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We construct the marginal loosely trapped surface (marginal LTS) for the Kerr spacetime with a small Kerr parameter perturbatively, where the LTS condition is saturated. An LTS is a surface that specifies the strong gravity region, which is a generalization of the photon sphere in the Schwarzschild spacetime. It turns out that there are an infinite number of marginal LTSs. At the leading order of the small Kerr parameter, all of the marginal LTSs have the same area. However, one can see that the maximal marginal LTS among them is uniquely determined at the higher order. [ABSTRACT FROM AUTHOR]

In general asymptotically flat spacetimes, bearing the null geodesics reaching the future null infinity in mind, we propose new concepts, the "dark horizons" (outer dark horizon and inner dark horizon) as generalizations of the photon sphere. They are defined in terms of the structure of escape/capture cones of photons with respect to a unit timelike vector field to capture the motion of light sources. More specifically, considering a two-sphere that represents a set of emission directions of photons, the dark horizons are located at positions where a hemisphere is marginally included in the capture and escape cones, respectively. In addition, our definition succeeds in incorporating relativistic beaming effect. We show that the dark horizon is absent in the Minkowski spacetime, while they exist in spacetimes with black hole(s) under a certain condition. We derive the general properties of the dark horizons in spherically symmetric spacetimes and explicitly calculate the locations of the dark horizons in the Vaidya spacetime and the Kerr spacetime. In particular, in the Kerr spacetime, the outer dark horizon coincides with the shadow observed from infinity on the rotation axis. [ABSTRACT FROM AUTHOR]

Under certain conditions, it is shown that the positivity of the Geroch/Hawking quasi-local mass holds for attractive gravity probe surfaces in any higher dimensions than three. We also comment on the Arnowitt–Deser–Misner mass. [ABSTRACT FROM AUTHOR]

We show the well-posed variational principle in constraint systems. In a naive procedure of the variational principle with constraints, the proper number of boundary conditions does not match that of physical degrees of freedom , which implies that, even in theories with up to first-order derivatives, the minimal (or extremal) value of the action with the boundary terms is not a solution of the equation of motion in the Dirac procedure of constrained systems. We propose specific and concrete steps to solve this problem. These steps utilize the Hamilton formalism, which allows us to separate the physical degrees of freedom from the constraints. This reveals the physical degrees of freedom that are necessary to be fixed on boundaries, and also enables us to specify the variables to be fixed and the surface terms. [ABSTRACT FROM AUTHOR]

In 4D spacetimes with a positive cosmological constant, we introduce a new geometrical object associated with the cosmological horizon and then show the areal inequality. We also examine the attractive gravity probe surfaces as an indicator for the existence of attractive gravity. [ABSTRACT FROM AUTHOR]

We obtain the matter-graviton scattering amplitude in the gravitational theory of quadratic curvature, which has R μν 2 term in the action. Unitarity bound is not satisfied because of the existence of negative norm states, while an analog of unitarity bound for S-matrix unitarity holds due to the cancelation among the positive norm states and negative norm ones in the unitarity summation in the optical theorem. The violation of unitarity bound is a counter example of Llewellyn Smith's conjecture on the relation between tree-level unitarity and renormalizability. We have recently proposed a new conjecture that an analog of the unitarity bound for S-matrix unitarity gives the equivalent conditions to those for renormalizability. We show that the gravitational theory of quadratic curvature is a nontrivial example consistent with our conjecture. [ABSTRACT FROM AUTHOR]

A generalization of the Riemannian Penrose inequality in n -dimensional space (3 ≤ n < 8) is done. We introduce a parameter α (⁠|$-\frac{1}{n-1}\lt \alpha \lt \infty$|⁠) indicating the strength of the gravitational field, and define a refined attractive gravity probe surface (refined AGPS) with α. Then, we show the area inequality for a refined AGPS, |$A \le \omega _{n-1} \left[ (n+2(n-1)\alpha)Gm /(1+(n-1)\alpha) \right]^{\frac{n-1}{n-2}}$|⁠ , where A is the area of the refined AGPS, ω n − 1 is the area of the standard unit (n − 1)-sphere, G is Newton's gravitational constant, and m is the Arnowitt–Deser–Misner mass. The obtained inequality is applicable not only to surfaces in strong gravity regions such as a minimal surface (corresponding to the limit α → ∞), but also to those in weak gravity existing near infinity (corresponding to the limit |$\alpha \rightarrow -\frac{1}{n-1}$|⁠). [ABSTRACT FROM AUTHOR]

Glucocorticoid remains the mainstay for treatment of large vessel vasculitis (LVV) including giant cell arteritis (GCA); however, the disease affects the elderly for whom the adverse effects of glucocorticoid are problematic. Recently, some reports have suggested that intravenous tocilizumab (TCZ) monotherapy is effective for this disease. To date, it remains unknown whether subcutaneous TCZ monotherapy is also effective. Here, we present a first case of GCA successfully treated with subcutaneous TCZ monotherapy. A 75-year-old woman presented with shoulder and hip pain. She was diagnosed with polymyalgia rheumatica (PMR) and treated with low-dose prednisolone (15 mg daily); however, she discontinued glucocorticoid therapy at her discretion due to the psychiatric adverse effect (cognitive dysfunction). Seven months later, her shoulder and hip pain relapsed. Furthermore, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) revealed uptake in the descending thoracic aorta, indicating a complication of LVV. She refused to take glucocorticoid for fear of psychiatric adverse effects and chose subcutaneous TCZ monotherapy (162 mg weekly) for treating this life-threatening urgent condition. Nine months later, her shoulder and hip pain resolved and FDG-PET/CT demonstrated no uptake in the descending thoracic aorta, indicating a successful treatment with subcutaneous TCZ monotherapy for the disease. No adverse events and disease relapse were found during observation period. Our case and the literature review suggest that not only intravenous injection but also subcutaneous injection of TCZ monotherapy can serve as an alternative treatment for patients with GCA who have comorbidities or refuse to take glucocorticoid. [ABSTRACT FROM AUTHOR]

