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An isomeric state in the proton drip-line nucleus 26P has been observed by the γ-ray spectroscopy. The γ-ray energy and the half-life are 164.4 ± 0.1 keV and 120 ± 9 ns, respectively. For the isomeric transition of the mirror nucleus 26Na, the γ-ray energy of 82.40 ± 0.04 keV and the half-life of 4.35 ± 0.16 μs are also revised. Comparing the experimental reduced transition probabilities of 26Na and 26P with theoretical ones calculated by the shell model with the USDA interaction, the spin-parity (Jπ) of the isomeric state in 26P is most likely to be 1+.

T-cell-mediated immunity to a virulent strain of Plasmodium berghei NK65 (Pb NK65) and to an attenuated derivative (Pb XAT) of the strain were examined in CBA mice by the administration of monoclonal antibodies against T-cell subsets or interferon-gamma (IFN-γ). The injection of anti- CD8+ or anti-IFN-γ delayed the mortality of mice infected with Pb NK65, although it did not affect the parasitaemia. In the late stage of PB NK65 infection, T cells, especially CD8+ T cells, were increased in number in the liver at the expense of splenic CD8+ T cells. These CD8+ T cells released IFN-γ in culture without antigen stimulation and were thought to induce tumour necrosis factor- alpha (TN F-α) production by the cells in the liver. In mice infected with Pb XAT, or mice primed with Pb XAT and then challenged with Pb NK65, CD4+ T cells had a crucial role in preventing parasite growth and in protective immunity. IFN-γ was again the key molecule in protective immunity. These results suggest that T cells stimulated with malaria antigen play important roles both in protective immunity and pathogenesis depending upon their subsets; CD8+ T cells in pathogenesis, and CD4+ T cells in protective immunity. These apparently contradictory responses may be mediated by the same cytokine, IFN-γ. [ABSTRACT FROM AUTHOR]

Abstract The von Willebrand Factor A (vWF A) domain is one of the most widely distributed structural modules in cell-matrix adhesive molecules such as intergrins and extracellular matrix proteins. Mutations in the vWF A domain of matrilin-3 cause multiple epiphyseal dysplasia (MED), however the pathological mechanism remains to be determined. Previously we showed that the vWF A domain in matrilin-1 mediates formation of a filamentous matrix network through metal-ion dependent adhesion sites in the domain. Here we show two new functions of the vWF A domain in cartilage-specific matrilins (1 and 3). First, vWF A domain regulates oligomerization of matrilins. Insertion of a vWF A domain into matrilin-3 converts the formation of a mixture of matrilin-3 tetramer, trimer, and dimer into a tetramer only, while deletion of a vWF A domain from matrilin-1 converts the formation of the native matrilin-1 trimer into a mixture of trimer and dimer. Second, the vWF A domain protects matrilin-1 from proteolysis. We identified a latent proteolytic site next to the vWF A2 domain in matrilin-1, which is sensitive to the inhibitors of matrix proteases. Deletion of the abutting vWF A domain results in degradation of matrilin-1, presumably by exposing the adjacent proteolytic site. In addition, we also confirmed the vWF A domain is vital for the secretion of matrilin-3. Secretion of the mutant matrilin-3 harbouring a point mutation within the vWF A domain, as occurred in MED patients, is markedly reduced and delayed, resulting from intracellular retention of the mutant matrilin-3. Taken together, our data suggest that different mutations/deletions of the vWF A domain in matrilins may lead to distinct pathological mechanisms due to the multiple functions of the vWF A domain.

Polythiophene-modified densely packed C 60 -ethylenediamine adduct microparticle films were prepared using a combination of liquid-liquid interfacial precipitation of the adduct microparticles and electrochemical polymerization of 2,2'-bithiophene. The amount of polythiophene was varied as a function of scanning cycles of the applied potential during electrochemical polymerization. Fluorescence-emission properties of these composite films suggested the role of C 60 -ethylenediamine adduct microparticle film as a photosensitizer in addition to an electron acceptor for polythiophene. Furthermore, cathodic photocurrents were generated via excitation of C 60 -ethylenediamine adduct microparticle film and polythiophenes using the half-photocell properties of the electrode modified with composite film in the presence of methylviologen., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Objective: To investigate whether abatacept (ABA) causes more adverse events (AE) than conventional synthetic disease-modifying antirheumatic drugs (csDMARD) after orthopedic surgery in patients with rheumatoid arthritis (RA)., Methods: A retrospective multicenter nested case-control study was performed in 18 institutions. Patients receiving ABA (ABA group) were matched individually with patients receiving csDMARD and/or steroids (control group). Postoperative AE included surgical site infection, delayed wound healing, deep vein thrombosis or pulmonary embolism, flare, and death. The incidence rates of the AE in both groups were compared with the Mantel-Haenszel test. Risk factors for AE were analyzed by logistic regression model., Results: A total of 3358 cases were collected. After inclusion and exclusion, 2651 patients were selected for matching, and 194 patients in 97 pairs were chosen for subsequent comparative analyses between the ABA and control groups. No between-group differences were detected in the incidence rates of each AE or in the incidence rates of total AE (control vs ABA: 15.5% vs 20.7% in total, 5.2% vs 3.1% in death)., Conclusion: Compared with csDMARD and/or steroids without ABA, adding ABA to the treatment does not appear to increase the incidence rates of postoperative AE in patients with RA undergoing orthopedic surgery. Large cohort studies should be performed to add evidence for the perioperative safety profile of ABA.

Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for treatment of RA in Japan in 1999 at the recommended dose of 6-8 mg/week; it was approved as first-line drug with the maximum dose of 16 mg/week in February 2011. However, more than half of Japanese patients with RA are unable to tolerate a dose of 16 mg/week of MTX. Moreover, some serious adverse events during the treatment with MTX, such as pneumocystis pneumonia (PCP) and lymphoproliferative disorders (LPD) have been observed much more frequently in Japan than in other countries. Therefore, this article, an abridged English translation summarizing the 2016 update of the Japan College of Rheumatology (JCR) guideline for the use of MTX in Japanese patients with RA, is not intended to be valid for global use; however, it is helpful for the Japanese community of rheumatology and its understanding might be useful to the global community of rheumatology.

Background: Measuring the area of the psoas muscle on computed tomography is useful for the evaluation of skeletal muscle mass. The skeletal muscle is thought to be involved in weight loss after gastric surgery, and weight loss causes a decrease in compliance with chemotherapy continuity., Patients and Methods: The psoas muscle index(PMI)was determined in 33 patients undergoing surgery for Stage Ⅱ-ⅢB gastric cancer. The rate of change in PMIwas calculated, and patients were classified into maintained and reduced muscle groups using a cutoff of -0.23 month-1. Relationships between the rate of PMIchanges and prognosis and chemotherapy continuity were examined., Results: The rate of PMIchanges was significantly associated with recurrence-free survival in univariate(maintained vs reduced muscle: p=0.002)and multivariate(p= 0.0018)analyses. A reduction in the muscle mass was associated with dropout from adjuvant chemotherapy and was a predictor of a poor prognosis., Conclusion: The rate of PMIchanges is related to the period of adjuvant chemotherapy and is an independent prognostic factor after surgery for StageⅡ-ⅢB gastric cancer.

Background: The purpose of this study was to investigate the long-term clinical outcome and its related factors regarding the severity of adhesion of CH ligament over long head of biceps (LHB) after shoulder arthroscopic capsular release for frozen shoulder with technical points in 255 patients., Methods: We performed arthroscopic capsular release for frozen shoulder in 267 shoulders of 255 patients, 112 males and 143 females, with mean age of 56.39 years, mean disease duration periods of 0.934 years for conservative treatment, and mean follow-up periods of 5.6 years. The frozen shoulders were divided based on the severity of adhesion between CH ligament over LHB: those with slight degree of synovitis, no adhesion by obtuse rod, and slight thickness of the released capsule (type A), those with moderate degree of synovitis, moderate adhesion of the LHB by obtuse rod, and moderate thickness of the released capsule (type B), and those with severe degree of synovitis, severe adhesion of the LHB by obtuse rod, and severe thickness of the released capsule adhesion and a flatly shaped LHB (type C). We assessed the clinical factors related to the scoring of the shoulders by the criteria of the American Shoulder and Elbow Surgeons (ASES) and the relationship with severity of LHB adhesion., Results: The ASES scores improved at 5 years postoperatively in all three groups significantly. The range of motion also significantly improved in all three groups significantly. The severity of the LHB adhesion over the CH ligament was confirmed to influence the ASES scores before and after the arthroscopic capsular release. There was a significant difference between type A and type B (p < 0.0001) or type C (p < 0.0001) before and after surgery. Logistic regression analysis showed disease duration, diabetes mellitus (DM), and ASES score were significantly associated to the severity type of LHB, especially DM has high odds ratio and was a risk factor for LHB adhesion. There is no adverse event including dislocation or axillary nerve injury and recurrence after arthroscopic capsular release at 5 years after surgery., Conclusions: The long-term results of arthroscopic capsular release in frozen shoulder were confirmed in 255 patients. The severity of LHB adhesion over the CH ligament, a pathological condition related to DM as a risk factor, seems to play an important role in the functional outcome. Therefore, the sufficient release of LHB was essential technical point for arthroscopic capsular release in frozen shoulder.

Objective: To investigate the long-term efficacy of rehabilitation following arthroscopic synovectomy in patients with rheumatoid arthritis treated with biologic agents., Methods: Arthroscopic synovectomy was performed in 29 joints of 17 patients, which were divided into two groups. Group 1 included arthroscopic synovectomy plus rehabilitation for 19 joints in 10 patients, and group 2 included arthroscopic synovectomy without rehabilitation for 10 joints in 7 patients. The Disease Activity Score C-reactive protein (DAS28-CRP), Health Assessment Questionnaire-Disability Index (HAQ-DI), and Functional Independence Measure (FIM) values (motor subscale) at 9.7 years after arthroscopic synovectomy were evaluated to identify the clinical factors related to outcomes., Results: The increase in FIM score was significant in group 1 (p=0.05). HAQ-DI at 9 years was significantly decreased in group 1 (p=0.02). Therefore, arthroscopic synovectomy with rehabilitation was significant in improving FIM and HAQ-DI scores over a long period. Multiple regression analysis of FIM scores at 9 years indicated that rehabilitation (p=0.03) and disease duration (p=0.02) were significantly related to outcomes. FIM score at 9 years was significantly negatively correlated with disease duration (p=0.01, r=-0.58, Y=88.89-0.21X)., Conclusion: Rehabilitation following arthroscopic synovectomy was effective in achieving high FIM scores over time in patients with rheumatoid arthritis., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

