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We herein report a case of systemic sclerosis (SSc)-related pericarditis successfully treated with mycophenolate mofetil (MMF) and low-dose prednisolone (PSL). The patient was a 72-year-old woman with anti-centromere antibody. Her clinical manifestations were Raynaud phenomenon, bilateral pleural effusion, pericardial effusion and skin tightness. Based on the findings of exudative pericardial effusion with the absence of pulmonary arterial hypertension from the results of the cardiac catheter and pericardiocentesis, she was diagnosed with SSc-related pericarditis and treated with PSL10 mg and MMF 1 g per day, leading to the complete resolution of pericarditis. These findings suggested that MMF and low-dose PSL were effective for SSc-related pericarditis.

To clarify the characteristics of patients with elderly-onset Adult-onset Still’s disease (AOSD). Patients were classified into elderly-onset (>60 years: 47 patients) and younger-onset (≤60 years: 95 patients) groups according to their age at diagnosis of AOSD. Clinical features, treatments, and prognosis were compared between the elderly-onset and younger-onset groups. In the elderly-onset group, compared with the younger-onset group, typical skin rashes were less frequent (21.3% vs 58.9%, respectively; p p = .0011) and disseminated intravascular coagulation (19.1% vs 2.1%, respectively; p = .0004) were more frequent, and serum ferritin levels were higher (median 12,700 ng/ml vs 2526 ng/ml, respectively; p p = .0006 and p = .0023, respectively) and drug-free remission was less frequent (p = .0035) in the elderly-onset group compared with the younger-onset group. Our results demonstrated that elderly-onset AOSD patients had several characteristics that differed from younger-onset AOSD patients, including less typical skin lesions, more AOSD-related complications, higher ferritin levels, and poorer prognoses.

Objectives To investigate the usefulness of severity classification for predicting outcomes in patients with adult-onset Still’s disease (AOSD). Methods This was a multi-centre retrospective cohort study. AOSD patients were classified into mild, moderate, and severe groups based on severity classification (Japanese Ministry of Health, Labour and Welfare) during the initial treatment, and clinical features were compared among these groups. The primary endpoints were the AOSD-related mortality and drug-free remission rate. For comparison, the same analysis was performed in parallel for patient groups stratified by the modified Pouchot systemic score. Results According to severity classification, 49 (35%), 37 (26%), and 56 patients (39%) were classified into mild, moderate, and severe groups, respectively. Patients in the severe group showed higher frequency of severe complications and the use of biological agents. Although AOSD-related survival was not significantly different (p = .0776), four of the five fatal cases were classified into the severe group. The severe group showed a reduced rate of drug-free remission (p = .0125). Patient groups classified by systemic score did not correlate with survival or drug-free remission. Conclusions Severity classification is useful for predicting outcomes in patients with AOSD.

Background Pepsin agglutinators, discovered over 50 years ago, have been recently referred to as anti-hinge antibodies (AHAs) because of their reaction with the IgG hinge epitope. AHAs have different reactivity for each hinge epitope generated by each protease that cleaves the hinge region at different sites. Moreover, AHAs have different reactivity against different hinge epitopes derived from each IgG subclass even when the same protease is used. Since the expression of matrix metalloproteinase-3 (MMP-3) is enhanced in rheumatoid arthritis (RA), AHA production could also be increased. The purpose of this study was to determine whether the levels of AHAs against IgG hinge epitopes produced by MMP-3 are elevated in RA. Methods The serum levels of IgG or IgA AHAs against the IgG1/IgG4 F(ab’)2 fragments, generated by either MMP-3 or pepsin, were measured using ELISA in 111 patients with RA and 81 healthy controls (HC). Receiver operating characteristic (ROC) analysis was used for obtaining optimal cutoff values and cutoff values indicating high specificity (> 95%) of the AHA. The targeted epitope of a specific AHA was investigated through inhibition ELISA. Results Seven AHAs were statistically higher in RA patients than in HC, except IgG AHA against IgG1 F(ab’)2, which was generated by MMP-3 proteolytic cleavage. The areas under the ROC curve were 0.66–0.80, although the sensitivities at high specificity were low (5.4–24.3%). The cumulative number of positive AHAs in each individual was statistically higher in RA patients than in HC, suggesting the extreme extent of AHA repertoires in RA. Inhibition studies revealed that IgG AHAs against IgG4 F(ab’)2 fragments generated by pepsin cross-reacted with IgG1 F(ab’)2 fragments generated by pepsin. Multivariate logistic regression analysis identified the IgG AHA against IgG4 F(ab’)2 fragments generated by pepsin as an independent variable for RA diagnosis, even in RA patients who were negative for both RF and ACPA (odds ratio 1.18, 95% CI 1.06–1.32; P = 0.003). Additional experiments using non-RA patients finally strengthened the diagnostic utility. Conclusion In RA patients, we observed diversification and amplification of AHA repertoires and diagnostic utility of the specific AHA against IgG4 F(ab’)2 fragments generated by pepsin but not MMP-3.