We obtain the matter-graviton scattering amplitude in the gravitational theory of quadratic curvature, which has R μν 2 term in the action. Unitarity bound is not satisfied because of the existence of negative norm states, while an analog of unitarity bound for S-matrix unitarity holds due to the cancelation among the positive norm states and negative norm ones in the unitarity summation in the optical theorem. The violation of unitarity bound is a counter example of Llewellyn Smith's conjecture on the relation between tree-level unitarity and renormalizability. We have recently proposed a new conjecture that an analog of the unitarity bound for S-matrix unitarity gives the equivalent conditions to those for renormalizability. We show that the gravitational theory of quadratic curvature is a nontrivial example consistent with our conjecture. [ABSTRACT FROM AUTHOR]

Introduction: /objectives Several biological disease-modifying anti-rheumatic drugs (bDMARDs) have been widely used for the management of rheumatoid arthritis (RA). These drugs target different molecules important for the pathophysiology of RA; however, only a few studies have compared the effects of these biological drugs on cytokines and bone metabolic markers. The main aim of this study is to clarify the effects of bDMARDs with different modes of action on the cytokine and bone metabolic marker levels in patients with RA. Methods: Patients with RA who were initiated on infliximab, tocilizumab, or abatacept as the first bDMARD were prospectively enrolled in this study. Serum cytokine and bone metabolic marker levels were measured longitudinally, and changes in their levels were compared. Results: A total of 174 patients were enrolled in this study, with 55, 70, and 49 patients in the infliximab, tocilizumab, and abatacept groups, respectively. At six months, despite the similar clinical effectiveness of the three drugs, changes in the cytokine and bone metabolic marker levels were distinct; interferon-γ and tumor necrosis factor-α levels were significantly increased with infliximab, interleukin-6 levels were increased with tocilizumab, and interleukin-1β and interleukin-8 levels were increased with abatacept treatment. Bone-specific alkaline phosphatase and osteocalcin levels increased more significantly with tocilizumab than with infliximab, while osteopontin and osteonectin levels decreased with infliximab treatment. Conclusions: bDMARDs with different modes of action exert different effects on the cytokine and bone metabolic marker levels in patients with RA. Key Points • While clinical effectiveness is comparable with infliximab, tocilizumab, and abatacept in patients with rheumatoid arthritis, changes in cytokine and bone metabolic marker levels are distinct among bDMARDs. • Especially, changes in interferon-γ, tumor necrosis factor-α levels with infliximab, interleukin-6, bone-specific alkaline phosphatase, osteocalcin levels with tocilizumab, and interleukin-1β, interleukin-8 levels with abatacept are significant. [ABSTRACT FROM AUTHOR]

We propose a wrist joint subluxation/ankylosis classification model for an automatic radiographic scoring system for X-ray images. In managing rheumatoid arthritis, the evaluation of joint destruction is important. The modified total Sharp score (mTSS), which is conventionally used to evaluate joint destruction of the hands and feet, should ideally be automated because the required time depends on the skill of the evaluator, and there is variability between evaluators. Since joint subluxation and ankylosis are given a large score in mTSS, we aimed to estimate subluxation and ankylosis using a deep neural network as a first step in developing an automatic radiographic scoring system for joint destruction. We randomly extracted 216 hand X-ray images from an electronic medical record system for the learning experiments. These images were acquired from patients who visited the rheumatology department of Keio University Hospital in 2015. Using our newly developed annotation tool, well-trained rheumatologists and radiologists labeled the mTSS to the wrist, metacarpal phalangeal joints, and proximal interphalangeal joints included in the images. We identified 21 X-ray images containing one or more subluxation joints and 42 X-ray images with ankylosis. To predict subluxation/ankylosis, we conducted five-fold cross-validation with deep neural network models: AlexNet, ResNet, DenseNet, and Vision Transformer. The best performance on wrist subluxation/ankylosis classification was as follows: accuracy, precision, recall, F1 value, and AUC were 0.97±0.01/0.89±0.04, 0.92±0.12/0.77±0.15, 0.77±0.16/0.71±0.13, 0.82±0.11/0.72±0.09, and 0.92±0.08/0.85±0.07, respectively. The classification model based on a deep neural network was trained with a relatively small dataset; however, it showed good accuracy. In conclusion, we provided data collection and model training schemes for mTSS prediction and showed an important contribution to building an automated scoring system. [ABSTRACT FROM AUTHOR]

Immunosuppressive treatment is a common cause of cytomegalovirus (CMV) reactivation. However, there is no consensus regarding the risk factors for CMV reactivation in rheumatic diseases. Therefore, this study aimed to elucidate the risk factors associated with CMV reactivation. We retrospectively collected the data of 472 patients with rheumatic diseases whose CMV pp65 antigen (C7-HRP) titer was measured. We divided the patients into those with and those without C7-HRP. We retrospectively collected data on age, sex, primary condition and organ involvement, and blood test results. We also investigated the use of immunosuppressants and the maximum and cumulative doses of prednisolone (PSL). We performed univariate and multivariate analyses to identify risk factors for CMV reactivation. Multivariate analysis showed that higher age (71.2 vs. 64.4 years, p = 0.0022), hypoalbuminemia (2.9 vs. 3.4 g/dL, p = 0.0104), higher creatinine level (1.2 vs. 0.9 mg/dL, p = 0.0026), cyclosporine use (8.2 vs. 3.6%, p = 0.0101), and higher maximum (552.4 vs. 243.3 mg, p < 0.0001) and cumulative (2785.9 vs. 1330.5 mg, p < 0.0001) doses of PSL were associated with CMV reactivation. Older age, hypoalbuminemia, higher creatinine level, cyclosporine use, and higher maximum and cumulative doses of PSL were significant risk factors for CMV reactivation in rheumatic diseases. [ABSTRACT FROM AUTHOR]

