Comparing the safety and efficacy of nintedanib starting dose in patients with connective tissue disease-associated interstitial lung diseases.

OBJECTIVE: This study aimed to analyse whether initiating nintedanib treatment at a reduced dose could improve the treatment continuation rate while maintaining efficacy in patients with connective tissue disease (CTD)-associated interstitial lung disease. METHOD: In total, 51 patients (age 61.6 ± 13.2 years; 38 women, 13 men) were retrospectively analysed. The primary endpoint was the cumulative discontinuation rate due to adverse events. Secondary endpoints included changes in drug dosage, efficacy evaluated based on annual changes in forced vital capacity (FVC), and safety assessed based on the frequency of adverse events. RESULTS: Eighteen patients who started treatment at the standard dose of 300 mg (standard dosage group) were compared with 33 patients who started treatment at a reduced dose (reduced dosage group). Systemic sclerosis was the most common CTD (n = 32), followed by idiopathic inflammatory myopathies and, rarely, rheumatoid arthritis. Both groups exhibited comparable cumulative discontinuation rates due to adverse events and similar frequencies of adverse events. No significant differences were observed in maintenance doses between the two groups; however, patients in the reduced dosage group had a lower cumulative dose for up to 52 weeks than those in the standard dosage group. No significant differences were observed in changes in FVC between the two groups. CONCLUSION: There was no evidence for a difference between the two groups in terms of discontinuation rates, efficacy, and safety. To provide further evidence, future studies using more precise dose-escalation protocols are warranted.

Contrast-enhanced CT rim sign may predict vestibular schwannoma adhesion and postoperative complications.

AIM: To investigate the clinical and radiological features to predict adhesion between vestibular schwannoma (VS) and brain tissue which is a critical risk factor for postoperative infarction and residual tumour. MATERIAL AND METHODS: One hundred and seven consecutive VS surgeries were analysed. After excluding cases without contrast-enhanced (CE) computed tomography (CT), Koos grades 1 and 2, and cases with incomplete clinical data, 44 patients were finally included in the study. Enhancement of the tumour capsule on the brainstem side on CE-CT was defined as the CE-CT rim sign, which was analysed along with clinical characteristics, including tumour adhesion and postoperative complications. RESULTS: Eight patients exhibited CE-CT rim signs; 17 had tumour adhesions. Four patients had postoperative infarction at the ipsilateral middle cerebellar peduncle; 18 exhibited postoperative infarction and/or residual tumour at the middle cerebellar peduncle. The CE-CT rim sign significantly correlated with tumour adhesion, postoperative infarction, and postoperative infarction and/or residual tumour in the cerebellar peduncle. Univariate regression analysis revealed that the CE-CT rim sign significantly correlated with tumour adhesion (odds ratio [OR] 6.81, 95% confidence interval [CI] 1.18-39.25, p=0.032) and postoperative infarction and/or residual tumour at the cerebellar peduncle (OR 6.00, 95% CI 1.04-34.31, p=0.044). CONCLUSION: The CE-CT rim sign was identified in 18.2% of patients with VS and significantly correlated with tumour adhesion and postoperative complications, such as postoperative infarction and residual tumour. This study highlights the importance of the preoperative CE-CT rim sign in VS, which is predictive of tumour adhesion and postoperative complications.

Association between habitual hot spring bathing and depression in Japanese older adults: A retrospective study in Beppu.

OBJECTIVES: Thermal therapy is used to manage various psychological diseases, such as depression. We investigated the relationship between hot spring bathing and depression in older adults using questionnaire responses. DESIGN AND SETTING: We comprehensively evaluated the preventive effects of long-term hot spring bathing in 10429 adults aged ≥ 65 years in Beppu, Japan, by conducting a questionnaire study on the prevalence of depression (n = 219). MAIN OUTCOME MEASURES: Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a multivariable logistic regression model for history of depression. RESULTS: A separate multivariable logistic regression model for inference showed that female sex (OR, 1.56; 95 % CI, 1.17-2.08; p = 0.002), arrhythmia (OR, 1.73; 95 % CI, 1.18-2.52; p = 0.004), hyperlipidemia (OR, 1.63; 95 % CI, 1.14-2.32; p = 0.006), renal disease (OR, 2.26; 95 % CI, 1.36-3.75; p = 0.001), collagen disease (OR, 2.72; 95 % CI, 1.48-5.02; p = 0.001), allergy (OR, 1.97; 95 % CI, 1.27-3.04; p = 0.002), and habitual daily hot spring bathing (OR, 0.63; 95 % CI, 0.41-0.94; p = 0.027) were independently significantly associated with a history of depression. CONCLUSIONS: We found an inverse relationship between habitual daily hot spring bathing and history of depression. Prospective randomized controlled trials on habitual daily hot spring bathing as a treatment for depression are warranted to investigate whether the use of hot springs can provide relief to those with psychiatric and mental health disorders.