Background. Pepsin agglutinators, discovered over 50 years ago, have been recently referred to as anti-hinge antibodies (AHAs) because of their reaction with the IgG hinge epitope. AHAs have different reactivity for each hinge epitope generated by each protease that cleaves the hinge region at different sites. Moreover, AHAs have different reactivity against different hinge epitopes derived from each IgG subclass even when the same protease is used. Since the expression of matrix metalloproteinase-3 (MMP-3) is enhanced in rheumatoid arthritis (RA), AHA production could also be increased. The purpose of this study was to determine whether the levels of AHAs against IgG hinge epitopes produced by MMP-3 are elevated in RA.Methods. The serum levels of IgG or IgA AHAs against the IgG1/IgG4 F(ab’)2 fragments, generated by either MMP-3 or pepsin, was measured using ELISA in 111 patients with RA and 81 healthy controls (HC). Receiver operating characteristic (ROC) analysis was used for obtaining optimal cutoff values and cutoff values indicating high specificity (>95%) of the AHA. The targeted epitope of a specific AHA was investigated through inhibition ELISA. Results. Seven AHAs were statistically higher in RA patients than HC, except IgG AHA against IgG1 F(ab’)2, which was generated by MMP-3 proteolytic cleavage. The areas under the ROC curve were of 0.66--0.80, although the sensitivities at high specificity were low (5.4--24.3%). The cumulative number of positive AHAs in each individual was statistically higher in RA patients than HC, suggesting the extreme extent of AHA repertoires in RA. Inhibition studies revealed that IgG AHAs against IgG4 F(ab’)2 fragments generated by pepsin cross-reacted with IgG1 F(ab’)2 fragments generated by pepsin. Multivariate logistic regression analysis identified the IgG AHA against IgG4 F(ab’)2 fragments generated by pepsin as an independent variable for RA diagnosis, even in RA patients who were negative for both RF and ACPA (odds ratio 1.18, 95% CI: 1.06−1.32; P=0.003). Additional experiments using non-RA patients finally strengthened the diagnostic utility.Conclusion. In RA patients, we observed diversification and amplification of AHA repertoires and diagnostic utility of the specific AHA against IgG4 F(ab’)2 fragments generated by pepsin but not MMP-3.

Background The pepsin agglutinator, discovered over 50 years ago, has recently referred to be an anti-hinge antibody (AHA) because of main reacting with the IgG hinge epitope. AHA shows different reactivity for each hinge epitope generated by each protease that cleaves the hinge region at different sites. Moreover, AHA shows different reactivity against different hinge epitopes derived from each IgG subclass even when the same protease is used. Since production of matrix metalloproteinase-3 (MMP-3) is enhanced in rheumatoid arthritis (RA), the specific AHA might be increasingly produced. The purpose of this study is to determine whether AHA against IgG hinge epitopes produced by MMP-3 is specifically elevated in RA. Methods Serum IgG or IgA class of AHA against the IgG1- or IgG4 F(ab’) 2 generated by either matrix metalloproteinase 3 (MMP-3) or pepsin was measured by ELISA in 81 healthy controls (HC) and 111 patients with RA. Receiver operating characteristic (ROC) analysis was used for obtaining optimal cutoff values and cutoff values indicating high specificity (>95%) of the AHA. Targeted epitope of the AHA was investigated by inhibition ELISA. Results Seven AHAs were statistically higher in RA than HC, except IgG AHA against IgG1 F(ab’) 2 generated by proteolytic cleavage of MMP-3. The areas under the curve of ROC curve were 0.66-0.80, although the sensitivities at high specificity were low (5.4-24.3%). The cumulative number of positive AHA in each individual was statistically higher in RA than HC, suggesting the extreme extent of AHA repertoires in RA. Inhibition studies revealed that IgG AHA against IgG4 F(ab’) 2 generated by pepsin cross-reacted with IgG1 F(ab’) 2 generated by pepsin. Although development of IgA AHAs in RA seems to be remarkable and specific, multivariate logistic regression analysis identified IgG AHA against IgG4 F(ab’) 2 generated by pepsin as an independent variable for RA diagnosis, even in RA patients who were negative for both RF and ACPA [odds ratio 1.18 (95% confidence interval 1.06-1.32); P =0.003]. Conclusion In RA, we observed diversification and amplification of AHA repertoires and diagnostic utility of the specific AHA against IgG4 F(ab’) 2 generated by pepsin, but not MMP-3.

The nationwide surveillance on antimicrobial susceptibility of bacterial respiratory pathogens from the patients in Japan was conducted by Japanese Society of Chemotherapy, Japanese association for infectious diseases and Japanese society for Clinical Microbiology in 2012. The isolates were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections during the period between January and December in 2012 by three societies. Antimicrobial susceptibility testing was conducted at the central reference laboratory according to the method recommended by Clinical Laboratory Standard Institutes. Susceptibility testing was evaluated in 1236 strains (232 Staphylococcus aureus, 225 Streptococcus pneumoniae, 16 Streptococcus pyogenes, 231 Haemophilus influenzae, 147 Moraxella catarrhalis, 167 Klebsiella pneumoniae and 218 Pseudomonas aeruginosa). Ratio of methicillin-resistant S. aureus was 51.3%, and those of penicillin-intermediate S. pneumoniae was 0.4%. Among H. influenzae, 5.6% of them were found to be β-lactamase-producing ampicillin-resistant strains, and 37.2% to be β-lactamase-non-producing ampicillin-resistant strains. Extended spectrum β-lactamase-producing K. pneumoniae and multi-drug resistant P. aeruginosa with metallo β-lactamase were 4.2% and 3.2%, respectively. Continuous national surveillance is important to determine the actual situation of the resistance shown by bacterial respiratory pathogens to antimicrobial agents.

To develop enzyme-linked immunosorbent assay (ELISA) for measurement of IgM antibody (anti-antibody) against human IgG antibody that is binding to antigen, to distinguish anti-antibody from other antiglobulins, e.g. rheumatoid factor (RF), and to search their localization of epitope on IgG molecule.We chose purified human IgG anti-dsDNA antibody from a patient with systemic lupus erythematosus as IgG antibody and calf thymus dsDNA as antigen. IgG F (ab')₂ fragment was obtained by digestion of the IgG with pepsin. Those IgG and IgG F (ab') 2 with anti-dsDNA antibody were reacted with pre-coated dsDNA and formed immune complex on ELISA plate. On the other hand we prepared ELISA plate on which those IgG and IgG F (ab') 2 were coated directly for measurement of IgM RF and IgM antihinge antibody. Twenty-three sera from patients with rheumatoid arthritis were tested.Correct IgM anti-antibodies were obtained after subtraction of absorbance of IgM anti-dsDNA anti- bodies. Remarkable correlation between IgM anti-antibodies obtained by using whole IgG and those by using IgG F(ab')₂(n=23, r²=0.914, p=1.11X10-12). There were correlations neither between IgM antiantibodies and IgM RF(n=23, r²=0.001, p=0.889) nor between IgM antiantibodies and IgM antihinge antibodies (n=23, r²=0.063, p=0.249).IgM molecule with anti-antibody specificity seems to be different from IgM RF and IgM antihinge antibody. Moreover, epitope recognized by IgM anti-antibody seems to localize on IgG F (ab') 2 but not on hinge region. [Original].