Objectives: The objective of this study is to investigate the inhibitory effect of golimumab on large joint destruction in patients with rheumatoid arthritis., Methods: We recruited 45 patients with rheumatoid arthritis and evaluated the radiographic severity of large joint destruction using the assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging (ARASHI) score. We evaluated 450 large joints including the elbow, shoulder, hip, knee, and ankle at baseline and 52 weeks after treatment with golimumab. Rapid radiographic progression (RRP) and rapid radiographic improvement (RRI) were calculated and the correlation between large joint destruction and clinical factors was analyzed., Results: The mean age of the study population was 61.29 ± 14.71 years old, and most patients (91.1%) were female. The mean disease duration was 12.6 ± 12.48 years. The cohort included patients in all clinical stages of disease as defined by the Steinbroker criteria (I:7, II:10, III:9, IV:19) as well as clinical classes 2 (n = 18), 3 (n = 26), and 4 (n = 1) and the mean disease activity score-CRP (DAS28-CRP) was 4.431 ± 1.044. Patients were treated with methotrexate (mean dose 6.44 ± 1.78 mg/week), prednisolone (PSL) (mean dose 1.078 ± 1.871 mg/d), and golimumab (44.4% of 100 mg). RRP was evident in 20% of the large joints treated with golimumab, and, therefore, golimumab was effective at inhibiting large joint destruction in 80% of joints. RRI was evident in 33.3% of large joints following golimumab treatment. We also observed that EULAR response criteria significantly correlated with the ARASHI change score at 52 weeks after treatment. The total ARASHI status score significantly correlated with the Sharp-van der Heijde score, but not with the delta total sharp score. Multiple regression analyses revealed that the total ARASHI change score was only correlated with EULAR response criteria significantly., Conclusions: Golimumab therapy was effective at inhibiting large joint destruction of RA patients who have good clinical response, including higher improvement of the shoulder and ankle joints than other large joints.

A non-invasive method of pancreatic β-cell mass measurement is needed to enhance our understanding of the pathogenesis of diabetes, facilitate the early diagnosis of this disease, and promote the development of novel therapeutics. Here, we described the synthesis of a novel indium-111 ( 111 In) exendin-4 derivative, [Lys 12 (In-BnDTPA-Ahx)]exendin-4, through a process involving isothiocyanate-benzyl-DTPA (BnDTPA) and 6-aminohexanoic acid (Ahx) attached to an ɛ-amino group at the lysine-12 residue. We further evaluated the potential use of this derivative as a SPECT probe for pancreatic β-cell imaging. An in vitro binding assay revealed that [Lys 12 ( nat In-BnDTPA-Ahx)]exendin-4 has a high affinity for GLP-1 receptors (IC 50 =0.43nM). In biodistribution experiments involving normal mice, high [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 uptake was observed in the pancreas (21.8 ± 4.0%ID/g) and was maintained for 2h after injection. Pre-injection of excess exendin(9-39) markedly reduced the pancreatic uptake of [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 (95.2%), indicating that the uptake of this tracer is specific and mediated by GLP-1 receptors. Ex vivo autoradiography experiments involving pancreatic sections from MIP-GFP mice confirmed the accumulation of [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 in pancreatic β-cells. Finally, in mice, [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 SPECT/CT yielded clear images of the pancreas at 30min post-injection. In conclusion, SPECT with [Lys 12 ( 111 In-BnDTPA-Ahx)]exendin-4 enables to visualize β-cells in vivo non-invasively., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rapidly progressive interstitial lung disease (RP-ILD) in patients with clinically amyopathic dermatomyositis (CADM) associated with antibodies to melanoma differentiation-associated gene5 (MDA5) results in a high mortality rate. We experienced a case of anti-MDA5-positive RP-ILD of CADM which showed a response to rituximab, although there was no significant effect due to standard immunosuppressive treatment. This case suggests that rituximab has the potential to offer an effective agent for the treatment of anti-MDA5-positive RP-ILD of CADM.

Matrilin-1 (Matn1), a cartilage-specific peri-cellular and extracellular matrix (ECM) protein, has been hypothesized to regulate ECM interactions and transmit mechanical signals in cartilage. Since Matn1 knock-out (Matn1-/-) mice exhibit a normal skeleton, its function in vivo is unclear. In this study, we found that the anabolic Acan and Col2a transcript levels were significantly higher in wildtype (Matn1+/+) mouse cartilage than that of MATN1-/- mice in vivo. However, such difference was not observed between Matn1+/+ and MATN1-/- chondrocytes cultured under stationary conditions in vitro. Cyclic loading significantly stimulated Acan and Col2a transcript levels in Matn1+/+ but not in MATN1-/- chondrocytes. This suggests that, while Matn1+/+ chondrocytes increase their anabolic gene expression in response to mechanical loading, the MATN1-/- chondrocytes fail to do so because of the deficiency in mechanotransduction. We also found that altered elastic modulus of cartilage matrix in Matn1-/- mice, suggesting the mechanotransduction has changed due to the deficiency of Matn1. To understand the impact of such deficiency on joint disease, mechanical loading was altered in vivo by destabilization of medial meniscus. While Matn1+/+ mice exhibited superficial fissures and clefts consistent with mechanical damage to the articular joint, Matn1-/- mice presented more severe cartilage lesions characterized by proteoglycan loss and disorganization of cells and ECM. This suggests that Matn1 deficiency affects pathogenesis of post-traumatic osteoarthritis by failing to up-regulate anabolic gene expression. This is the first demonstration of Matn1 function in vivo, which suggests its protective role in cartilage degeneration under altered mechanical environment.

The aim of this study was to analyze the histological changes related to mitogen-activated protein (MAP) kinases in bone and cartilage treated with abatacept for rheumatoid arthritis (RA). A total of 20 patients of bone and cartilage were assessed: 10 abatacept with methotrexate (MTX)-treated RA patients were compared with 10 MTX-treated RA patients (control). The histology of bone and cartilage was observed by staining with hematoxylin and eosin and analyzed immunohistochemically for the expression of tumor necrosis factor-α, interleukin-6, CD4 (T cell), CD68 (macrophage), receptor activator of nuclear kappa-B ligand, osteoprotegerin, osteopontin, CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK (extracellular signal-regulated kinase, ERK1/ERK2), and phosphor-c-Jun N-terminal kinase. The expressions of CD29 known as mechanoreceptor and ERK known as mechanotransduction signal protein in MAP kinases in the bone and cartilage of patients treated with abatacept were significantly different from those of control. These findings suggest that increases in CD29 and ERK in MAP kinases may change the metabolism of bone and cartilage in RA patients treated with abatacept.