In this paper we study various dynamical aspects of the AdS/BCFT correspondence in higher dimensions. We study properties of holographic stress energy tensor by analyzing the metric perturbation in the gravity dual. We also calculate the stress energy tensor for a locally excited state on a half plane in a free scalar CFT. Both of them satisfy a reflective boundary condition that is expected for any BCFTs. We also study the behavior of the scalar field perturbation in the AdS/BCFT setup and show that they also show complete reflections. Moreover, we find that the entanglement entropy of a BCFT computed from the AdS/BCFT matched with that calculated from the Island formula, which supports the Island/BCFT correspondence in higher dimensions. Finally we show how we can calculate one point functions in a BCFT in our gravity dual. [ABSTRACT FROM AUTHOR]

Currently, no standard treatment strategy has been established for immune-mediated necrotizing myopathy (IMNM). Here we present a case of IMNM which was successfully treated with intensive combined therapy with high-dose glucocorticoids, tacrolimus, and intravenous immunoglobulins. Her muscle weakness was rapidly progressive and severe so that she became bedridden one week after admission. She was complicated with dysphagia and had serum myogenic enzymes elevation, ventricular diastolic dysfunction, and interstitial lung disease. Serum anti-SRP antibody was positive and her muscle biopsy revealed many necrotic fibers with minimal inflammation. Further histological analysis demonstrated infiltration of phagocytic macrophages with deposition of membrane attack complex (C5b-9) in the necrotic muscle fibers, suggesting activation of complement pathway and macrophages as a pathomechanism of this disease. She was diagnosed as IMNM and was immediately initiated a combination therapy described above, which led to dramatic clinical improvements. Recent studies suggest that intravenous immunoglobulins and tacrolimus can inhibit the activation of complement pathway and macrophages. Our present case suggests that early initiation of intensive combined therapy including intravenous immunoglobulins and tacrolimus might be effective for preventing irreversible muscle damages by disrupting a pathogenic activation of complement and macrophages in IMNM. [ABSTRACT FROM AUTHOR]

Dropped head syndrome is a rare disease entity characterized by severe weakness of the cervical para-spinal muscles, resulting in a chin-on-chest deformity. Systemic sclerosis is one of the causes of dropped head syndrome, but its characteristics and prognosis remain unclear due to the extreme rarity of this condition. We present a case of dropped head which occurred in systemic sclerosis. He presented with severe dropped head and relatively mild weakness of the proximal limb muscles. Serum level of creatine kinase was elevated, myopathic change was observed in electromyography, and gadolinium enhancement was found in magnetic resonance imaging of his posterior neck muscles. Anti-topoisomerase I antibody was positive, while other autoantibodies such as anti-PM/Scl and anti-Ku antibodies were negative. Since his dropped head acutely progressed, high dose of glucocorticoid therapy was initiated, which successfully improved dropped head, serum level of creatine kinase, and gadolinium enhancement in magnetic resonance imaging. Our present case and literature review suggest that dropped head occurring in systemic sclerosis can be treatable with immunosuppressive therapy. It is important to recognize this rare but treatable involvement of systemic sclerosis because early diagnosis and treatment initiation are crucial to prevent the irreversible organ damage and the significant decrease of daily activities. [ABSTRACT FROM AUTHOR]

BACKGROUND: There is a lack of studies that investigated the effect of a wide range of work environmental factors on stress and depression in Japan. OBJECTIVES: To examine the association of work environment factors with stress and depression among workers in Japan. METHODS: We conducted questionnaire surveys of workers that mainly engage in desk work in Japan. Stress was assessed through the Perceived Stress Scale (PSS), depression through the Patient Health Questionnaire-9 (PHQ-9), and work environment through physical and psychological workplace environment questionnaires. Workers were divided into low and high stress groups based on PSS score (median split), and divided into non-depressed and depressed groups based on their PHQ-9 score (< 5, and ≥5); these groups were then compared with their working environment. In addition, a multiple regression analysis was performed. RESULTS: Responses were obtained from 210 subjects. Multiple regression analysis showed that "Ability to work at one's own pace" and "Ability to apply personal viewpoint to work," etc., had effect on stress, while "Workplace harassment" and "Support from colleagues," etc., had effect on depression. CONCLUSIONS: The results suggest that stress and depression in Japanese workers are related to factors such as job demands, control of work, workplace harassment, and psychological safety. [ABSTRACT FROM AUTHOR]

We discuss a field transformation from fields ψ a to other fields ϕ i that involves derivatives, |$\phi _i = \bar{\phi }_i(\psi _a, \partial _\alpha \psi _a, \ldots ;x^\mu)$|⁠ , and derive conditions for this transformation to be invertible, primarily focusing on the simplest case that the transformation maps between a pair of fields and involves up to their first derivatives. General field transformation of this type changes the number of degrees of freedom; hence, for the transformation to be invertible, it must satisfy certain degeneracy conditions so that additional degrees of freedom do not appear. Our derivation of necessary and sufficient conditions for invertible transformation is based on the method of characteristics, which is used to count the number of independent solutions of a given differential equation. As applications of the invertibility conditions, we show some non-trivial examples of the invertible field transformations with derivatives, and also give a rigorous proof that a simple extension of the disformal transformation involving a second derivative of the scalar field is not invertible. [ABSTRACT FROM AUTHOR]