Background: Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still’s disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. Methods: Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 ‘definite AOSD’ patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. Results: Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. Conclusion: We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi’s Criteria.

Background Currently, although several categories of biological disease-modifying antirheumatic drugs (bDMARDs) are available, there are few data informing selection of initial treatment for individual patients with rheumatoid arthritis (RA). Therefore, tumor necrosis factor inhibitor (TNF-i) and tocilizumab (TCZ) are treated as equivalent treatments in the recent disease management recommendations. We focused on two anticytokine therapies, TCZ and TNF-i, and aimed to develop a scoring system that predicts a better treatment for each RA patient before starting an IL-6 or a TNF-i. Methods The expression of IL-6 and TNF-α mRNA in peripheral blood from 45 newly diagnosed RA patients was measured by DNA microarrays to evaluate cytokine activation. Next, laboratory indices immediately before commencing treatment and disease activity score improvement ratio after 6 months in 98 patients treated with TCZ or TNF-i were retrospectively analyzed. Some indices correlated with TCZ efficacy were selected and their cutoff values were defined by receiver operating characteristic (ROC) analysis to develop a scoring system to discriminate between individuals more likely to respond to TCZ or TNF-i. The validity of the scoring system was verified in these 98 patients and an additional 228 patients. Results There was significant inverse correlation between the expression of IL-6 and TNF-α mRNA in newly diagnosed RA patients. The analysis of 98 patients revealed significant correlation between TCZ efficacy and platelet counts, hemoglobin, aspartate aminotransferase, and alanine aminotransferase; in contrast, there was no similar correlation in the TNF-i group. The cutoff values were defined by ROC analysis to develop a scoring system (1 point/item, maximum of 4 points). A good TCZ response was predicted if the score was ≥2; in contrast, TNF-i seemed to be preferable if the score was ≤1. Similar results were obtained in a validation study of an additional 228 patients. If the case scored ≥3, the good responder rates of TCZ/TNF-i were 75.0%/37.9% (p

A 24-year-old male presented with orogenital ulcers, folliculitis, and progressive painful skin ulcers with a raised inflammatory border. Colonoscopy revealed volcano-shaped intestinal ulcers in the ascending colon, and hence, he was diagnosed as intestinal Behcets disease (BD) with pyoderma gangrenosum (PG). Treatment with systemic glucocorticoids and adalimumab dramatically improved the patient's symptoms. Our case demonstrates that early induction of adalimumab may contribute to the successful treatment of such difficult-to-treat conditions as intestinal BD with PG.

The efficacy of biologics in treating adult Still’s disease (ASD) is suggested, but the information is still lacking and the validation is insufficient. To determine the efficacy of several biologic agents in refractory ASD in Japan, a multicenter survey was performed. Clinical data on 16 ASD patients who had been treated with at least 1 of the biological agents (total 24 occasions) were collected retrospectively. Infliximab was used in 9 cases, etanercept in 4, and tocilizumab in 11. Half of the patients that had been treated initially with infliximab or etanercept were changed to another biologics. Tocilizumab was effective in cases switched from another 2 drugs. Tocilizumab showed efficacy in treating both systemic and arthritic symptoms and showed apparent steroid-sparing effect and the highest continuation rate. Tocilizumab may be a promising biologic agent in refractory ASD.

A 17-year-old woman was previously diagnosed with autoimmune hepatitis (AIH) by liver biopsy. Adult-onset Still's disease (AOSD) was subsequently diagnosed on the basis of high fever, arthralgia, erythema, leukocytosis (>80% granulocytes), cervical lymph node swelling, splenomegaly, and hyperferritinemia. Her symptoms and liver dysfunction improved with prednisolone of 60 mg daily and subsequently methotrexate was added. However her symptoms and liver dysfunction relapsed when prednisolone was tapered to 20 mg/day. Therefore infliximab was introduced additionally and her symptoms and liver dysfunction subsided. To our knowledge, this is the first reported case of AOSD with AIH diagnosed by liver biopsy.

For the purpose of nationwide surveillance of the antimicrobial susceptibility of bacterial respiratory pathogens collected from patients in Japan, the Japanese Society of Chemotherapy conducted a third year of nationwide surveillance during the period from January to April 2008. A total of 1,097 strains were collected from clinical specimens obtained from well-diagnosed adult patients with respiratory tract infections. Susceptibility testing was evaluable with 987 strains (189 Staphylococcus aureus, 211 Streptococcus pneumoniae, 6 Streptococcus pyogenes, 187 Haemophilus influenzae, 106 Moraxella catarrhalis, 126 Klebsiella pneumoniae, and 162 Pseudomonas aeruginosa). A total of 44 antibacterial agents, including 26 β-lactams (four penicillins, three penicillins in combination with β-lactamase inhibitors, four oral cephems, eight parenteral cephems, one monobactam, five carbapenems, and one penem), three aminoglycosides, four macrolides (including a ketolide), one lincosamide, one tetracycline, two glycopeptides, six fluoroquinolones, and one oxazolidinone were used for the study. Analysis was conducted at the central reference laboratory according to the method recommended by the Clinical and Laboratory Standard Institute (CLSI). The incidence of methicillin-resistant S. aureus (MRSA) was as high as 59.8%, and those of penicillin-intermediate and penicillin-resistant S. pneumoniae (PISP and PRSP) were 35.5 and 11.8%, respectively. Among H. influenzae, 13.9% of them were found to be β-lactamase-non-producing ampicillin (ABPC)-intermediately resistant (BLNAI), 26.7% to be β-lactamase-non-producing ABPC-resistant (BLNAR), and 5.3% to be β-lactamase-producing ABPC-resistant (BLPAR) strains. A high frequency (76.5%) of β-lactamase-producing strains was suspected in Moraxella catarrhalis isolates. Four (3.2%) extended-spectrum β-lactamase-producing K. pneumoniae were found among 126 strains. Four isolates (2.5%) of P.aeruginosa were found to be metallo β-lactamase-producing strains, including three (1.9%) suspected multidrug-resistant strains showing resistance to imipenem, amikacin, and ciprofloxacin. Continual national surveillance of the antimicrobial susceptibility of respiratory pathogens is crucial in order to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis.