Background: Tight control of severe rheumatoid arthritis (RA) in patients with high disease activity, even when using biologics, is sometimes difficult using a treat-to-target strategy. Switching from one biologic to another is associated with lower efficacy than that in treatment-naive cases. We developed the K-method that involves simultaneous treatment with golimumab and intra-articular joint injection of triamcinolone acetonide (TA) in patients undergoing switching of biologics. We performed this retrospective case-control study to investigate the efficacy of achieving an immediate treatment response using the K-method., Methods: This study involved 20 patients with RA (control group, 10 patients; K-method group, 10 patients). Patients in the control group were switched to golimumab from other biologics without intra-articular injection of TA. The K-method involved injection of 1 mL of TA (40 mg/mL) and 2 mL of 1% lidocaine hydrochloride into swollen or painful joints on the same day as golimumab treatment. A quick response one day after treatment was compared between the two groups according to the disease activity score 28 based on C-reactive protein (DAS28 CRP), clinical disease activity index (CDAI), simplified disease activity index (SDAI), European League Against Rheumatism (EULAR) response, and remission rate. These parameters were investigated for 24 weeks., Results: The K-method group showed significant improvements in DAS28 CRP, CDAI, and SDAI at one day, 12 weeks, and 24 weeks compared with the control group. The number of swollen and tender joints and the patient and doctor global visual analog scale scores were also significantly different between the two groups. The remission rates based on DAS28 CRP were 30% at one day, 50% at 12 weeks, and 60% at 24 weeks in the K-method group. The EULAR good/moderate response rates were 80% at one day, 90% at 12 weeks, and 90% at 24 weeks in the K-method group; however, these rates were only 10%, 40%, and 40%, respectively, in the control group. No adverse events occurred in either group., Conclusion: Simultaneous treatment with biologics and intra-articular injection of TA is useful for cases involving switching of biologics for RA. This strategy is safe and practical for RA treatment.

Objectives: The aim of this study was to determine whether the levels of stromal cell-derived factor (SDF)-1 and its receptor C-X-C chemokine receptor 4 (CXCR4) in synovium were correlated with clinical outcome and bone and joint destruction in rheumatoid arthritis (RA) patients being treated with golimumab., Methods: Synovial tissues were obtained from 15 golimumab-treated patients and were assessed for SDF-1 and CXCR4 using a new immunohistological scoring system (IH score). The IH score was used to assess correlations between synovial SDF-1 or CXCR4 and the disease activity score (DAS28 CRP), Rooney score, tumor necrosis factor alpha, interleukin-6 (IL-6), CD4, CD20, CD68 and the Assessment of RA by Scoring of Large-Joint Destruction and Healing in Radiographic Imaging (ARASHI) score. Receiver-operating characteristic (ROC) curves were used to predict ARASHI scores from the CXCR4 IH scores., Results: SDF-1 strongly correlated with the DAS28 CRP and serum IL-6. CXCR4 correlated with synovial CD4 and the ARASHI score. ROC analysis of CXCR4 and ARASHI scores >10 indicated a cutoff of 12 points on the IH score for predicting joint destruction during treatment., Conclusions: Synovial SDF-1 correlated with disease activity, and its receptor CXCR4 was related to joint destruction in RA patients treated with golimumab.

The aim of this study was to investigate remission and biologic-free remission after orthopaedic surgery and related clinical factors in non-responder to infliximab for rheumatoid arthritis (RA). We analyzed 74 patients who were treated with 3 mg/kg infliximab and methotrexate and underwent orthopaedic surgery after non-responder to infliximab with disease activity score (DAS) 28 (CRP) of ≥3.2. The rates of remission and biologic-free remission at 52 weeks after orthopaedic surgery were investigated and the clinical factors related to remission and biologic-free remission were analyzed by logistic regression and receiver-operating characteristic analyses. The rates of total remission and biologic-free remission were 37/74 (50 %) and 9/74 (12.2 %), respectively. Regarding orthopaedic surgery, the rates of remission and biologic-free remission were 25/38 (65.8 %) and 7/38 (18.4 %) for synovectomy, 7/20 (35 %) and 0/20 (0 %) for arthroplasty, and 5/16 (31.3 %) and 2/16 12.5) for others including spine surgery and foot surgery. DAS28(CRP) at baseline was significantly related to both remission and biologic-free remission. Prednisolone was negatively associated with remission, and DAS28(CRP) was related to biologic-free remission by logistic regression analyses. DAS28(CRP) below 3.7 was cutoff point for acquiring biologic-free remission of non-responder to infliximab after orthopaedic surgery. Therefore orthopaedic surgery may be effective to obtain remission or biologic-free remission in RA patients treated with biologics.

