Subtle Radiographic Progression at Six Months Can Be Detected Using Automated Quantitative Software in Rheumatoid Arthritis While Receiving Tocilizumab.

OBJECTIVES: We investigated whether our in-house software equipped with partial image phase-only correlation (PIPOC) can detect subtle radiographic joint space narrowing (JSN) progression at six months and predict JSN progression in rheumatoid arthritis (RA) patients receiving Tocilizumab. METHODS: The study included 39 RA patients who were treated with Tocilizumab. Radiological progression of the metacarpophalangeal and the proximal interphalangeal joints was evaluated according to the Genant-modified Sharp score (GSS) at 0, 6, and 12 months. Automatic measurements were performed with the software. We validated the software in terms of accuracy in detecting the JSN progression. RESULTS: The success rate of the software for joint space width (JSW) measurement was 96.8% (449/464). The 0-12-month JSW change by the software was significantly greater in joints with the 0-6-month PIPOC (+) group than the 0-6-month PIPOC (-) group (p < 0.001). The 0-12-month JSW change by the software was 0-12-month GSS (+) than with 0-12-month GSS (-) (p = 0.02). Here, "(+)" indicates the JSN progression during the follow-up period. Meanwhile, "(-)" indicates no JSN progression during the follow-up period. Linear regression tests showed significant correlations between the 0-6-month and the 0-12-month PIPOC in the left 2nd and 3rd MCP joints (R2 = 0.554 and 0.420, respectively). CONCLUSIONS: Our in-house software equipped with PIPOC could predict subsequent JSN progression with only short-term observations.

Gappability Index for Quantum Many-Body Systems.

We propose an index I_{G} which characterizes the degree of gappability, namely the difficulty to induce a unique ground state with a nonvanishing excitation gap, in the presence of a symmetry G. I_{G} represents the dimension of the subspace of ambient uniquely gapped theories in the entire G-invariant "theory space." The celebrated Lieb-Schultz-Mattis theorem corresponds, in our formulation, to the case I_{G}=0 (completely ingappable) for the symmetry G including the lattice translation symmetry. We illustrate the usefulness of the index by discussing the phase diagram of spin-1/2 antiferromagnets in various dimensions, which do not necessarily have the translation symmetry.

Efficacy and safety of sodium RISedronate for glucocorticoid-induced OsTeoporosis with rheumaTOid arthritis (RISOTTO study): A multicentre, double-blind, randomized, placebo-controlled trial.

OBJECTIVE: No evidence has shown the efficacy of Sodium Risedronate (Risedronate) for glucocorticoid-induced osteoporosis (GIO) in patients with Rheumatoid arthritis (RA). The aim of this study was to explore the effectiveness and safety of Risedronate for GIO complicated with RA. METHODS: This was a six-month randomized, double-blind, placebo-controlled trial of 95 patients with GIO complicated with RA from 19 centers. The primary endpoint was the change from baseline in lumbar spine bone mineral density (L-BMD). Secondary endpoints included changes in femoral neck and total hip BMD and bone turnover markers, as well as rheumatoid arthritis Disease Activity Score with 28-joint counts. Incident of non-traumatic spine fractures and adverse events were tracked as safety endpoints. RESULTS: Increase in L-BMD was significantly greater in the Risedronate group compared to the Placebo group (Risedronate: 3.49% [95% CI: 1.92-5.05] vs Placebo: 0.12% [95% CI: -2.07 to 2.30], p < .0001). No significant difference was found in the femoral neck and total hip BMD. Although adverse events were observed in 28 patients, none were considered serious. Non-traumatic vertebral fractures were identified in 10 patients. CONCLUSION: Risedronate was effective in increasing L-BMD and was well tolerated in patients with GIO complicated with RA.

Weekly split-dose regimen for oral methotrexate reduced polyglutamation in red blood cells in patients with rheumatoid arthritis compared with single-dose regimen: Results from a multicentered randomized control trial.