Mitral inflow patterns reflect not only left ventricular diastolic function but also left atrial (LA) remodeling. The aim of this study was to determine the effects of left ventricular diastolic dysfunction on LA volumetric and functional parameters assessed using two-dimensional speckle-tracking echocardiography.Two-dimensional speckle-tracking analysis of the LA wall in the apical four-chamber view was performed in 268 subjects. Subjects were classified according to diastolic dysfunction grade. Indexed maximum and minimum LA volumes and indexed LA volume before atrial contraction were measured from LA volume waveforms. Expansion, passive emptying, and active emptying indices were calculated.LA volumes increased progressively with advanced stages of diastolic dysfunction. The expansion index and passive emptying index showed progressive decreases according to the grade of diastolic dysfunction. The active emptying index increased until mild diastolic dysfunction and thereafter progressively decreased until reaching severe diastolic dysfunction. Significant correlations were noted between the active emptying index and A-wave velocity (r = 0.31, P.01) and between the E/E' ratio and the expansion index (r = 0.56, P.01).LA volumes and functional parameters derived from two-dimensional speckle-tracking echocardiography vary according to the level of diastolic dysfunction. These results suggest that left ventricular diastolic dysfunction also predicts the severity of LA remodeling.

To compare magnetic resonance imaging (MRI) and ultrasonography (US) in the detection of joint inflammation of rheumatoid arthritis (RA), 6 patients with RA were examined by US and low-field 0.3-T nonenhanced dedicated extremity MRI (compacTscan). All patients were females, with mean age of 50.2 years, mean disease duration of 13.5 years, and mean disease activity score (DAS)28-CRP of 1.78. Each patient was treated with either infliximab, etanercept, adalimumab, or tocilizumab. Intercarpal joints, radioulnar joints, second through fifth proximal interphalangeal (PIP) joints, and first through fifth metacarpophalangeal (MCP) joints (a total of 132 joints, 22 joints in each patient) were assessed by MRI for presence of joint inflammation. A total of 156 joints (24 first interphalangeal and radiocarpal joints plus the above 132 joints), were assessed by grayscale US (GS-US) and power Doppler US (PD-US) for presence of joint inflammation by two trained ultrasonographers. We assessed correlations between joint inflammations on MRI and GS-US/PD-US, and also interobserver correlation between the two ultrasonographers by calculating intraclass correlation coefficients (ICC). Synovial hypertrophy and/or synovial fluid was detected in 74/156 joints on GS-US, and synovitis was detected in 10/156 joints on PD-US and in 38/132 joints on MRI. Using PD-US as a reference, sensitivity of MRI in detection of synovitis was 80%. Using MRI as a reference, sensitivity of PD-US was 21%. Specificity of PD-US was higher than that of MRI. Overall agreement between GS-US and MRI and between PD-US and MRI was 0.56 and 0.76, respectively, suggesting that results of PD-US are close to those of MRI. ICC was 0.545 for GS-US and 0.807 for PD-US, suggesting specificity of PD-US in detecting joint inflammation. Our results show that findings of PD-US correlated with those of MRI. Low-field MRI and PD-US are useful tools for assessment of patients with RA.

Background: Aging and westernization of lifestyle has accelerated the prevalence and severity of atherosclerotic cardiovascular diseases in the Japanese population. The aim of this study was to examine the prevalence of complex plaque formation in the descending thoracic aorta (DTA) as assessed by real-time 3-dimensional transesophageal echocardiography (3DTEE) and its relation to clinical factors. Methods and Results: A prospective analysis of atherosclerotic plaque in the DTA of 350 consecutive patients who were clinically indicated for real-time 3DTEE was performed. Systematic assessment of the DTA plaques was performed using a biplane mode from the aorta at the level of the stomach to the aortic arch. When a large plaque (>4 mm) was identified, detailed 3-dimensional (D) observations were performed using a 3D zoom mode. Complex plaque was defined as either mobile or an ulcer-like pouch in the DTA. Complex plaques were detected in 51 patients (15%), who were more advanced in age and had a higher prevalence of chronic kidney disease. A multivariate analysis revealed that the presence of complex plaque was an independent predictor of renal impairment. Conclusions: The prevalence of complex plaque was not low in the this Japanese study population. A close association between complex plaque and renal dysfunction raises the possibility that complex plaque in the DTA is a potential cause of renal dysfunction. (Circ J 2010; 74: 2627 – 2632)

抗CCP抗体や画像検査(関節MRI検査,関節エコー検査)が新登場し,それぞれがRA診療へ組み込まれるべくスタンバイの状態にある.抗CCP抗体陽性や画像検査による骨びらん像はRAの診断確率を一層高めることになり,特に早期RAの診断過程には欠かせない検査になると考えられる. RF検査は大部分の施設で定量検査へ移行しているが,試薬間差を反映した測定結果の不一致や偽陽性・偽陰性がみられ,けっして見過ごすことのできない問題である.

Recently, a urate transporter, hURAT1 (human uric acid transporter 1) encoded by SLC22A12, was isolated from the human kidney. hURAT1 is presumed to play the central role in reabsorption of urate from glomerular filtrate. In the present study, we analyzed SLC22A12 in seven unrelated Japanese patients with renal hypouricemia whose serum level of urate was less than 1.0 mg/dl, and their family members. We performed direct DNA sequencing of the exon and exon-intron boundaries of SLC22A12 using genomic DNA. Six of the seven patients (86%) possess mutations in SLC22A12. In five patients, a homozygous G to A transition at nucleotide 774 within exon 4 of SLC22A12, which forms a stop codon (TGA) at codon 258 (TGG), was identified (W258X). In one patient, the C to T transition within exon 3, which changes threonine at codon 217 to methionine (T217 M), and the W258X mutation were found (compound heterozygote). Thus, among 12 mutational alleles in six patients, 11 were the W258 X mutation (92%). Family members with the heterozygous W258X mutation (carriers) show relatively low levels of serum urate. The present study demonstrates that homozygous W258X mutation is the predominant genetic cause of idiopathic renal hypouricemia in Japanese patients.