Shoulder synovectomy is a well-known surgical treatment for rheumatoid arthritis. However, synovectomy alone is insufficient for improving range of motion clinically. We investigated the clinical factors related to the efficacy of shoulder synovectomy performed with capsular release in patients with rheumatoid arthritis. Fifty-four shoulders of 54 patients (12 males, 42 females; mean age 53.3 years) with rheumatoid arthritis were treated by synovectomy plus capsular release. The patients had a mean disease duration of 8.33 years, a mean follow-up period of 5.02 years, and 66.7% received biological treatment. The disease activity score 28 using C-reactive protein, range of motion of the shoulder, and Japanese Orthopaedic Association (JOA) score assessment were used to investigate clinical factors, analyzed by multiple regression analysis, associated with improved outcome. The average disease activity score 28 using C-reactive protein and JOA score improved significantly from 4.29 and 36.7 to 3.11 and 84.6, respectively, with the restoration of range of motion. Multiple regression analysis showed that disease duration and prednisolone were significantly associated with flexion degree and JOA score. Larsen grade and JOA score were not correlated significantly. There was no significant difference in the JOA score between the groups with or without biological medicinal treatment. Shoulder arthroscopic synovectomy performed with capsular release with or without biological treatment effectively improved function. Short disease duration and low prednisolone dose in rheumatoid arthritis were important for prediction of efficacy.

In order to investigate the predictive factors related to clinical efficacy and radiographic progression at 24 weeks by looking at the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 including baseline characteristics in patients with rheumatoid arthritis (RA) treated with golimumab, serum concentrations of TNF-α and IL-6 were analyzed every 4 weeks up to 24 weeks in 47 patients treated with golimumab. Baseline levels of the Disease Activity Score 28 C-reactive protein (DAS28-CRP) and Simplified Disease Activity Index (SDAI) scores were also assessed. Radiographic progression using the van der Heijde-modified Sharp (vdH-S) score was assessed in 29 patients. Multiple regression analyses related to the DAS28-CRP score and delta total sharp score at 24 weeks was undertaken using the baseline characteristics of patients and serum concentrations of matrix metallo-proteinase (MMP)-3, TNF-α, and IL-6. The DAS28-CRP score and SDAI decreased significantly at 4 weeks up to 24 weeks compared with baseline. Serum levels of TNF-α were not changed significantly up to 24 weeks compared with baseline, but those of IL-6 decreased significantly at 4 weeks up to 8 weeks. Multiple regression analyses showed that disease duration and serum levels of MMP-3 were related significantly to the DAS28-CRP score at 24 weeks. Radiographic progression was related significantly to disease duration with regard to joint space narrowing and bone erosion. However, serum levels of TNF-α and IL-6 were not correlated significantly with the DAS28-CRP score and radiographic progression. These data suggest that decreasing serum levels of IL-6 significantly, MMP-3, and disease duration are predictive factors for RA activity in patients taking golimumab.

Onabotulinum toxin type A treatment for post-stroke upper limb spasticity was investigated to contribute to establishing a standard dosage for Japanese patients. A total of 100 patients participated in the study. The outcome one month (33.6±6.5 days) after the treatment was assessed by the Modified Ashworth Scale (MAS) to estimate the mean effect with a 10-unit injection and the standard dosage expected to improve MAS 1 degree. Average improvement of 263 muscles treated with a higher concentration of 10 units diluted in 0.2 ml was 0.207±0.414 degrees, and that of 231 muscles treated with a lower concentration of 10 units in 0.4 ml was 0.149±0.244 degrees without significant difference among diluted concentrations. To improve MAS 1 degree, 64.6±31.1 units were required for the pectoralis major, 51.2±21.3 units for the teres major, 111.7±48.0 units for the biceps brachii, 51.6±26.8 units for the brachioradialis, 54.1±23.2 units for the brachialis, 34.4±10.7 units for the pronator teres, 64.6±27.9 units for the flexor carpi radialis, 62.4±26.8 units for the flexor carpi ulnalis, 58.5±31.1 units for the flexor digitorum profundus, 69.7±35.1 units for the flexor digitorum superficialis, 24.6±13.4 units for the flexor pollicis longus, and 15.6±11.3 units for the adductor pollicis. Although the results shown here had no significant differences among concentrations, increasing the volume would disturb injection into small muscles, so we considered that a lower volume with a higher concentration should assure larger benefits. It is difficult to make effective injections into all spastic muscles within the officially permitted health insurance dosage of 240 units. Hence, it is advisable to increase the applicable upper limit based on safely achieved cumulative experience.

Objectives: This study aimed to analyze the relationship between the expression of tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6) in synovium and the disease activity score (DAS) 28 (C-reactive protein, CRP) in treatment of infliximab for rheumatoid arthritis (RA)., Methods: Synovial tissues were obtained from 16 infliximab-treated patients and assessed for TNF-α and IL-6 with a new immunohistology (IH) scoring system. The validation of IH score was performed and applied for the analysis of correlation between synovial TNF-α or IL-6 and DAS28 (CRP) in addition to Rooney score., Results: The IH score had high internal validity; the IH score of TNF-α strongly correlated with serum CRP and matrix metalloprotease-3 (MMP-3), as well as DAS28 (CRP) and the Rooney score. IL-6 did not correlate with DAS28 (CRP)., Conclusions: This study indicates that the IH score is useful as a new procedure to assess the cytokine expression easily and TNF-α in synovium correlates with disease activity in patients with RA treated with infliximab.

