate an output value from values in the local area of each pixel independently. However, in several tasks, such as area detection, information on more distant areas is helpful to processing. In this paper, we introduce a new neural network model for automatic construction of image transformations. The proposed model is composed of a regular array of identical evolutionary neural networks, the Real-Valued Flexibly Connected Neural Networks (RFCN) that we previously proposed, and each RFCN is connected to neighboring RFCNs. The proposed model is called Cellular RFCN (CRFCN). Because of the local connections, each RFCN can consider information on distant areas indirectly. We apply CRFCN to three image transformation tasks, compare it with other methods, and examine its effectiveness. © 2013 Wiley Periodicals, Inc. Electron Comm Jpn, 96(5): 17–27, 2013; Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/ecj.11460

Rationale: Inhaled granulocyte/macrophage–colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a PaO2 of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar–arterial oxygen difference [A–aDO2] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 μg Days 1–8, none Days 9–14; × six cycles; 12 wk); low-dose therapy (125 μg Days 1–4, none Days 5–14; × six cycles; 12 wk), and follow-up (52 wk). Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high- and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A–aDO2 of 12.3 mm Hg (95% confidence interval, 8.4–16.2; n = 35, P < 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A–aDO2 and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP. Clinical trial registered with www.controlled-trials.com/isrctn (ISRCTN18931678), www.jmacct.med.or.jp/english (JMA-IIA00013).

Objective. Accumulating evidence suggests that B-cell depletion therapy by rituximab may be effective for autoimmune disorders. However, an optimal dose of rituximab and a mechanism of its action remain to be established. We performed a dose-escalation study for treatment of Japanese patients with autoimmune diseases including eight with SLE and one with Evans’ syndrome. Methods. Rituximab was infused intravenously, weekly 4 times in a dose-escalating fashion at three different doses of 100, 250 or 375 mg/m 2 to three patients each. Immunological parameters were monitored at certain points until 12 months after the treatment. Results. Rituximab was well tolerated and safe in these patients. Seven out of eight SLE patients and one with Evans’ syndrome clinically responded completely or partially to the treatment. Four patients achieved long-term remission (18–30 months) without any additional treatment. In these patients, a significant decrease in circulating B cells continued for 6 months after the treatment. The mean fluorescence intensities of CD19, CD21, CD40 and BR3 on the residual B cells as well as the percentage of CD69þ CD4þ T cells decreased significantly. Serum TNF-� levels decreased significantly on day 2. The Th1/Th2 balance of CD4þ T cells gradually shifted towards a Th1 type by 6 months. Conclusion. In addition to B-cell depletion, modification of B-cell and T-cell phenotypes as well as cytokine profiles may be involved in the action of rituximab.

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.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the activation of autoreactive B lymphocytes, which are supposed to carry aberrant signal transduction after the stimulation of B-cell receptor (BCR). To investigate abnormalities in BCR-mediated signaling pathway in lupus B lymphocytes, we analyzed HS1, a molecule downstream of BCR, in 80 Japanese SLE patients. We identified 37 amino acid deletion of HS1 in a 25-year-old female patient, and the aberrant HS1 lacked a part of a functional motif. Analysis of genomic DNA revealed that the aberrant HS1 was caused by exon skipping. Family study showed that the patient as well as her father and sister are heterozygous for the abnormality. WEHI-231 cell, a mouse B cell line, transfected with the aberrant HS1 displayed a significantly increased cell death upon cross-linking of BCR. Additionally, peripheral B lymphocytes from the patient exerted increased apoptosis after BCR stimulation compared to those from control SLE patients. These data suggest that the aberrant HS1 molecule may transmit an accelerated signal after BCR stimulation and may play a role in the activation of autoreactive B lymphocytes.