Generation of a novel CD30+ B cell subset producing GM-CSF and its possible link to the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is a T helper type 2 (Th2)-associated autoimmune disease characterized by vasculopathy and fibrosis. Efficacy of B cell depletion therapy underscores antibody-independent functions of B cells in SSc. A recent study showed that the Th2 cytokine interleukin (IL)-4 induces granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector B cells (GM-Beffs ) in humans. In this study, we sought to elucidate the generation mechanism of GM-Beffs and also determine a role of this subset in SSc. Among Th-associated cytokines, IL-4 most significantly facilitated the generation of GM-Beffs within memory B cells in healthy controls (HCs). In addition, the profibrotic cytokine transforming growth factor (TGF)-ß further potentiated IL-4- and IL-13-induced GM-Beffs . Of note, tofacitinib, a Janus kinase (JAK) inhibitor, inhibited the expression of GM-CSF mRNA and protein in memory B cells induced by IL-4, but not by TGF-ß. GM-Beffs were enriched within CD20+ CD30+ CD38-/low cells, a distinct population from plasmablasts, suggesting that GM-Beffs exert antibody-independent functions. GM-Beffs were also enriched in a CD30+ fraction of freshly isolated B cells. GM-Beffs generated under Th2 conditions facilitated the differentiation from CD14+ monocytes to DC-SIGN+ CD1a+ CD14- CD86+ cells, which significantly promoted the proliferation of naive T cells. CD30+ GM-Beffs were more pronounced in patients with SSc than in HCs. A subpopulation of SSc patients with the diffuse type and concomitant interstitial lung disease exhibited high numbers of GM-Beffs . Together, these findings suggest that human GM-Beffs are enriched in a CD30+ B cell subset and play a role in the pathogenesis of SSc.

Functional analysis of a novel G87V TNFRSF1A mutation in patients with TNF receptor-associated periodic syndrome.

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease that is caused by heterozygous mutations in the TNFRSF1A gene. Although more than 150 TNFRSF1A mutations have been reported to be associated with TRAPS phenotypes only a few, such as p.Thr79Met (T79M) and cysteine mutations, have been functionally analyzed. We identified two TRAPS patients in one family harboring a novel p.Gly87Val (G87V) mutation in addition to a p.Thr90Ile (T90I) mutation in TNFRSF1A. In this study, we examined the functional features of this novel G87V mutation. In-vitro analyses using mutant TNF receptor 1 (TNF-R1)-over-expressing cells demonstrated that this mutation alters the expression and function of TNF-R1 similar to that with the previously identified pathogenic T79M mutation. Specifically, cell surface expression of the mutant TNF-R1 in transfected cells was inhibited with both G87V and T79M mutations, whereas the T90I mutation did not affect this. Moreover, peripheral blood mononuclear cells (PBMCs) from TRAPS patients harboring the G87V and T90I mutations showed increased mitochondrial reactive oxygen species (ROS). Furthermore, the effect of various Toll-like receptor (TLR) ligands on inflammatory responses was explored, revealing that PBMCs from TRAPS patients are hyper-responsive to TLR-2 and TLR-4 ligands and that interleukin (IL)-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) are likely to be involved in the pathogenesis of TRAPS. These findings suggest that the newly identified G87V mutation is one of the causative mutations of TRAPS. Our findings based on unique TRAPS-associated mutations provide novel insight for clearer understanding of inflammatory responses, which would be basic findings of developing a new therapeutic and prophylactic approach to TRAPS.

Correction: Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis.