Background: The chemokine receptors (CKRs), mainly CCR5 and CXCR4 function as major coreceptors in infections caused by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). Approximately 20 G protein-coupled receptors (GPCRs) have been identified as minor coreceptors, alike CCR6 that we reported recently. Since CKR-L3 is indentified as a natural isoform of CCR6, we attempted in this study to explore the coreceptor function of CKR-L3., Methods: NP-2 cells transduced with CD4-receptor (NP-2/CD4) normally remain resistant to HIV or SIV infection. However, the introduction of functional coreceptors can make these cells susceptible to these viruses. NP-2/CD4/CKR-L3 cells were produced to examine the coreceptor activity of CKR-L3. Likely, CCR6-isoform and the major coreceptors, CCR5 and CXCR4 were also examined in parallel. Presence of viral antigen in infected NP-2/CD4/coreceptor cells was detected by indirect immunofluorescence assay (IFA). The results were validated by detection of syncytia, proviral DNA and by measuring reverse transcriptase (RT) activities., Results: HIV-2MIR and SIVsmE660 were found to infect NP-2/CD4/CKR-L3 cells, indicative of the coreceptor function of CKR-L3. Viral antigens appeared faster in NP-2/CD4/CKR-L3 cells than in NP-2/CD4/CCR6, indicating that CKR-L3 is a more efficient coreceptor. Moreover, syncytia formation was more rapid and RT release evidenced earlier and at higher levels with CKR-L3 than with CCR6. Sequence analysis in the C2-V3 envelope region of HIV-2MIR replicated through CKR-L3 and CCR6 coreceptor showed two and three amino acid substitutions respectively, in the C2 region compared to the CCR5-variant. The SIVsmE660-CKRL3 variant showed three amino acid substitutions in the V1 region, one change in the V2 and two changes in the C2 region. The SIVsmE660-CCR6 variant produced two changes in the V1 region, and three in the C2 region., Conclusions: Isoform CKR-L3 exhibited coreceptor activity for limited primary HIV and SIV isolates with better efficiency than the parent CCR6-isoform. Amino acid substitutions in the envelope region of these viruses may confer selective pressure towards CKR-L3-use. CKR-L3 with other minor coreceptors may contribute to HIV and SIV pathogenesis including dissemination, trafficking and latency especially when major coreceptors become compromised. However, further works will be required to determine its clinical significance in HIV and SIV infection.

The aim of this study was to investigate immunohistological changes in mitogen-activated protein kinases (MAPKs) in the synovium following treatment with golimumab, compared with methotrexate (MTX). We assessed synovial tissues for 13 different molecules to detect cytokine levels histologically from 10 methotrexate (MTX)-treated rheumatoid arthritis (RA) patients as controls and 10 golimumab plus MTX-treated RA patients. Synovium samples from both groups were assessed by hematoxylin and eosin (HE) staining and analyzed for expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD4 (T cells), CD8 (T cells), CD20 (B cells), CD68 (macrophages), receptor activator of nuclear (kappa) B ligand (RANKL), bromodeoxyuridine (BrdU), CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK (ERK1/ERK2), and phospho-c-Jun N-terminal kinase (JNK), by an immunohistological examination. HE staining showed that there was a significant decrease in cell proliferation in the synovium in RA patients who received golimumab compared with the controls. TNF-α, IL-6, MMP3, BrdU, p38, and ERK were not seen at significant levels in either group. On the other hand, CD4, CD8, CD20, CD29, CD68, RANKL, and JNK were significantly decreased in the golimumab group compared with the control. Based on a histological analysis of the synovium, it appears that the efficacy of the treatment with golimumab may involve the inhibition of cell proliferation, with decreases in T cells, B cells, macrophages, β-1 integrin, RANKL, and JNK in the synovium, compared with MTX treatment, in RA.

An artificial patch can be used in open and arthroscopic surgery in a massive rotator cuff tear but there is no evidence of biological attachment between the artificial patch and the cuff or bone tissue. We used an artificial polytetrafluoroethylene (PTFE) patch for the arthroscopic treatment for a massive rotator cuff tear. One year after surgery, we could undertake second-look arthroscopy to evaluate whether the PTFE patch was attached to cuff tissue and humeral bone with regard to histological features. We found a tight connection between the PTFE patch and bone, and also recognized smooth attachment to cuff tissue without proliferation of inflammatory cells in the synovium. We assessed the outcome of surgery using the American Shoulder and Elbow Surgeons (ASES) scale and range of motion before and after surgery: A score of 24 before surgery improved to 75 after surgery. MRI after surgery showed continuous low intensity from the PTFE patch to cuff and bone. This is the first report to describe the histological findings of PTFE patch reconstruction of massive rotator cuff tear after 1 year: A major biological reaction was not observed in this respect.

Objective: To assess the reliability and sensitivity of a novel scoring method to evaluate the radiographic appearance of and longitudinal changes including joint remodeling in large joints with early and established rheumatoid arthritis (RA)., Methods: The ARASHI study group devised new radiographic scoring systems (Status score; range 0-16 points, and Change score; range -11 to 12 points) for evaluation of large joints with RA. Radiographs showing anterior/posterior views of large joints (shoulder, elbow, hip, knee, and ankle joints) taken at two time points (mean interval 2.3 years) were collected from 25 patients with established RA (5 patients for each of the 5 joints, 50 films in total), and an additional 5 films of each joint with severe joint destruction were collected from 5 different sets of RA patients. After consensus on the definition of each component and reader training, images were evaluated using the Larsen's grading system and the ARASHI Status and Change score by 9 independent senior orthopedic surgeons. The reliability was estimated by intra-class correlation coefficients (ICCs) and measurement error by 95% confidence intervals of minimum detectable change (MDC95)., Results: ARASHI Status score and Change score significantly correlated with Larsen's grade (r = 0.89, P < 0.0001) and follow-up-baseline differences in Larsen's grade (r = 0.83, P < 0.0001), respectively. Inter-reader ICCs were very high for both Status score (0.88, 95% confidence interval [CI], 0.83-0.92, P < 0.001) and Change score (0.92, 95% CI, 0.87-0.96, P < 0.001). Intra-reader ICCs were also very high for both Status score (0.92, 95% CI, 0.71-0.98, P < 0.001) and Change score (0.97, 95% CI, 0.91-0.99, P < 0.001). The MDC95 for inter-reader agreement were 4.18 (25% of maximum obtainable score, MOS) and 4.99 (21% of MOS) for Status score and Change score, respectively. The MDC95 for intra-reader agreement was acceptable with 2.82 (17% of MOS) and 3.02 (13% of MOS) for Status score and Change score, respectively., Conclusion: The ARASHI scoring method showed good inter-/intra-reader reliability with high ICCs and acceptable MDC95 with respect to each large joint and the components of both Status and Change scores. The results suggest that the ARASHI scoring method might be useful for the assessment of status, as well as longitudinal monitoring of destruction and remodeling of large joints with RA.