Objective: To determine whether serum levels of a proliferation-inducing ligand (APRIL) are raised in patients with systemic lupus erythematosus (SLE) and correlate with autoantibody titres or disease activity, or both. Methods: Serum samples from 48 patients with SLE, 41 normal healthy subjects, and 21 patients with rheumatoid arthritis (RA) were assayed for APRIL by enzyme linked immunosorbent assay. Medical charts were retrospectively reviewed for autoantibody titres and immunoglobulin levels. Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index. Results: The APRIL levels in the serum samples from patients with SLE were significantly higher than in those from healthy controls and those from patients with RA. Serum APRIL levels did not correlate with serum IgG and IgM levels, but had a tendency to correlate with anti-double stranded DNA antibody titres. Moreover, serum APRIL levels correlated significantly with musculoskeletal manifestations among patients with SLE when assessed by the BILAG index. Conclusion: APRIL may be an important factor in raised autoantibody titres and musculoskeletal disease in patients with SLE. Patients with raised serum APRIL levels may be ideal candidates for therapeutic targeting of APRIL.

Fuzzy ORiented Classifier Evolution (FORCE) is a graph-based genetic fuzzy system which we have previously proposed. FORCE constructs fuzzy classification rules automatically by evolving directed graphs composed of fuzzy conditions using Genetic Algorithm. In this work, to improve FORCE about efficiency of rule optimization and expressiveness of Membership Functions (MFs), we introduce two new ideas into FORCE: Edge Mutation (EM) and Parameter tunable MFs (PMFs). EM changes node connections with considering current graph structure to develop rules efficiently unlike the original mutation changing them just randomly. PMFs are MFs characterized by real-coded parameters optimized using uniform and non-uniform mutation. PMFs improve the expressiveness of MFs, which are represented by combination of user-defined parameters in the previous work. We tested the improved FORCE with 21 classification data sets in comparison with our previous model and a common method, and experimental results showed the proposed ideas improved classification accuracy of FORCE.

We have previously proposed Fuzzy ORiented Classifier Evolution (FORCE), a method to construct fuzzy classification rules automatically with evolution of a directed graph composed of fuzzy conditions. In this work, we introduce (1) flexible optimization of Membership Functions (MFs) for each condition and (2) comparison operators between two input variables into FORCE. The original FORCE has used fixed MFs because optimizing MFs can decrease interpretability of rules. However optimizing MFs can also improve accuracy and compactness of rules. Hence we introduce flexible optimization of MFs into FORCE to investigate its effectiveness. The comparison operators between two input variables enable rules to consider relationships between two input variables easily, and can also improve performance of FORCE. We apply the proposed model to three different image classification tasks to investigate its performance in comparison with conventional methods.

Objective To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cell–specific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE). Methods The entire coding region of the HS1 gene was analyzed by reverse transcriptase–polymerase chain reaction/single-strand conformational polymorphism analysis. HS1-transfected WEHI-231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometric analysis and MTT assay. Results We identified a glutamic acid–proline–glutamic acid–proline insertion between codons 366 and 367 (EPEP366–367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP+ allele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P = 0.016). The allele frequency of EPEP366–367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P = 0.006). WEHI-231 cells transfected with EPEP+ HS1 were 100-fold more sensitive to B cell receptor (BCR)–mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP+ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele. Conclusion These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.

We herein describe a 70-year-old male patient who developed colonic necrosis following severe acute pancreatitis. He was referred to our hospital with a diagnosis of acute pancreatitis. In the course of the disease, he developed sudden and massive hematochezia and died. The autopsy findings revealed large bowel ischemia with transmural infarction. The possible pathogenic mechanisms of colonic ischemia are also discussed.

This paper presents Cellular Fuzzy Oriented Classifier Evolution (CFORCE), a generic method for constructing fuzzy rules to divide an image into two segments: object and background. In CFORCE, a pair of fuzzy classification rule sets for object and background is defined as a processing unit, and the identical units are allocated in each pixel of an input image. Each unit computes matching degree of each pixel with object and background class iteratively with considering the matching degree of neighbor units. The algorithm has mainly two features: 1) designing the fuzzy rules using Fuzzy Oriented Classifier Evolution (FORCE) which develops fuzzy rules represented as directed graphs flexibly and automatically by Genetic Algorithm, and 2) performing iterative segmentation with considering spatial relationship between pixels besides local features. In natural image segmentation, many pixels are overlapped between different clusters. Therefore, considering the spatial relationship is important to classify the overlapped pixels correctly. We applied CFORCE to three different object segmentation, and showed that CFORCE extracted object regions successfully.