The importance of workers' well-being has been recognized in recent years. The assessment of well-being has been subjective, and few studies have sought potential biomarkers of well-being to date. This study examined the relationship between well-being and the LF/HF ratio, an index of heart rate variability that reflects sympathetic and parasympathetic nerve activity. Pulse waves were measured using photoplethysmography through a web camera attached to the computer used by each participant. The participants were asked to measure their pulse waves while working for 4 weeks, and well-being was assessed using self-reported measures such as the Satisfaction With Life Scale (SWLS), the Positive and Negative Affect Schedule (PANAS), and the Flourishing Scale (FS). Each of the well-being scores were split into two groups according to the median value, and the LF/HF ratio during work, as well as the number of times an LF/HF ratio threshold was either exceeded or subceeded, were compared between the high and low SWLS, positive emotion, negative emotion, and FS groups. Furthermore, to examine the effects of the LF/HF ratio and demographic characteristics on well-being, a multiple regression analysis was conducted. Data were obtained from 169 participants. The results showed that the low FS group had a higher mean LF/HF ratio during work than the high FS group. No significant differences were seen between the high and low SWLS groups, the high and low positive emotion groups, or the high and low negative emotion groups. The multiple regression analysis showed that the mean LF/HF ratio during work affected the FS and SWLS scores, and the number of times the mean LF/HF ratio exceeded +3 SD had an effect on the positive emotion. No effect of the LF/HF ratio on negative emotions was shown. The LF/HF ratio might be applicable as an objective measure of well-being. [ABSTRACT FROM AUTHOR]

We reexamine the Israel-type proof of the uniqueness theorem of the static spacetime outside the photon surface in the Einstein-conformal scalar system. We derive in a systematic fashion a new divergence identity which plays a key role in the proof. Our divergence identity includes three parameters, allowing us to give a new proof of the uniqueness. [ABSTRACT FROM AUTHOR]

We define an attractive gravity probe surface (AGPS) as a compact 2-surface |$S_\alpha$| with positive mean curvature |$k$| satisfying |$r^a D_a k / k^2 \ge \alpha$| (for a constant |$\alpha>-1/2$|⁠) in the local inverse mean curvature flow, where |$r^a D_a k$| is the derivative of |$k$| in the outward unit normal direction. For asymptotically flat spaces, any AGPS is proved to satisfy the areal inequality |$A_\alpha \le 4\pi [ (3+4\alpha)/(1+2\alpha) ]^2(Gm)^2$|⁠ , where |$A_{\alpha}$| is the area of |$S_\alpha$| and |$m$| is the Arnowitt–Deser–Misner mass. Equality is realized when the space is isometric to the |$t=$| constant hypersurface of the Schwarzschild spacetime and |$S_\alpha$| is an |$r=\mathrm{constant}$| surface with |$r^a D_a k / k^2 = \alpha$|⁠. We adapt the two methods of the inverse mean curvature flow and the conformal flow. Therefore, our result is applicable to the case where |$S_\alpha$| has multiple components. For anti-de Sitter (AdS) spaces, a similar inequality is derived, but the proof is performed only by using the inverse mean curvature flow. We also discuss the cases with asymptotically locally AdS spaces. [ABSTRACT FROM AUTHOR]

Introduction: Mental disorders are a leading cause of disability worldwide. Depression has a significant impact in the field of occupational health because it is particularly prevalent during working age. On the other hand, there are a growing number of studies on the relationship between "well-being" and employee productivity. To promote healthy and productive workplaces, this study aims to develop a technique to quantify stress and well-being in a way that does not disturb the workplace. Methods and analysis: This is a single-arm prospective observational study. The target population is adult (>20 years old) workers at companies that often engage in desk work; specifically, a person who sits in front of a computer for at least half their work hours. The following data will be collected: (a) participants' background characteristics; (b) participants' biological data during the 4-week observation period using sensing devices such as a camera built into the computer (pulse wave data extracted from the facial video images), a microphone built into their work computer (voice data), and a wristband-type wearable device (electrodermal activity data, body motion data, and body temperature); (c) stress, well-being, and depression rating scale assessment data. The analysis workflow is as follows: (1) primary analysis, comprised of using software to digitalize participants' vital information; (2) secondary analysis, comprised of examining the relationship between the quantified vital data from (1), stress, well-being, and depression; (3) tertiary analysis, comprised of generating machine learning algorithms to estimate stress, well-being, and degree of depression in relation to each set of vital data as well as multimodal vital data. Discussion: This study will evaluate digital phenotype regarding stress and well-being of white-collar workers over a 4-week period using persistently obtainable biomarkers such as heart rate, acoustic characteristics, body motion, and electrodermal activity. Eventually, this study will lead to the development of a machine learning algorithm to determine people's optimal levels of stress and well-being. Ethics and dissemination: Collected data and study results will be disseminated widely through conference presentations, journal publications, and/or mass media. The summarized results of our overall analysis will be supplied to participants. Registration: UMIN000036814 [ABSTRACT FROM AUTHOR]

We examine the de Sitter entropy in the braneworld model with the Gauss–Bonnet/Lovelock terms. We find that the de Sitter entropy computed through the Euclidean action exactly coincides with the holographic entanglement entropy. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) involvement, including encephalopathy, encephalitis, leptomeningitis, and pachymeningitis, in rheumatoid arthritis (RA) is rather rare. We report the case of a 61-year-old female with a history of RA in remission for 7 years, who presented with numbness, weakness of the left upper limb, dysarthria, and headache. Magnetic resonance imaging (MRI) of the brain showed meningeal enhancement in the frontal, parietal, and temporal lobes. Cerebrospinal fluid (CSF) examination detected high levels of both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA), with a high ACPA-immunoglobulin G index (> 2.0). She was diagnosed with rheumatoid meningitis. Following combined therapy with oral prednisolone and intravenous infusion of cyclophosphamide, her symptoms promptly improved. After treatment, RF and ACPA levels in the CSF were reduced, and MRI showed improvement of the meningeal structures. This case, along with existing literature, suggests that the ACPA level in the CSF may serve as a useful marker for diagnosing of CNS involvement in RA, as well as an index of effectiveness of the associated treatment. [ABSTRACT FROM AUTHOR]

The authors regret that the original published version of the above article contained errors. The authors requested that these be noted. [ABSTRACT FROM AUTHOR]

Here we present our case of severe COVID-19 in dermatomyositis, in which chest computed tomography was examined before COVID-19 pneumonia, at the time of COVID-19 pneumonia, and at 4 months after surviving COVID-19 pneumonia. COVID-19 pneumonia can cause irreversible lung damage in dermatomyositis with pre-existing interstitial lung disease Considering the similarities of lung lesions in anti-MDA5 antibody-positive dermatomyositis to COVID-19 pneumonia,4 we suggest that viral infection may be one of the environmental factors that cause irreversible interstitial lung disease of dermatomyositis in susceptible individuals. [Extracted from the article]