The aim of this study was to investigate the histological changes following the treatment with abatacept compared with methotrexate (MTX) by an immunohistological examination of synovial tissue for eleven different molecules to detect the expression patterns of cytokines. We histologically assessed the synovial tissues from 10 methotrexate (MTX)-treated RA patients as controls and 5 abatacept plus MTX-treated RA patients. The synovium samples from both group were assessed by hematoxylin and eosin (HE) staining and analyzed for their expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD20, CD68, vascular endothelial growth factor (VEGF), CD4, CD8, CD28, CD80, and CD86 by an immunohistological examination. HE staining showed that there was a decrease in cell proliferation in the synovium of the RA patients who received abatacept compared with the controls. TNF-α, IL-6, and VEGF were not significantly different in either of the groups. On the other hand, MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 were significantly decreased in the abatacept group compared with the control (P < 0.05). Based on the histological analysis of the synovium, it appears that the efficacy of the treatment with abatacept may involve the inhibition of cell proliferation, with decreases in the expression of MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 in the synovium. These findings indicate inhibition of not only T cells but also B cells and macrophages, which likely plays a role in the efficacy of abatacept in RA patients.

Objective: To evaluate perioperative changes in rheumatoid arthritis (RA) patients treated with tocilizumab., Methods: We collected RA cases with tocilizumab and orthopaedic surgery from 1999 to 2010. Incidences of postoperative infections, delayed wound healing, and RA symptom flare-ups were extracted from the data for comparison with patients without these postoperative events. We also evaluated the changes in C-reactive protein (CRP) and body temperature in patients without postoperative complications with normal CRP before surgery, i.e., patients without postoperative events in whom the tocilizumab level was maintained, for each duration to discontinuation before surgery., Results: A total of 161 cases (n = 122) were collected. The patients had mean age of 56.9 years, and mean disease duration of 12.8 years at operation. Joint replacement surgery was performed in 89 cases. Three patients had postoperative infections (two superficial and one organ/space surgical-site infection), 20 had delayed wound healing, and 36 had RA symptom flare-ups. Delayed wound healing occurred most commonly in patients who underwent spinal surgery (P = 0.0061, versus patients without delayed wound healing). CRP levels were high when tocilizumab was restarted in patients with RA symptom flare-ups (P = 0.0010, versus patients without RA symptom flare-ups). Increased postoperative CRP was observed in patients without postoperative events when the duration from final tocilizumab infusion to surgery was long. The changes in body temperature showed a similar trend to CRP., Conclusions: Although it has been demonstrated that infection rates in patients treated with tocilizumab are by no means high, incidence of delayed wound healing was significantly higher in cases with surgical interventions such as foot and spinal surgeries. Many patients treated with tocilizumab remained in a normal range of CRP even during the perioperative period. For prevention of perioperative complications, observation of postoperative conditions and surgical wounds, and subjective symptoms of patients are considered important.

The aim of this study was to investigate histological changes of bone marrow in response to tocilizumab for rheumatoid arthritis (RA). After tocilizumab therapy, bone marrow tissues were extracted from ten RA patients at the time of total knee arthroplasty (TKA). Control samples were obtained from ten RA patients who underwent MTX mono-therapy. Histological examination of structural differences between the tocilizumab and control groups in bone marrow was performed using hematoxylin and eosin (H&E) to evaluate differences. In immunohistochemical examination, the expression of seven molecules including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), CD68, osteoprotegerin (OPG), receptor activator of nuclear kappa B ligand (RANKL), CD4 and osteopontin (OPN) were compared between two groups. NTx was significantly low at 44.5 ± 2 nM BCE/mM Cr compared with control at 73.2 ± 8 nM BCE/mM Cr. Immunohistochemical examination revealed that the bone marrow tissues of the RA patients who underwent tocilizumab therapy demonstrated significant positive OPG as compared with the control. However, immunohistochemical examinations after tocilizumab revealed that TNF-α, IL-6, CD68, CD4, OPN and RANKL were not significantly different with control of MTX in bone marrow. Therefore, treatment with tocilizumab increased the expression of OPG as the histological changes with respect to inhibit RANKL-related bone resorption of bone marrow in RA.

We evaluated the feasibility and the benefits of total prostatectomy with suprapubic cystostomy drainage instead of a urethral Foley catheter. Of 65 consecutive total retropubic prostatectomies, 42 were carried out with the suprapubic cystostomy, and 23 with the urethral Foley catheter. Patients were asked postoperatively to complete a 5-cm visual analog scale on pain intensity related to the catheter and to urination after catheter removal. No problem related to cystostomy per se was observed. In the cystostomy group, over 85% and 69% of men perceived no urinary symptoms during catherization and no painful urination after catheter removal, respectively; whereas in the Foley group, 91% and 65% perceived those symptoms (P < 0.001 and P < 0.01, respectively). These findings suggest that urethral catheter-free prostatectomy is a good alternative to that with a urethral Foley catheter, and it gives patients an improved quality of early postoperative life., (© 2012 The Japanese Urological Association.)