Owing to the insufficient specificity of the anti-myeloproliferative leukemia protein (MPL) antibody in the original version of this Article, Figure 6 and parts of Figures 2a, 4e, and 5a do not represent the correct information. The corrected version of Figure 6 is in this correction and those of Figures 2a, 4e, and 5a are shown in the supplemental information.

Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis.

Myelofibrosis (MF) may be caused by various pathogenic mechanisms such as elevation in circulating cytokine levels, cellular interactions and genetic mutations. However, the underlying mechanism of MF still remains unknown. Recent studies have revealed that fibrocytes, the spindle-shaped fibroblast-like hematopoietic cells, and the thrombopoietin (TPO)/myeloproliferative leukemia protein (MPL; TPO receptor) signaling pathway play a certain role in the development of MF. In the present study, we aimed to investigate the relationship between fibrocytes and MPL activation. We showed that TPO or a TPO receptor agonist directly induces fibrocyte differentiation using murine fibrocyte cell lines and a murine MF model. Conversely, elimination of macrophages expressing MPL by clodronate liposomes reversed the MF phenotype of the murine model, suggesting that fibrocyte differentiation induced by MPL activation contributes to the progression of MF. Furthermore, we revealed that SLAMF7high MPLhigh monocytes in human peripheral blood mononuclear cells were possible fibrocyte precursors and that these cells increased in number in MF patients not treated with ruxolitinib. Our findings confirmed a link between fibrocytes and the TPO/MPL signaling pathway, which could result in a greater understanding of the pathogenesis of MF and lead to the development of novel therapeutic interventions.

Human adipose tissue-derived stromal cells can differentiate into megakaryocytes and platelets by secreting endogenous thrombopoietin.

UNLABELLED: Essentials Manufacturing platelets from a donor-independent source is highlighted in transfusion medicine. We examined the differentiation of adipose tissue-derived stromal cells (ASCs) into platelets. Endogenous thrombopoietin (TPO) induced ASCs differentiation into megakaryocytes and platelets. TPO secretion from ASCs was due to an interaction of transferrin with its receptor CD71. SUMMARY: Background Ex vivo production of megakaryocytes (MKs) and platelets from a donor-independent source is currently of intense interest in transfusion medicine. Adipose tissue-derived stromal cells (ASCs) constitute an attractive candidate cell source, because inducing these cells into MK lineages requires no gene transfer and only endogenous transcription factors containing p45NF-E2/Maf, an MK-inducing factor. Objectives To examine whether ASCs differentiate into MK lineages by using endogenous thrombopoietin (TPO), a primary cytokine that drives MK lineages. Methods TPO levels were measured by quantitative real-time PCR and ELISA. To investigate the effects of endogenous TPO on MK and platelet production, surface marker expression and functions for platelets were analyzed in ASC-derived cells cultured in the presence or absence of recombinant TPO. Based on a screening test, the role of transferrin receptor CD71 in TPO production and MK differentiation was examined with anti-CD71 antibody, small interfering RNA (siRNA) against CD71 (siRNA-CD71), and CD71-positive/negative cells. Results ASCs secreted TPO during MK differentiation, and the endogenous TPO facilitated MK and platelet production from ASCs. TPO secretion from ASCs occurred in a transferrin-dependent manner. ASCs treated with anti-CD71 antibody or transfected with siRNA-CD71 produced markedly less TPO. The TPO levels and MK yield were significantly higher when CD71-positive ASCs were used than when CD71-negative ASCs were used. Conclusions CD71 might be an appropriate marker for MK progenitor cells among human ASCs, because of the higher capacity of CD71-positive cells to produce TPO and their ability to differentiate into MKs. These findings could help to establish an efficient method for platelet production.

Randomized clinical trial comparing long-term quality of life for Billroth I versus Roux-en-Y reconstruction after distal gastrectomy for gastric cancer.