Tocilizumab (TCZ) is a humanized antihuman interleukin-6 (IL-6) receptor antibody used for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). While TCZ could act as a therapeutic agent, it has a potential for inducing adverse drug events including psoriasis-like eruption. Seven cases with specific reference to TCZ-induced psoriasis eruption have been reported worldwide so far. In these cases, treatments with the same dosage of TCZ were either maintained or discontinued. Herein, we report a case involving a 74-year-old man diagnosed with rheumatoid factor-positive and anti-citrullinated protein antibody-positive RA with comorbidity of atopic dermatitis. TCZ was administered intravenously with oral methotrexate. After the third infusion, the patient developed TCZ-induced psoriasis-like eruptions, which were resolved by shortening the dose interval. Eruption recurrence was not observed after frequent TCZ subcutaneous injection. Our case may help physicians manage TCZ-induced psoriasis-like eruption. [ABSTRACT FROM AUTHOR]

Objective: To explore the baseline predictors of clinical effectiveness after tocilizumab or infliximab treatment in biologic-naïve rheumatoid arthritis patients. Methods: Consecutive biologic-naïve patients with rheumatoid arthritis initiating infliximab (n = 57) or tocilizumab (n = 70) treatment were included in our prospective cohort study. Our cohort started in February 2010, and the patients observed for at least 1 year as of April 2013 were analysed. We assessed baseline variables including patients' characteristics (age, sex, disease duration, prednisolone dose, methotrexate dose, other disease-modifying antirheumatic drug use, Clinical Disease Activity Index [CDAI]) and serum biomarker levels (C-reactive protein, immunoglobulin M-rheumatoid factor, anti-cyclic citrullinated protein/peptide antibodies, interferon-γ, interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10, IL-17, tumor necrosis factor-α, soluble intercellular adhesion molecule-1, bone alkaline phosphatase, osteonectin, osteopontin) to extract factors associated with clinical remission (CDAI≤2.8) at 1 year using univariate analyses, and the extracted factors were entered into a multivariate logistic regression model. Similar analyses were also performed for Simplified Disease Activity Index (SDAI) remission (≤3.3) and Disease Activity Score with 28 joint counts, erythrocyte sedimentation rate (DAS28-ESR) remission (<2.6). Results: There were no significant differences in the baseline characteristics except for methotrexate use between the groups. In the multivariate analyses, the low baseline osteopontin levels (OR 0.9145, 95% CI 0.8399–0.9857) were identified as predictors of CDAI remission in the tocilizumab group, whereas no predictors of CDAI remission were found in the infliximab group. Similar results were obtained when using SDAI and DAS28-ESR remission criteria. Conclusion: Baseline low serum osteopontin levels predict clinical remission 1 year after tocilizumab treatment and not infliximab treatment in biologic-naïve patients with rheumatoid arthritis. Our prediction model provided insights into how to optimize the choice of biologics and warrants external validation in other cohorts. [ABSTRACT FROM AUTHOR]

The Dvali-Gabadadze-Porrati brane-world model provides a possible approach to address the late-time cosmic acceleration. However, it has subsequently been pointed out that a ghost instability will arise on the self-accelerating branch. Here, we carefully investigate whether this ghost problem could be possibly cured by introducing the Gauss-Bonnet term in the five-dimensional bulk action, a natural generalization to the Dvali-Gabadadze-Porrati model. Our analysis is carried out for a background where a de Sitter brane is embedded in an anti-de Sitter bulk. Our result shows that the ghost excitations cannot be avoided even in this modified model. [ABSTRACT FROM AUTHOR]

Objectives. To explore the effectiveness and safety of tocilizumab (TCZ) with or without methotrexate (MTX) in active rheumatoid arthritis (RA) patients showing inadequate responses to DMARDs and/or TNF inhibitors in clinical practice. Methods. We observed consecutive 115 RA patients initiating TCZ treatment in Keio University Hospital, dividing them into two groups with (TCZ + MTX group) or without MTX (TCZ group), and evaluated clinical, functional and structural outcomes besides safety at week 52. Results. Overall mean age, RA duration, and DAS28-ESR were 55.4, 8.4 years, and 5.0, respectively. Proportions of the prior use of TNF inhibitors and concomitant MTX were 45.5% and 57.4%, respectively. Mean dose of concomitant MTX was 8.4 mg/week. Baseline characteristics were comparable between the groups. TCZ improved disease activity measured by DAS28-ESR to 2.1 at week 52 overall, without significant difference between the groups. Clinical (DAS28-ESR < 2.6), functional (HAQ-DI ≤ 0.5), and structural (ΔTSS ≤ 0.5) remission rates in the TCZ group and the TCZ + MTX group were 79.1%/63.8% ( P = 0.10), 62.8%/54.4% ( P = 0.40), and 70.0%/53.8% ( P = 0.61), respectively. Retention rates were 81.0% in the TCZ + MTX group and 88.5% in the TCZ group ( P = 0.47). The rate of serious adverse events was comparable between the groups. Conclusions. TCZ was clinically, functionally, and radiographically effective and safe either with or without low-dose MTX. [ABSTRACT FROM AUTHOR]