A 18-year-old female had low grade fever, butterfly rush, proteinuria, leukocytopenia and hypocomplimentemia in 1988, and she was diagnosed as systemic lupus erythematosus (SLE) with lupus nephritis (WHOIIb). Treatments with prednisolone and mizoribine resulted in the remission for three years. In May 2001, she presented neurosis and polakisuria despite of the increase of prednisolone to 20 mg/day. Finally, she admitted in our hospital because of manic and repressive state and disorientaion. A brain MRI revealed high intensity lesions in bilateral basal ganglia in T2 weighted images, and cerebrospinal fluid showed elevated protein and IFN-alpha (421 IU/ml). In addition, she manifested neurogenic bladder, muscle weakness and hyperactive deep tendon reflex of bilateral lower limbs due to both supranuclear disorder and hypesthesia under the Th 10 level. Spinal MRI revealed marked atrophy and high intensity signals at the middle to lower thoracic spinal cord in T2 weighted images, indicating complication of lupus myelitis as well as cerebral involvement. Although the symptoms of CNS lupus did not respond to prednisolone, twelve monthly cyclophosphamide pulse therapy (IV-CY) has resolved urinary disturbance, muscle weakness and sensory loss, along with the improvement of both cerebral and spinal MRI images. Lupus myelitis and neurogenic bladder are the rare, but very refractory manifestation among CNS involvement of SLE. We here propose IV-CY as an invaluable choice for the treatment of not only active lupus myelitis but also neurogenic bladder resisted for steroid.

This report describes a case of atrophic bladder and bilateral hydroureteronephrosis that occurred in a patient with systemic sclerosis (SSc). A 49-year-old woman who had a 12-year history of SSc was admitted to our hospital because of bilateral hydroureteronephrosis indicated by uroflowmetric and radiological studies. Histological examination of the patient's bladder after biopsy revealed fibrotic replacement of submucosa and infiltration of mononuclear cells, but no deposition of immunoglobulins and complement components were observed. Nephrostomy to relieve the urinary retention was required. There have been few reports regarding SSc complications in hydronephrosis. The association between hydronephrosis and the pathological disorder of SSc is discussed.

A 66-year-old non-hemophiliac man developed widely spreaded hematoma in soft tissues around neck. On the day of admission, he was nearly choked by the giant hematoma which markedly compressed trachea. Initially, to keep air way, an intratracheal intubation using a fiber scope was carried out. Coagulation studies revealed a marked prolongation of activated partial thromboplastin time (129 seconds, control: 24.9-33.2), a diminished activity of factor VIII (less than 1%) and a significant increase of factor VIII inhibitor titer (60 Bethesda unit/ml). We thereby diagnosed coagulopathy related to acquired inhibitor against factor VIII. The general combination therapy of intravenous infusion of both prothrombin complex concentrates and activated prothrombin complex concentrates, prednisolone and plasma exchange successfully stopped expansion of the giant hematoma. However, because the titer of factor VIII inhibitor remained increased and the activity of factor VIII was continued to reduced, cyclosporin was additionally administrated. As a result, the titer of factor VIII inhibitor was markedly improved, but the reduced activity of factor VIII was continued and re-bleeding around neck was observed. We thereby administered steroid pulse therapy, which resulted in complete remission of the disease activity and recovery of factor VIII activity.

We experienced two cases of primary cancer of the appendix which is a rare entity. Case 1 and 2 involved a 69-year-old woman and a 51-year-old man, respectively. Both patients were seen at the hospital because of a right lower abdominal tumor and their serum CEA levels were high. They had the following common findings: 1) On barium enema study, no appendix was visualized and an oppression finding in the ileocecal region was seen; 2) on colonoscopic fiber, no openning of the appendix was confirmed, extratubal oppression was seen in the ileocecal region, and ulcer formation existed in the ileum; and 3) abdominal CT and ultrasonography revealed a cystic tumor. In Case 1, tumor cells were able to be taken and the preoperative definite diagnosis (mucinous carcinoma) was made. In both Case 1 and 2, the tumors arising in the appendix invaded the terminal ileum and right hemicolectomy with lymph node dissection was carried out. These tumors were cystic macroscopically, and are mucinous carcinoma without lymph node metastasis in Case 1 and moderately or well differentiated adenocarcinoma with positive lymph nodes in Case 2, histopathologically. In conclusion, it is important to entertain the cancer of the appendix as a probable causative disease forming a right lower abdominal tumor, and a through exploration enables us to make the preoperative diganosis.

In the treatment of intestinal obstruction of the left-sided colorectal cancer, transnasal ileus tube can not provide enough decompression in a short time and often leads to emergency operation. In addition, we often have difficulty in performing an operation on an one-step approach and that resulting in a radical operation. In our institution we employ the following procedures for intestinal obstruction of the left-sided colorectal cancers; first, the obstructed site and its condition are confirmed by barium enema study using gastrographin; second, a guide wire is inserted into the oral side of the obstructed site under a fiberoptic colonoscopy and the colonoscope is pulled out; and finally, under fluoroscopy, a transanal ileus tube with a devised tip is inserted into the lumen guided by the guide wire. Immediately after insertion of the decompression tube, the intestinal obstruction is relieved that enables us to conduct satisfactory preoperative examinations and pretreatment of the large intestine. This paper presents these procedures and the availability in three such cases in which an operation on an one-step approach could be safely performed.