To investigate the histological changes of mitogen-activated protein kinase (MAPK) in synovium with tocilizumab in rheumatoid arthritis (RA), synovial tissue samples were assessed from ten methotrexate (MTX)-treated RA patients for control and ten tocilizumab with MTX-treated RA patients. The synovium was observed using hematoxylin and eosin (H&E) stain and analyzed immunohistochemically for the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD4 (T cell), CD20 (B cell), CD68 (macrophage), vascular endothelial growth factor (VEGF), CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK [extracellular signal-regulated kinase (ERK) 1/ERK2], and phospho-c-Jun N-terminal kinase (JNK). H&E staining showed that there is a significant difference of cell proliferation; however, there is no change of hypervascularity in the synovium between both groups. An immunohistochemical examination showed that the decrease of CD29 (β-1 integrin) and JNK was found significant, while ERK was increased in the tocilizumab group. CD20, B-lymphocyte, was decreased in the tocilizumab group compared with the MTX group significantly. IL-6 was completely blocked in the patients who received tocilizumab. TNF-α was similarly expressed in the interstitial cells of synovium of patients in both groups. MMP-3 and CD68 were similarly expressed on the surface of synovium. VEGF was less expressed in both groups. These findings indicate that the inhibition of CD20, CD29, and JNK in MAPK may be involved in the efficacy of tocilizumab compared with MTX treatment in RA.

Objective: The aim of the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan (JESMR) study is to compare the efficacy of continuation versus discontinuation of methotrexate (MTX) when starting etanercept (ETN) in patients with active rheumatoid arthritis (RA)., Methods: In total, 151 patients with active RA who had been taking MTX were randomized to either ETN 25 mg twice a week with 6-8 mg/week MTX (the E+M group), or ETN alone (the E group). The primary endpoint at Week 52 was the radiographic progression assessed by van der Heijde-modified Sharp score., Results: The mean progression in total score at Week 52 was not significantly different, statistically, between the E+M group and the E group (0.8 vs 3.6, respectively; p = 0.06). However, a significant difference was observed in radiographic progression between Weeks 24 and 52 (0.3 vs 2.5; p = 0.03), and the mean progression of the erosion score was negative in the E+M group, which was significantly better than the E group at Week 52 (-0.2 vs 1.8; p = 0.02). Clinically, the cumulative probability plot of the American College of Rheumatology (ACR)-N values at Week 52 clearly demonstrated a superior response in the E+M group than in the E group. ACR20, 50, and 70 response rates at Week 52 in the E+M group (86.3%, 76.7%, and 50.7%) were significantly greater than those in the E group (63.8%; p = 0.003, 43.5%; p < 0.0001 and 29.0%; p = 0.01, respectively)., Conclusion: MTX should be continued when starting ETN in patients with active RA. (ClinicalTrials.gov: NCT00688103).

Aims: In order to investigate the histological change in the secondary non-responder cases of adalimumab compared with methotrexate (MTX) treatment, we performed immunohistochemical examination of synovial tissue by seven different molecules to detect expression patterns of cytokines., Methods: We histologically assessed synovial tissues from five MTX-treated rheumatoid arthritis (RA) patients as controls and five adalimumab plus MTX-treated RA patients after arthroscopic synovectomy in the knee joints. The synovium of both groups were assessed by hematoxylin and eosin (H&E) and analyzed the positive expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), B-cell precursor and mature B-cell transmembrane protein, CD20, macrophage marker, CD68, vascular endothelial growth factor (VEGF), receptor activator of nuclear (kappa) B ligand (RANKL) by immunohistochemical examination., Results: H&E staining showed the increase of vascular and cell proliferations in the synovium of the RA patients who received adalimumab compared with the controls. TNF-α, IL-6 and CD20 were not significantly different in either group. On the other hand, MMP-3 and CD68 showed a significant decrease in the adalimumab group compared with controls (P < 0.05). VEGF and RANKL were weakly positive in both groups., Conclusion: Based on the histological analysis of synovium, the effect attenuation of adalimumab may be involved in vascular and cell proliferations; however, there was inhibition of the expression of CD68 and MMP-3 in synovium. These findings indicate CD68 and MMP-3 may have key roles in the mechanism of efficacy of adalimumab., (© 2011 The Authors. International Journal of Rheumatic Diseases © 2011 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.)

Aims: To determine what clinical factors relating to efficacy besides complications of orthopedic surgery for patients treated with anti-tumor necrosis factor (TNF)-α therapy (infliximab), we analyzed the clinical data of 52 cases of orthopedic surgery, such as total hip arthroplasy (THA), total knee arthroplasty (TKA), total shoulder arthroplasy (TSA), total elbow arthroplasty (TEA), arthroscopic synovectomy, foot arthroplasty, spine surgery, hand surgery and fracture., Methods: We analyzed clinical factors including age, disease duration, preoperative C-reactive protein (CRP), disease activity score (DAS)-28, matrix metalloproteinase (MMP)-3, and rheumatoid arthritis particle-agglutination (RAPA) in 52 cases of rheumatoid arthritis (RA) undergoing orthopedic surgery. For complications of orthopedic surgery, signs of postoperative infection were recorded, including rubor, discharge, systemic infection and frequencies of wound dehiscence, as well as the incidence of any surgical complication requiring a secondary revision procedure were measured., Results: Signs of infection or surgical complications occurred in two of 52 patients (3.8%). There is significant correlation between RAPA and improvement of CRP 3 months after surgery; however, there is no correlation between infection and clinical factors including age, disease duration, preoperative CRP, MMP-3, RAPA and the period until surgery after infliximab infusion., Conclusion: Infliximab did not increase the risk of either infections or surgical complications occurring in patients with RA within 1 year of orthopedic surgery. Improvement of CRP after surgery is likely to be due to infliximab for high RAPA in RA patients., (© 2010 The Authors. International Journal of Rheumatic Diseases. © 2010 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.)