Epidemiologic studies have found that obesity is associated with malignant grade and mortality in prostate cancer. Several adipokines have been implicated as putative mediating factors between obesity and prostate cancer. Fatty acid binding protein 4 (FABP4), a member of the cytoplasmic fatty acid binding protein multigene family, was recently identified as a novel adipokine. Although FABP4 is released from adipocytes and mean circulating concentrations of FABP4 are linked with obesity, effects of exogenous FABP4 on prostate cancer progression are unclear. In this study, we examined the effects of exogenous FABP4 on human prostate cancer cell progression. FABP4 treatment promoted serum-induced prostate cancer cell invasion in vitro. Furthermore, oleic acid promoted prostate cancer cell invasion only if FABP4 was present in the medium. These promoting effects were reduced by FABP4 inhibitor, which inhibits FABP4 binding to fatty acids. Immunostaining for FABP4 showed that exogenous FABP4 was taken up into DU145 cells in three-dimensional culture. In mice, treatment with FABP4 inhibitor reduced the subcutaneous growth and lung metastasis of prostate cancer cells. Immunohistochemical analysis showed that the number of apoptotic cells, positive for cleaved caspase-3 and cleaved PARP, was increased in subcutaneous tumors of FABP4 inhibitor-treated mice, as compared with control mice. These results suggest that exogenous FABP4 might promote human prostate cancer cell progression by binding with fatty acids. Additionally, exogenous FABP4 activated the PI3K/Akt pathway, independently of binding to fatty acids. Thus, FABP4 might be a key molecule to understand the mechanisms underlying the obesity-prostate cancer progression link. [ABSTRACT FROM AUTHOR]

Background: Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease. Methods: C57BL/6 wild-type (WT) and SP-D-/- mice (C57BL/6 background) were chronically challenged with house dust mite antigen (Dermatophagoides pteronyssinus, Dp). Studies with SP-D rescue and neutralization of TGF-β were conducted. Lung histopathology and the concentrations of collagen, growth factors, and cytokines present in the airspace and lung tissue were determined. Cultured eosinophils were stimulated by Dp in presence or absence of SP-D. Results: Dp-challenged SP-D-/- mice demonstrate increased sub-epithelial fibrosis, collagen production, eosinophil infiltration, TGF-β1, and IL-13 production, when compared to Dp-challenged WT mice. By immunohistology, we detected an increase in TGF-β1 and IL-13 positive eosinophils in SP-D-/- mice. Purified eosinophils stimulated with Dp produced TGF-β1 and IL-13, which was prevented by co-incubation with SP-D. Additionally, treatment of Dp challenged SP-D-/- mice with exogenous SP-D was able to rescue the phenotypes observed in SP-D-/- mice and neutralization of TGF-β1 reduced sub-epithelial fibrosis in Dp-challenged SP-D-/- mice. Conclusion: These data support a protective role for SP-D in the pathogenesis of sub-epithelial fibrosis in a mouse model of allergic inflammation through regulation of eosinophil-derived TGF-β. [ABSTRACT FROM AUTHOR]

Background and Aim The chemopreventive effect of RAS inhibitors on colorectal cancer is unknown. Because aberrant crypt foci ( ACF), earliest preneoplastic lesions, are highly positive for K- RAS mutation, RAS inhibitors are likely to be effective for chemoprevention. Therefore, in the present study, the suppressive effect of a RAS inhibitor, manumycin A, on ACF formation in an azoxymethane ( AOM)-induced rat colorectal carcinogenesis model was investigated. Methods Rats injected with AOM were administered manumycin A (30 mg/kg) subcutaneously thrice weekly for 8 weeks or for 4 weeks (latter half), sacrificed at 8 weeks, and examined for ACF in the colorectum. Phosphorylated ERK and Ki-67 expression was evaluated by immunohistochemistry. Apoptosis was assessed by TUNEL staining. Results The mean number of ACF in the 8-week manumycin A group (72.9 ± 20.1) was significantly lower than in the vehicle group (155.6 ± 56.7, P < 0.01), and it was significantly lower even in the 4-week manumycin A group than in the vehicle group (92.2 ± 13.0 vs 222.3 ± 83.3, P < 0.01). The positive rate for phosphorylated ERK in the manumycin A group (13.5 ± 19.2%) was significantly lower than in the vehicle group (50.2 ± 19.8%, P < 0.01). The positive rate for Ki-67 in the manumycin A group (2.2 ± 3.4%) was significantly lower than in the vehicle group (14.7 ± 8.2%, P < 0.01). There were significantly more terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive cells in tissue samples from the manumycin A group versus the vehicle group (8.6 ± 9.7% vs 2.9 ± 2.0%, P < 0.05). Conclusion Manumycin A suppressed ACF formation in the AOM-induced colorectal carcinogenesis model, demonstrating that RAS inhibitors may be very effective for chemoprevention of colorectal cancers. [ABSTRACT FROM AUTHOR]

We study the Cauchy problem in a special case of nonlinear massive gravity. Despite being ghost free, it has recently been argued that the theory is inherently problematic due to the existence of superluminal shock waves. Furthermore, it is claimed that an acausal characteristic can arise for any choice of background. In order to further understand the causal structure of the theory, we carefully perform a detailed analysis of the characteristic equations and show that the theory does admit a well-posed Cauchy problem, i.e., there exists hypersurfaces that are not a characteristic hypersurface. Puzzles remain regarding the existence of a superluminal propagating mode in both the minimal ghost-free theory that we analyzed, as well as in the full nonlinear massive gravity. That is, our result should not be taken as any indication of the healthiness of the theory. We also give a detailed review of Cauchy–Kovalevskaya theorem and its application in the appendix, which should be useful for investigating causal structures of other theories of gravity. [ABSTRACT FROM AUTHOR]

The irradiation of fat-containing food forms 2-dodecylcyclobutanone (2-DCB) from palmitic acid (PA). In this study, we investigated whether 2-DCB and PA induce apoptosis in human lymphoma U937 cells. We found that cell viability decreased by 2-DCB and apoptosis was induced by 2-DCB and PA. 2-DCB and PA significantly enhanced the formation of intracellular reactive oxygen species (ROS). Apoptosis induced by 2-DCB and PA was strongly prevented by an antioxidant, N-acetyl- l-cysteine. The treatment with 2-DCB and PA resulted in the loss of mitochondrial membrane potential, and Fas, caspase-8 and caspase-3 activation. Pretreatment with a pan-caspase inhibitor (z-VAD) significantly inhibited apoptosis induced by 2-DCB and PA. Moreover, 2-DCB and PA also induced Bax up-regulation, the reduction in Bcl-2 expression level, Bid cleavage and the release of cytochrome c from the mitochondria to the cytosol. In addition, an increase in intracellular Ca concentration ([Ca]) was observed after the treatment with 2-DCB and PA. Our results indicated that intracellular ROS generation, the modulation of the Fas-mitochondrion-caspase-dependent pathway and the increase in [Ca] involved in apoptosis are induced by 2-DCB and PA in U937 cells. [ABSTRACT FROM AUTHOR]