A rare case of perforated diverticulum of the transverse colon was experienced. Perforated diverticulum of the transverse colon presented difficulty in diagnosis preoperatively, because it can produce abdominal pains in every area of the abdomen; has no characteristic clinical findings; and our clinical surgeons pay less attention to the existence of the disease as a probable differential diagnosis due to its low frequency. Our case involved an 81-year-old woman complaining of a lower abdominal pain and abdominal disention. Peritoneal signs were minimal and we had difficulty in diagnosis. With barium enema study due to gastrographin, intestinal leakage of contrast medium at the left-sided transverse colon was suspected. Abdominal CT also visualized a pool of the medium out of the intestine. An emergency operation was performed with a diagnosis of perforated transverse colon. Histopathological diagnosis of perforation of the pseudodiverticulum was made. We see 30 reported cases of the disease in the English and none in the Japanese literature as far as we could review. Their clinical features and the diagnosis and treatment of the disease are also discussed in this paper.

Although the etiology of rheumatic diseases has not been elucidated, it seems to be involved in excessive autoimmune responses. In 1976, we began to research rheumatic diseases, especially rheumatoid arthritis. Anti-human immunoglobulin allotype antibodies in Japanese sera were collected from blood donors or patients by hemagglutination and the hemagglutination inhibition method using anti-D sensitized erythrocytes. Many rheumatoid factors without any specificity to IgG allotypes (Gm allotypes) were detected in patient sera. On the other hand, so-called anti-antibodies, Andresen type but not Milgrom type, were mainly detected in blood donors. Thirty-nine sera possessing anti-Gm and anti-Km antibody specificities were finally obtained by screening about 80,000 Japanese. The antibody to G1m (f) was most frequently detected, but the antibody to G1m (z), which is an allele of G1m (f), was not obtained. Quantitative evaluation of rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPA) was adopted in the 2010 ACR/EULAR classification criteria for rheumatoid arthritis; however, quality management of RF has been incompletely implemented in Japan. We therefore mounted an effort to standardize the cutoff value. We found marked hyperferritinemia in patients with active adult Still's disease in 1987. Additionally, ratios of glycosylated ferritin in the patients were extremely reduced, even if they came into the inactive phase. This depressive production of glycosylated ferritin might be a marked characteristic of this disease. Finally, the development of musculoskeletal ultrasonography in rheumatic diseases is introduced.

Positive photoresist systems comprising phenolic resin and quinonediazide are studied in detail. The structure of several novolak resins, which were synthesized from multi-substituted phenols, are analyzed with 13C-NMR. It is proved that these phenols are useful for the structural control of novolak resins. Phenols with two methyl substituents at meta-positions especially show a remarkable structural effect to control methylene bond types of novolak resins. The alkaline dissolution rate is also investigated on novolak resins synthesized from multi-substituted phenols to understand both the dissolution inhibition effect and the dissolution promotion effect. Key-structure of novolak resins for realizing high resolution is elucidated. In addition, the molecular design concept of novolak resin is clarified from several standpoints. Unsubstituted aromatic carbon of resin, hydrophobic effect of methyl substitutent and suitable structure of low Mw parts of novolak resin are also explored. Furthermore, it is proposed that a resist using a resin, which is based on the molecular design concept, has enough potential to produce critical dimensions of 0.2 μm or less taking advantage of phase-shifting technology.

Musculoskeletal ultrasonography (MSUS) possessing grey-scale and Doppler mode has become an established imaging modality for the diagnosis and follow up of patients with rheumatic diseases. Among rheumatic diseases, rheumatoid arthritis (RA) has been recognized as a good disorder to examine the joint inflammation as known synovitis. Early diagnosis and therapeutic intervention have given good outcomes to patients with RA. The 2010 RA classification criteria was reported and early arthritis patients has been diagnosed as RA, although the diagnostic and discriminative abilities of the 2010 criteria are not well known in Japanese. In the new criteria, synovitis is detected as joint swelling or tenderness on physical examination. Now we have expected if MSUS were used for detection of true synovitis, because we have confirmed that sensitivity of synovitis detection by MSUS was superior to that by physical examination.

The medical insurance system in Japan has been focusing on how to reduce the annual increases in medical expenses. In this context, the circumstances in the laboratory department in large hospitals have been growing more strict. Therefore, medical staff working in large hospitals need to know how to reduce the expenditure consumed in laboratory tests. In this paper we report economical loss resulted from physicians' excessive test-orders and suggest how to manage the problem.

Received August 10, 2010; revised manuscript received November 28, 2010; accepted December 6, 2010; released online February 4, 2011 Time for primary review: 34 days Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan Mailing address: Masaaki Takeuchi, MD, Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-0855, Japan. E-mail: takeuchi@med.uoeh-u.ac.jp ISSN-1346-9843 doi: 10.1253/circj.CJ-10-0798 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp Simultaneous Visualization of 2 Intracardiac Masses in Both Atria on 3-Dimensional Transesophageal Echocardiography

Background: Precise evaluation of the aortic root geometry prior to transcatheter aortic valve implantation is important for procedural success in patients with aortic stenosis (AS). To determine the potential for 3-dimensional transesophageal echocardiography (3DTEE), the aims of the present study were: (1) to assess the accuracy of 3DTEE measurements of the aortic root using multidetector computed tomography (MDCT) as a reference, and (2) to examine whether aortic root geometry differs between patients with and without AS. Methods and Results: 3DTEE and contrast-enhanced MDCT were performed in 35 patients. Multiplanar reconstruction was used to measure the left ventricular outflow tract (LVOT) and aortic annulus diameter/area, aortic valve area (AVA), and distances between the annulus and coronary artery ostium. The same 3DTEE measurements were performed in patients with (n=71) and without AS (n=80). Aortic annular and LVOT areas measured by 3DTEE were slightly but significantly smaller compared with values obtained with MDCT. Both methods revealed that the aortic annulus and LVOT have an oval shape. Aortic annular and LVOT area, AVA and the distances between the aortic annulus and the coronary ostia correlated well between the 2 modalities. Only minor differences in aortic root geometry were observed between patients with AS and those without. Conclusions: The geometry of the aortic annulus can be reliably evaluated using 3DTEE as an alternative to MDCT for the assessment of aortic root. (Circ J 2010; 74: 2649-2657)