AIMS: We compared the incidence of adverse events between single and divided-dose regimens of methotrexate (MTX) by using a multicenter randomized controlled trial. METHODS: Eighty-nine patients with insufficient control on MTX 8 mg/wk were randomly assigned into single-dose (39 patients) or triple dose (39 patients) groups. The MTX dose for all patients was gradually increased to 16 mg/wk. The primary endpoint was the occurrence of liver dysfunction during the observation period (20 weeks). RESULTS: There were no differences in baseline data and MTX dose at Week 20 between groups. There was no significant difference in the incidence of liver dysfunction between groups (single dose, 3 [7.7%] patients vs. triple dose, 5 [13.2%] patients; P = .455). The incidence of adverse event increased in triple dose (single dose, 12 [30.8%] patients vs. triple dose, 20 [51.3%]), but the difference was not significant (P = .066). There was no significant difference in disease activity between groups, although MTX-triglutamate (PG3), MTX-PG4, and MTX-PG5 were significantly higher in the single dose group. CONCLUSIONS: Weekly split dosing reduced the polyglutamation of MTX. There was no significant difference in efficacy and safety between the 2 groups.

Quick and accurate selection of hand images among radiographs from various body parts using deep learning.

BACKGROUND: Although rheumatoid arthritis (RA) causes destruction of articular cartilage, early treatment significantly improves symptoms and delays progression. It is important to detect subtle damage for an early diagnosis. Recent software programs are comparable with the conventional human scoring method regarding detectability of the radiographic progression of RA. Thus, automatic and accurate selection of relevant images (e.g. hand images) among radiographic images of various body parts is necessary for serial analysis on a large scale. OBJECTIVE: In this study we examined whether deep learning can select target images from a large number of stored images retrieved from a picture archiving and communication system (PACS) including miscellaneous body parts of patients. METHODS: We selected 1,047 X-ray images including various body parts and divided them into two groups: 841 images for training and 206 images for testing. The training images were augmented and used to train a convolutional neural network (CNN) consisting of 4 convolution layers, 2 pooling layers and 2 fully connected layers. After training, we created software to classify the test images and examined the accuracy. RESULTS: The image extraction accuracy was 0.952 and 0.979 for unilateral hand and both hands, respectively. In addition, all 206 test images were perfectly classified into unilateral hand, both hands, and the others. CONCLUSIONS: Deep learning showed promise to enable efficiently automatic selection of target X-ray images of RA patients.

Validation of Fully Automatic Quantitative Software for Finger Joint Space Narrowing Progression for Rheumatoid Arthritis Patients.

In rheumatoid arthritis (RA), the radiographic progression of joint space narrowing (JSN) is evaluated using visual assessments. However, those methods are complicated and time-consuming. We developed an automatic system that can detect joint locations and compute the joint space difference index (JSDI), which was defined as the chronological change in JSN between two radiographs. The purpose of this study was to establish the validity of the software that automatically evaluates the temporal change of JSN. This study consisted of 39 patients with RA. All patients were treated with tocilizumab and underwent hand radiography (left and right hand separately) at 0, 6, and 12 months. The JSN was evaluated using mTSS (modified Total Sharp Score) by one musculoskeletal radiologist as well as our automatic system. Software measurement showed that JSDI between 0 and 12 months was significantly higher than that between 0 and 6 months (p < 0.01). While, there was no significant difference in mTSS between 0, 6, and 12 months. The group with higher disease activity at 0 months had significantly higher JSDI between 0 and 6 months than that with lower disease activity (p = 0.02). The automatic software can evaluate JSN progression of RA patients in the finger joint on X-ray.

Extraintestinal Clostridium difficile infection due to a ribotype different from that isolated from the feces of the patient: A case report.

Extraintestinal infections due to Clostridium difficile are uncommon. When such infections occur, extraintestinal C. difficile isolates are usually identical to fecal isolates. We present a rare case of a large postoperative abscess caused by C. difficile infection, in which different C. difficile strains were isolated from the abscess and from feces of the patient. An 82-year-old woman with cutaneous polyarteritis nodosa developed pain, skin ulcers, and extensive necrosis of the right leg. Above-knee amputation was performed without stopping antiplatelet therapy, leading to postoperative hematoma. Six weeks after surgery, a large femoral abscess was detected and C. difficile was isolated. Repeat amputation of the thigh was required to remove the abscess. C. difficile was also cultured from feces despite the lack of intestinal symptoms. However, genetic analysis confirmed that the C. difficile isolates from the abscess and feces were different strains. Thus, C. difficile can cause postoperative infection of a hematoma and the extraintestinal and fecal C. difficile isolates are not necessarily identical in the same patient.