Balamuthia mandrillaris is a free-living ameba that causes amebic encephalitis. Herein, we report an autopsy case of Balamuthia encephalitis proven with polymerase chain reaction (PCR) and immunohistochemistry from paraffin-embedded brain biopsy specimens. A 68-year-old Japanese male presented at a hospital with progressive right hemiparesis approximately 3 months before his death. An open-brain biopsy specimen showed diffuse meningitis with massive coagulative necrosis. The perivascular spaces contained numerous lymphocytes, histiocytes and giant cells, although the etiology was not determined. The patient deteriorated into coma and died from cerebral herniation. Autopsy revealed abundant trophozoites and cysts in the subarachnoid and Virchow-Robin's spaces. Electron-micrographs of the amebic cysts showed a characteristic triple-walled envelope. The amebas were identified as Balamuthia mandrillaris based on immunohistochemical analysis from the autopsy and biopsy specimens. Primer sets designed to amplify approximately 200 bp bands of mitochondrial 16S rRNA gene of Balamuthia by PCR produced positive results from the biopsy specimens but negative results from the autopsy specimens. In summary, PCR to amplify shorter segments of DNA may be of diagnostic value in detecting suspected cases of balamuthiasis in formalin-fixed, paraffin-embedded specimens. Increased awareness and timely diagnosis of Balamuthia encephalitis might lead to earlier initiation of therapy and improved outcome. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF) inhibitors have produced improvements in clinical, radiographic, and functional outcomes in rheumatoid arthritis (RA) patients. However, it remains unclear whether factors affecting physical functions remain following TNF therapy. The objective of our study was to assess factors affecting improvement of physical functions and to shed light on relations to disease activity and structural changes in patients with RA treated with etanercept. The study enrolled 208 patients, all of whose composite measures regarding clinical, radiographic, and functional estimation both at 0 and 52 weeks after etanercept therapy were completed. Mean disease duration of 208 patients was 9.6 years, mean Disease Activity Score for 28 joints (DAS28) was 5.4, and mean van der Heijde modified total Sharp score (mTSS) was 94.6. Mean Health Assessment Questionnaire Disability Index (HAQ-DI) improved from 1.4 at 0 weeks to 1.0 at 52 weeks after etanercept therapy, a 31% reduction, which was much less than changes in DAS28 and mTSS. By multivariate analysis, HAQ-DI and mTSS at baseline were significantly correlated HAQ remission. Median HAQ-DI improved in 100 versus 20% of the HAQ-DI ≤0.6 versus ≥2.0 groups, respectively. The mTSS cutoff point at baseline to obtain HAQ remission was 55.5. During etanercept treatment in the mTSS <55.5 versus >55.5 groups, median HAQ-DI improved in 70 versus 39%; remission was achieved in 59 versus 33%; and there was no improvement in14 versus 30%, respectively. HAQ-DI improvement was significantly correlated with that of DAS28 but not of mTSS. In conclusion, higher HAQ and mTSS at baseline inhibits HAQ-DI improvement within 1 year of etanercept treatment, and the cutoff point necessary for mTSS to improve physical functions in patients with RA was 55.5. [ABSTRACT FROM AUTHOR]

We previously reported monocyte-derived multipotential cells (MOMCs), which include progenitors capable of differentiating into a variety of mesenchymal cells and endothelial cells. In vitro generation of MOMCs from circulating CD14+ monocytes requires their binding to extracellular matrix (ECM) protein and exposure to soluble factor(s) derived from circulating CD14- cells. Here, we investigated the molecular factors involved in MOMC generation by examining the binding of monocytes to ECM proteins.We found that MOMCs were obtained on the fibronectin, but not on type I collagen, laminin, or poly-L-lysine. MOMC generation was followed by changes in the expression profiles of transcription factors and was completely inhibited by either anti- α5 integrin antibody or a synthetic peptide that competed with the RGD domain for the β1-integrin binding site. These results indicate that acquisition of the multidifferentiation potential by circulating monocytes depends on their binding to the RGD domain of fibronectin via cell-surface α5β1 integrin. [ABSTRACT FROM AUTHOR]

Background: Diagnosis of triple-negative breast cancer (ER-negative, PgR-negative, HER2-negative; TNBC) is performed by means of immunohistological staining. HER2-negative includes HER2(0) and HER2(1+), based on differences in the staining intensity, but there have been no reports on comparison of these two types in TNBC. Accordingly, this study was designed to investigate the possible differences in the biological characteristics of HER2(0) breast cancer and HER2(1+) breast cancer in TNBC. Methods: Tissue specimens from 89 TNBC patients were immunohistochemically stained for CK5/6, EGFR, p53, Ki67, E-cadherin, TOP2A and Bcl-2. The expressions of these markers and the clinicopathological findings were compared between the HER2(0) patient group and the HER2(1+) patient group. When either CK5/6 or EGFR was positive, the specimen was judged to be the basal-like phenotype of breast cancer. Results: The percentages of CK5/6- and/or EGFR-positive specimens in the HER2(0) and HER2(1+) groups were 44.9 and 16.8%, respectively, showing that there was a significantly greater number of basal-like phenotype patients in the HER2(0) group ( p < 0.01). The percentage of E-cadherin-positive specimens in the HER2(0) group was 66.6%, which was significantly greater than the 40.0% recorded in the HER2(1+) group ( p < 0.05). The respective percentages of TOP2A-positive specimens in the HER2(0) and HER2(1+) groups were 55.0 and 30.0%, and the difference was statistically significant ( p < 0.05). Conclusion: In TNBC, HER2(0) breast cancer showed a strong tendency to include more of the basal-like phenotype compared with HER2(1+) breast cancer. The staining results indicated the possibility that HER2(0) breast cancer and HER2(1+) breast cancer have different characteristics. [ABSTRACT FROM AUTHOR]