With the aging of the Japanese population, an increase in the number of elderly patients with rheumatoid arthritis (RA) has been noted in recent years. Although rheumatoid factor (RF) is found in a high proportion of RA patients, it is also known to be present in non-rheumatoid patients. However, no studies have investigated the rate of RF positivity in elderly non-rheumatoid individuals. In this study, we examined the rate of RF positivity in such individuals and the association between smoking and RF production. The subjects were 25 men (aged 67 to 87 years, with a mean of 74.0) and 24 women (aged 60 to 86 years, with a mean of 70.7). Of these subjects, nine (18.4%), including seven men, were RF-positive. A significant positive correlation was observed between age and RF values (n=49, p0.05). Of 23 subjects with a smoking habit, eight (34.8%) were RF-positive. In contrast, only one (3.8%) of 26 nonsmokers was RF-positive. This difference in the rate of RF positivity was significant (p0.01). In addition, a significant positive correlation was noted between the duration of smoking and rate of RF positivity (p0.05), particularly in men (p0.01). These results suggest that smoking is closely involved in RF production in the elderly.

We analyzed the mechanism of spontaneous B cell activation in lupus mice by using anticlass-II antibody in vitro. The in vitro culture of B cells from old NZB mice markedly produced Ig without any stimulation, while B cells from NZW mice did not. The addition of anticlass-II antibody (anti-Iad antibody) to the culture inhibited Ig production of NZB B cells in a concentration-dependent manner. On the other hand, the addition of anticlass-I antibody (anti-H-2Dd antibody) and anticlass-II antibody with different specificity (anti-Iak) gave no effect on the Ig production of NZB B cells. When mitomycin C-treated B cells were added to in vitro culture of responder B cells as a stimulator, Ig production of responder B cells was enhanced in a concentration-dependent manner. However, the enhancing effect of the stimulator B cells was abrogated by the pretreatment with anticlass-II antibody. The stimulator B-cell activity to NZB B cells was marked in NZB B cells, moderate in NZB/W F1 B cells, and weak in NZW B cells. Furthermore, the stimulator B-cell activity with regard to NZB B cells was marked in old female NZB B cells, moderate in old male NZB B cells, and weak in young NZB B cells. The expression of class II antigens on the surface of old female NZB B cells was significantly higher than that of old male NZB and young NZB B cells. These results suggest that in lupus mice the spontaneous B-cell activation is induced by an abnormal B-B cell interaction mediated by class II antigens.

The recent clinical practices for rheumatoid arthritis have changed greatly. First, biologic agents such as tumor necrosis factor blocker have been developed as well as disease-modifying antirheumatic drugs, with great efficacy in intractable RA. On the other hand, the importance of early effective therapeutic intervention has been recognized since early treatment prevents the progression of joint damage. However, early diagnosis of RA is not so easy because of the lack of appropriate diagnostic criteria. New laboratory tests have appeared for the diagnosis and prognostic prediction of RA. Among them, anticyclic citrullinated peptide antibodies (anti-CCP), which bind epitopes containing citrulline, seem to be attracting the most attention. Although rheumatoid factor (RF) is the only serologic marker among the seven classification criteria of the American College of Rheumatology (ACR) for RA, variability of the RF assay within laboratories and/or between laboratories, and quality assurance has not been established. We must address the standardization of RF assay as soon as possible.

(Case 1) A 13-years-old female had multiple arthralgia and butterfly rush, when she admitted in our hospital in May 2001. Nephropathy, hemolytic anemia (Hb 6.3 g/dl and direct Coombs 3+) and high titers of antinuclear antibodies and anti-ds-DNA antibody were disclosed and she was diagnosed as systemic lupus erythematosus (SLE). Although combination therapy of PSL 60 mg/day with a steroid pulse therapy, cyclosporine or an immunosorbent treatment, severe hemolytic anemia remained. However, monthly cyclophosphamide pulse therapy (IV-CY), which was started for the steroid-resistant hemolytic anemia, has gradually become effective and Hb improved up to 11.4 g/dl after 6 courses of IV-CY. (Case 2) A 53-years-old woman diagnosed as SLE in 1978 and she had PSL 5 mg for over 10 years. Severe anemia (Hb 5.9 g/dl) was disclosed with a slight fever in June 2001, and she admitted in our hospital for further examinations. Progressive hemolytic anemia was revealed with marked decrease of Hb (3.4 g/dl) and high titer of direct Coombs (3+). Neither PSL (50 mg/day) nor steroid pulse therapy were effective against hemolytic anemia. In contrast, 3 courses of monthly IV-CY (500 mg/day) resulted in the resolution of hemolysis. It is well known that the steroid-resistant hemolytic anemia is extremely hard to treat and leads to miserable prognosis, but we here propose IV-CY as an alternative and invaluable choice for the treatment of refractory hemolytic anemia complicated with SLE.

Ferritin is the principal iron storage protein participating in iron metabolism. As serum ferritin levels often reflect the amount of storage iron in the body, physicians have measured serum ferritin in order to evaluate iron deficiency or overload. Although a rise in serum ferritin concentration occurs in iron overload, hyperferritinemia without it has been reported in some inflammatory diseases and malignancies. Some cytokines have been reported to be responsible for the elevation of ferritin production. Studies on serum isoferritin in adult Still's disease and other diseases, especially measurements of the proportion of glycosylated ferritin, have been widely accepted. Pathophysiological properties of the increased serum ferritin are not clear. However, we should be aware that the hyperferritinemia is not a result, but is profoundly participating in the disease process.