Weyl points and Dirac lines protected by multiple screw rotations.

In three-dimensional noncentrosymmetric materials two-fold screw rotation symmetry forces electron's energy bands to have Weyl points at which two bands touch. This is illustrated for space groups No. 19 (P212121) and No. 198 (P213), which have three orthogonal screw rotation axes. In the case of space groups No. 61 (Pbca) and No. 205 (Pa-3) that have extra inversion symmetry, Weyl points are promoted to four-fold degenerate line nodes in glide-invariant planes. The three-fold rotation symmetry present in the space groups No. 198 and No. 205 allows Weyl and Dirac points, respectively, to appear along its rotation axes in the Brillouin zone and generates four-fold and six-fold degeneracy at the Γ point and R point, respectively.

Charge and spin transport in edge channels of a ν=0 quantum Hall system on the surface of topological insulators.

Three-dimensional topological insulators of finite thickness can show the quantum Hall effect (QHE) at the filling factor ν=0 under an external magnetic field if there is a finite potential difference between the top and bottom surfaces. We calculate energy spectra of surface Weyl fermions in the ν=0 QHE and find that gapped edge states with helical spin structure are formed from Weyl fermions on the side surfaces under certain conditions. These edge channels account for the nonlocal charge transport in the ν=0 QHE which is observed in a recent experiment on (Bi_{1-x}Sb_{x})_{2}Te_{3} films. The edge channels also support spin transport due to the spin-momentum locking. We propose an experimental setup to observe various spintronics functions such as spin transport and spin conversion.

Cross-correlated responses of topological superconductors and superfluids.

We study nontrivial responses of topological superconductors and superfluids to the temperature gradient and rotation of the system. In two-dimensional gapped systems, the Streda formula for the electric Hall conductivity is generalized to the thermal Hall conductivity. Applying this formula to the Majorana surface states of three-dimensional topological superconductors predicts cross-correlated responses between the orbital angular momentum and thermal polarization (entropy polarization). These results can be naturally related to the gravitoelectromagnetism description of three-dimensional topological superconductors and superfluids, analogous to the topological magnetoelectric effect in Z(2) topological insulators.

Acute Renal Failure due to Thrombotic Microangiopathy in Patient with Scleroderma: Autopsy Case Report.

This study presents a patient who died of acute renal failure (ARF) as a complication of scleroderma. The patient remained normotensive throughout the clinical course. Myeloperoxidase-anti-neutrophil cytoplasmic antibody was negative. Autopsy revealed fibrin thrombi in the glomerular capillaries and afferent arterioles, mesangiolysis, and double contour of the glomerular basement membrane. Contrarily, "onionskin lesions" of renal interlobular arteries, the histological hallmark of scleroderma renal crisis, were not discovered. These findings suggested that thrombotic microangiopathy (TMA) was the cause of ARF. Although the frequency is not high, close monitoring should be given to TMA in scleroderma because of possible mortality.

Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study.

OBJECTIVE: To clarify the association of clinical and prognostic features with dermatomyositis (DM)-specific autoantibodies (Abs) in adult Japanese patients with DM. DESIGN: Retrospective study. SETTING: Kanazawa University Graduate School of Medical Science Department of Dermatology and collaborating medical centers. Patients A total of 376 consecutive adult Japanese patients with DM who visited our hospital or collaborating medical centers between 2003 and 2008. MAIN OUTCOME MEASURES: Clinical and laboratory characteristics of adult Japanese patients with DM and DM-specific Abs that include Abs against Mi-2, 155/140, and CADM-140. RESULTS: In patients with DM, anti-Mi-2, anti-155/140, and anti-CADM-140 were detected in 9 (2%), 25 (7%), and 43 (11%), respectively. These DM-specific Abs were mutually exclusive and were detected in none of 34 patients with polymyositis, 326 with systemic sclerosis, and 97 with systemic lupus erythematosus. Anti-Mi-2 was associated with classical DM without interstitial lung disease or malignancy, whereas anti-155/140 was associated with malignancy. Patients with anti-CADM-140 frequently had clinically amyopathic DM and rapidly progressive interstitial lung disease. Cumulative survival rates were more favorable in patients with anti-Mi-2 compared with those with anti-155/140 or anti-CADM-140 (P < .01 for both comparisons). Nearly all deaths occurred within 1 year after diagnosis in patients with anti-CADM-140. Conclusion Dermatomyositis-specific Abs define clinically distinct subsets and are useful for predicting clinical outcomes in patients with DM.