Bone metastasis is a frequent complication of advanced breast cancer. On the basis of functional and molecular evidence, signaling mediated by the binding of platelet-derived growth factor (PDGF)-BB and -DD to PDGF receptor β (PDGFRβ) is critical for the survival and growth of metastatic breast cancer cells within the bone microenvironment. In this study, we propose a new approach to blocking PDGFRβ signaling using soluble PDGFRβ (sPDGFRβ) as a decoy receptor for PDGF-BB and -DD secreted from tumor cells and bone marrow stromal cells. A bone-seeking TNBCT/Bo cell line was established by in vivo selection from TNBCT human breast cancer cells, which are negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 protein expression. The TNBCT/Bo cells were transfected with a mammalian expression vector encoding the extracellular domain of PDGFRβ. A stable transfectant (TNBCT/Bo-sPDGFRβ) grew at a similar rate to that of control cells under normal culture conditions, although growth stimulation of human fibroblasts with PDGF-BB was neutralized by the culture medium from TNBCT/Bo-sPDGFRβ cells. Intratibial injection of TNBCT/Bo-sPDGFRβ cells into athymic nude mice resulted in a significant decrease in tumor incidence compared with control mice ( P < 0.01). This attenuated growth correlated with decreased cancer cell proliferation, angiogenesis, and recruitment of stromal cells, and with an increase in the number of apoptotic cells. These findings suggest that sPDGFRβ is useful for the treatment of breast cancer bone metastasis. ( Cancer Sci 2011; 102: 1904-1910) [ABSTRACT FROM AUTHOR]

Controlled proteolytic degradation of specialized junctional structures, corneodesmosomes, by epidermal proteases is an essential process for physiological desquamation of the skin. Corneodesmosin (CDSN) is an extracellular component of corneodesmosomes and, although considerable debate still exists, genetic studies have suggested that the CDSN gene in the major psoriasis-susceptibility locus (PSORS1) may be responsible for susceptibility to psoriasis, a human skin disorder characterized by excessive growth and aberrant differentiation of keratinocytes. CDSN is also expressed in the inner root sheath of hair follicles, and a heterozygous nonsense mutation of the CDSN gene in humans is associated with scalp-specific hair loss of poorly defined etiology. Here, we have investigated the pathogenetic roles of CDSN loss of function in the development of skin diseases by generating a mouse strain with targeted deletion of the Cdsn gene. Cdsn-deficient mouse skin showed detachment of the stratum corneum from the underlying granular layer and/or detachment within the upper granular layers due to the disrupted integrity of the corneodesmosomes. When grafted onto immunodeficient mice, Cdsn-deficient skin showed rapid hair loss together with epidermal abnormalities resembling psoriasis. These results underscore the essential roles of CDSN in hair physiology and suggest functional relevance of CDSN gene polymorphisms to psoriasis susceptibility. [ABSTRACT FROM AUTHOR]

Glucose homeostasis is believed to be regulated by multiple genetic components, in addition to numerous external factors. It is therefore crucial to dissect and understand what roles each causative gene plays in maintaining proper glucose metabolism. In OLETF (Otsuka Long-Evans Tokushima Fatty) rat, a model of polygenic type 2 diabetes, at least 14 quantitative trait loci (QTLs) influencing plasma glucose levels were identified. In congenic strains some of the OLETF allelic variants were shown to increase glucose levels. In this study the focus was on two of the hyperglycemic loci, Nidd1/of and Nidd2/of. Congenic rats possessing OLETF genome fragment at either locus showed similar levels of mild hyperglycemia. A newly established double congenic rat showed a further aggravation of hyperglycemia. The Nidd1/of locus was also shown to function in the reduction of plasma leptin levels and fat weights, while the Nidd2/of locus led to increased plasma insulin and fat weights. Interestingly, both plasma leptin and fat weights reverted to the control levels in the double congenic rat. These results indicate that there is an epistatic interaction between the two loci. However, it is unlikely that the abnormal level of enhanced glucose homeostasis is mediated, at least not directly, by leptin or fat mass. [ABSTRACT FROM AUTHOR]

Rationale: IkappaB kinase-beta is a critical regulator in the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor related to the expression and regulation of proinflammatory cytokines.Objective: To evaluate if inhibition of IkappaB kinase-beta ameliorates pneumonitis and pulmonary fibrosis.Methods: We examined whether a novel IkappaB kinase-beta inhibitor, IMD-0354, attenuates bleomycin-induced pulmonary fibrosis in mice.Measurements and Main Results: Administration of IMD-0354 significantly improved the loss of body weight and survival of mice treated with bleomycin, whereas IMD-0354 alone did not cause any morphologic change in the lung. When mice were evaluated 28 d after bleomycin administration, IMD-0354 dose-dependently reduced the collagen content and fibrotic scores as shown by histologic examination. The findings in the bronchoalveolar lavage demonstrated that the proportions of neutrophils and lymphocytes were decreased in mice treated with IMD-0354 on Day 7 and 14, respectively. IMD-0354 treatment was confirmed to inhibit the activation of NF-kappaB, but not activator protein-1, in the lungs treated with bleomycin. The production of inflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta was reduced in the lungs of mice treated with IMD-0354.Conclusions: These results suggest that IMD-0354 might be useful to ameliorate the inflammation in the lungs induced by fibrotic injury and the subsequent fibrogenesis via inhibiting the expression of profibrotic cytokines related to the activation of NF-kappaB. [ABSTRACT FROM AUTHOR]