Background: Urinary bladder augmentation is gaining popularity for the treatment of dysfunctional bladders in renal transplant patients. Although reported cases of adult and pediatric transplants into the augmented bladder have been favorable, the potential risk of urinary tract infection and graft failure under immunosuppression is still disputable. We report our experiences with 4 patients who underwent renal transplantation into an augmented bladder. Methods: Between 1971 and 1996, 1275 renal transplants were performed at our institution. Of these transplants, 4 patients underwent renal transplantation into an augmented urinary bladder. Augmentation cystoplasty was performed before transplantation in 3 patients and 7 years after transplantation in the other patient. The bladder was augmented with an ileal segment in 3 patients and a ureter in the fourth patient. Craft function was assessed by the serum creatinine level. Fluorocystometrograms were performed in all patients at fixed intervals. Results: Posttransplant renal function was satisfactory overall and no patient exhibited proteinuria. All patients except 1 acquired a large capacity low pressure bladder and remained continent with clean intermittent catheterization. One patient who underwent ureterocystoplasty is still incontinent because of his relatively small bladder capacity. Posttransplant pyelonephritis was documented in 3 patients during the follow-up period, but no other complications were observed. Conclusions: Our study demonstrates that renal transplantation into extensively reconstructed bladders can be safely performed with good success. Although urinary tract infection is a major consideration, we recommend pretransplant reconstruction not only to preserve graft function, but also to achieve urinary continence.

Adult Still's disease, a systemic inflammatory disorder of unknown etiology, shows few specific laboratory markers and histological features. We investigated T cell subsets in peripheral blood lymphocytes (PBL) of patients with adult Still's disease to elucidate immunological features of the disease.We studied T cell subsets in PBL of 12 patients with adult Still's disease by flow cytometric analysis. T cell subsets were also investigated for more than 6 months in PBL of 3 patients with adult Still's disease.Both the percentage and absolute number of T cell receptor gamma delta positive (TCR gamma delta +) T cells in active adult Still's disease (n = 6) were significantly (p0.05) higher than those in inactive adult Still's disease (n = 6), inactive rheumatoid arthritis (n = 8), or healthy controls (n = 20). An increase of TCR gamma delta + T cells was observed in 5 of 6 patients with adult Still's disease at the active phase. TCR gamma delta + T cells also increased for a considerable period in all the patients tested. In contrast, there were no significant differences in the other T cell subsets (CD3, CD4, CD8, TCR alpha beta) between all the patients and healthy donors. Levels of TCR gamma delta + T cells in PBL correlated well with those of serum ferritin and C-reactive protein in one of the 3 patients whose PBL could be serially investigated. These increased TCR gamma delta + T cells mostly consisted of a V gamma 9/V delta 2 subset.TCR gamma delta + T cells in PBL are significantly increased in the active phase in patients with adult Still's disease.

Design criteria for the development of the high resolution photoresists comprising novolak resin and DNQ-PAC are proposed by studying the dissolution behavior of photoresists across film thickness. We propose a new analytical method for the dissolution behavior, with which the dissolution rate curves at surface, middle, and bottom parts in a photoresist film can be analyzed separately. From the experimental results obtained by using this new analytical method, we established the following design criteria: (1) To obtain a large separation DOF, the photoresist has to show a steep slope and a large contrast of dissolution curve at the bottom part in some practical exposure dose range of clear region. (2) A small difference of dissolution rate between the surface part and bottom part is necessary to obtain a large profile DOF. In order to adjust a dissolution behavior taking account of the new criteria, we examined the effects of photoresist components. It was found that some phenolic additives were very useful to control the dissolution behavior. The results of the spectroscopic study suggest that such a strong effect is caused by the interaction between phenolic additive and PAC or developer. A photoresist developed by adopting these design criteria for the dissolution behavior control shows wide DOF at 0.35 micrometers L&S with good pattern profile.© (1995) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Herpes simplex virus type 1 (HSV-1) expresses a receptor that binds the Fc portion of IgG. This HSV-1 Fc gamma-binding protein is, like protein A of Staphylococcus aureus, known to bind human IgG1, IgG2 and IgG4 but not IgG3 subclasses. However, IgG3 with the allotype Gm(s+)(t+), prominent in the Oriental population, reacts with protein A. This prompted us to investigate the reactivity of Oriental IgG3 monoclonal myeloma proteins of various allotypes with the HSV-1 Fc gamma-binding protein. Of seven Oriental IgG3 myeloma proteins with allotypes Gm(s+)(t+)(u-)(b+)(g-), Gm(s-)(t-)(u+)(b+)(g-) and Gm(s-)(t-)(u+)(b-)(g+), all reacted with the HSV-1 Fc gamma-binding protein. This was in contrast to negative reactions obtained with three IgG3 myeloma proteins of Caucasian origin with Gm(b+)(g-) or Gm(b-)(g+) phenotypes. The same binding pattern, i.e. binding of IgG3 of Oriental but not of Caucasian origin, was found with protein A. The binding of the monoclonal Oriental IgG3 proteins was again independent of the G3m phenotype. These findings support the concept that the HSV-1 Fc gamma-binding protein A have a similar binding site on the IgG molecule. All monoclonal IgG3 proteins derived from Oriental subjects with or without histidine at position 435 bound to HSV Fc gamma-binding protein. This suggests that Oriental IgG3 myeloma proteins with Gm(s-)(t-) phenotypes have additional critical amino acid residue substitutions important for HSV Fc gamma binding different from those already known.

We studied the deprotecting chemistry of poly(4-hydroxystyrene) based positive-working CA resist systems by using model reactions. Detailed analyses of acid-catalyzed deprotecting reactions of TMS-, THP-, and t-BOC-protected p-cresols were carried out, and it was found that alkylated derivatives of p- cresol were formed as major products for THP- and t-BOC-protected p-cresol, while no alkylated products were obtained for TMS derivatives after deprotection treatment (90 degree(s)C, 2 min). In the THP- and t-BOC-protected PHS systems were also observed such alkylations, which decreased the alkaline dissolution rate of the polymer film. The alkylations are considered to lower the alkaline dissolution contrast between an exposed area and an unexposed area in a resist film, and to deteriorate the resist performance. Therefore, we propose to introduce an alkylation inhibitor to the resist components so as to improve the performance.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.