Chain of Majorana states from superconducting Dirac fermions at a magnetic domain wall.

We study theoretically a strongly type-II s-wave superconducting state of two-dimensional Dirac fermions in proximity to a ferromagnet having in-plane magnetization. It is shown that a magnetic domain wall can host a chain of equally spaced vortices in the superconducting order parameter, each of which binds a Majorana-fermion state. The overlap integral of neighboring Majorana states is sensitive to the position of the chemical potential of the Dirac fermions. Thermal transport and scanning tunneling microscopy experiments to probe the Majorana fermions are discussed.

The effects of phosphatidylserine-dependent antiprothrombin antibody on thrombin generation.

OBJECTIVE: Antibodies to prothrombin (APTs) and to beta2-glycoprotein I are the major autoantibodies responsible for lupus anticoagulant (LAC) activity. APTs comprise antibodies against prothrombin alone as well as antibodies against phosphatidylserine/prothrombin complex (anti-PS/PT), the latter being highly associated with the antiphospholipid syndrome (APS). The effect of anti-PS/PT on thrombin generation has not been elucidated, and the paradoxical effect of LAC (an anticoagulant in vitro, but a procoagulant in vivo) remains an enigma. The purpose of this study was to investigate the effects of anti-PS/PT on thrombin generation and to examine the LAC paradox. METHODS: We evaluated 36 anti-PS/PT-positive APS patients and 127 healthy subjects. Markers of in vivo thrombin/fibrin generation, including prothrombin fragment F1+2, thrombin-antithrombin III complex, soluble fibrin monomer, D-dimer, and fibrin degradation products, were measured. Mouse monoclonal anti-PS/PT antibody 231D was established, and its effects on in vitro thrombin generation were investigated by chromogenic assay. RESULTS: Significantly elevated levels of markers of thrombin/fibrin generation were observed in anti-PS/PT-positive patients, regardless of the presence or absence of anticardiolipin antibodies, as compared with healthy subjects. In the presence of low concentrations of human activated factor V (FVa), monoclonal antibody 231D increased thrombin generation in a dose-dependent manner. In contrast, when high concentrations of FVa were added, monoclonal antibody 231D decreased thrombin generation. Under a constant concentration of FVa, a high concentration of human FXa enhanced the effect of 231D. CONCLUSION: The presence of anti-PS/PT greatly correlated with increased thrombin generation in APS patients. The in vitro effects of monoclonal antibody 231D on thrombin generation are "biaxial" according to the FVa/FXa balance. These data may serve as a clue to understanding the LAC paradox and the thrombogenic properties of anti-PS/PT.

Immunological reconstitution after autologous hematopoietic stem cell transplantation in patients with systemic sclerosis: relationship between clinical benefits and intensity of immunosuppression.

OBJECTIVE: To analyze the relationship between clinical benefits and immunological changes in patients with systemic sclerosis (SSc) treated with autologous hematopoietic stem cell transplantation (HSCT). METHODS: Ten patients with SSc were treated with high-dose cyclophosphamide followed by highly purified CD34+ cells (n=5) or unpurified grafts (n=5). Two groups of patients were retrospectively constituted based on their clinical response (good responders, n=7; and poor responders, n=3). As well as clinical findings, immunological reconstitution through autologous HSCT was assessed by fluorescence-activated cell sorter analysis, quantification of signal joint T cell receptor rearrangement excision circles (sjTREC), reflecting the thymic function, and foxp3, a key gene of regulatory T cells, mRNA levels. RESULTS: Patients' clinical and immunological findings were similar between good and poor responders, or CD34-purified and unpurified groups at inclusion. The sjTREC values were significantly suppressed at 3 months after autologous HSCT in good responders compared with poor responders (p=0.0152). Reconstitution of CD4+CD45RO- naive T cells was delayed in good responders compared with poor responders. The phenotype of other lymphocytes, cytokine production in T cells, and foxp3 gene expression levels after autologous HSCT did not correlate with clinical response in good or poor responders. Clinical and immunological findings after autologous HSCT were similar between CD34-purified and unpurified groups. CONCLUSION: Our results suggest that immunosuppression intensity, sufficient to induce transient suppression of thymic function, is attributable to the feasible clinical response in patients with SSc treated with autologous HSCT. Appropriate monitoring of sjTREC values may predict clinical benefits in transplanted SSc patients after autologous HSCT.

Quantum Hall effect of massless dirac fermions in a vanishing magnetic field.

The effect of strong long-range disorder on the quantization of the Hall conductivity sigma{xy} in graphene is studied numerically. It is shown that increasing Landau-level mixing progressively destroys all plateaus in sigma{xy} except the plateaus at sigma{xy}=-/+e{2}/2h (per valley and per spin). The critical state at the Dirac point is robust to strong disorder and belongs to the universality class of the conventional plateau transitions in the integer quantum Hall effect. We propose that the breaking of time-reversal symmetry by ripples in graphene can realize this quantum critical point in a vanishing magnetic field.

Z2 topological term, the global anomaly, and the two-dimensional symplectic symmetry class of Anderson localization.

We discuss, for a two-dimensional Dirac Hamiltonian with a random scalar potential, the presence of a Z2 topological term in the nonlinear sigma model encoding the physics of Anderson localization in the symplectic symmetry class. The Z2 topological term realizes the sign of the Pfaffian of a family of Dirac operators. We compute the corresponding global anomaly, i.e., the change in the sign of the Pfaffian by studying a spectral flow numerically. This Z2 topological effect can be relevant to graphene when the impurity potential is long ranged and, also, to the two-dimensional boundaries of a three-dimensional lattice model of Z2 topological insulators in the symplectic symmetry class.

Fas ligand (CD178) cytoplasmic tail is a positive regulator of Fas ligand-mediated cytotoxicity.

The cytotoxic function of CD178 (Fas ligand (FasL)) is critical to the maintenance of peripheral tolerance and immune-mediated tissue pathology. The active site of FasL resides at the FasL extracellular region (FasL(Ext)) and it functions through binding/cross-linking Fas receptor on target cells. In this study, we report that FasL(Ext)-mediated cytotoxicity is regulated by the FasL cytoplasmic tail (FasL(Cyt)). Deleting the N-terminal 2-70 aa (delta70) or N-terminal 2-33 aa (delta33) reduced the cytotoxic strength as much as 30- to 100-fold. By contrast, change in the cytotoxic strength was not observed with FasL deleted of the proline-rich domains (45-74 aa, delta PRD) in the FasL(Cyt). Our study identifies a novel function of FasL(Cyt) and demonstrates that FasL(2-33), a sequence unique to FasL, is critically required for the optimal expression of FasL(Ext)-mediated cytotoxicity.

A woman with infectious endocarditis caused by Abiotrophia defectiva.

A 74-year-old woman with recurrent fever and multiple joint pain was admitted to Hokkaido University Hospital. Trans-esophageal echocardiogram revealed bacterial vegetation and destruction of the aortic valve. Although few bacteria grew in regular blood agar, Gram-positive coccobacillus was specifically grown in chocolate blood agar and Brucella agar, and it was identified to be Abiotrophia defectiva. Infectious endocarditis caused by Abiotrophia defectiva was diagnosed, she was treated with diuretics, penicillin G and gentamicin, and she immediately improved. Infectious diseases caused by Abiotrophia defectiva are extremely rare, and identification of this pathogen is important, as its bacterial characteristics require proper attention.