BACKGROUND: Patients' quality of life (QoL) deteriorates remarkably after gastrectomy. Billroth I reconstruction following distal gastrectomy has the physiological advantage of allowing food to pass through the duodenum. It was hypothesized that Billroth I reconstruction would be superior to Roux-en-Y reconstruction in terms of long-term QoL after distal gastrectomy. This study compared two reconstructions in a multicentre prospective randomized clinical trial to identify the optimal reconstruction procedure. METHODS: Between January 2009 and September 2010, patients who underwent gastrectomy for gastric cancer were randomized during surgery to Billroth I or Roux-en-Y reconstruction. The primary endpoint was assessment of QoL using the Functional Assessment of Cancer Therapy - Gastric (FACT-Ga) questionnaire 36 months after surgery. RESULTS: A total of 122 patients were enrolled in the study, 60 to Billroth I and 62 to Roux-en-Y reconstruction. There were no differences between the two groups in terms of postoperative complications or mortality, and no significant differences in FACT-Ga total score (P = 0·496). Symptom scales such as epigastric fullness (heaviness), diarrhoea and fatigue were significantly better in the Billroth I group at 36 months after gastrectomy (heaviness, P = 0·040; diarrhoea, P = 0·046; fatigue, P = 0·029). The rate of weight loss in the third year was lower for patients in the Billroth I group (P = 0·046). CONCLUSION: The choice of anastomotic reconstruction after distal gastrectomy resulted in no difference in long-term QoL in patients with gastric cancer. REGISTRATION NUMBER: NCT01065688 (http://www.clinicaltrials.gov).

Evaluation of the extent of ground-glass opacity on high-resolution CT in patients with interstitial pneumonia associated with systemic sclerosis: comparison between quantitative and qualitative analysis.

AIM: To verify whether quantitative analysis of the extent of ground-glass opacity (GGO) on high-resolution computed tomography (HRCT) could show a stronger correlation with the therapeutic response of interstitial pneumonia (IP) associated with systemic sclerosis (SSc) compared with qualitative analysis. MATERIALS AND METHODS: Seventeen patients with IP associated with SSc received autologous peripheral blood stem cell transplantation (auto-PBSCT) and were followed up using HRCT and pulmonary function tests. Two thoracic radiologists assessed the extent of GGO on HRCT using a workstation. Therapeutic effect was assessed using the change of vital capacity (VC) and diffusing capacity of the lung for carbon monoxide (DLco) before and 12 months after PBSCT. Interobserver agreement was assessed using Spearman's rank correlation coefficient and the Bland-Altman method. Correlation with the therapeutic response between quantitative and qualitative analysis was assessed with Pearson's correlation coefficients. RESULTS: Spearman's rank correlation coefficient showed good agreement, but Bland-Altman plots showed that proportional error could be suspected. Quantitative analysis showed stronger correlation than the qualitative analysis based on the relationships between the change in extent of GGO and VC, and change in extent of GGO and DLco. CONCLUSION: Quantitative analysis of the change in extent of GGO showed stronger correlation with the therapeutic response of IP with SSc after auto-PBSCT than with the qualitative analysis.

Novel exposure system using light-emitting diodes and an optical fiber array for printing serial numbers and code marks.

Feasibility of a novel exposure system to print serial numbers and two-dimensional code marks was demonstrated. The new system used light-emitting diodes (LEDs) combined with an optical fiber matrix array as a light source. At first, as preparatory experiments, code mark patterns were printed using a prototype exposure system without using the optical fiber array but using the combination of arrayed LEDs with a central wavelength of 428 nm, spherical lenses, and rod lenses. Although the code mark patterns were successfully printed, it took too much exposure time. For this reason, bullet-type LEDs with a high power and a shorter wavelength of 405 nm were used and the optical fiber matrix array was adopted. Because the emitted light rays were efficiently taken into the fiber, and the resist sensitivity was improved, practically available short exposure time of less than 2 s was obtained.

Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of cigarette smoking and systemic lupus erythematosus in a Japanese population.

OBJECTIVES: Exposure to reactive oxygen species (ROS) through cigarette smoking is thought to contribute to the development of systemic lupus erythematosus (SLE). Metabolic enzymes are involved in ROS production. The aim of this study was to evaluate the modifying effect of metabolic polymorphisms on the association of cigarette smoking with SLE risk in a Japanese population. METHODS: We investigated the relationship of the cytochrome P450 (CYP) 1A1 rs4646903 and glutathione S-transferase (GST) M1 deletion polymorphisms to SLE risk with attention to interaction with cigarette smoking among 151 SLE cases and 421 controls in female Japanese subjects. Unconditional logistic regression was used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs), with adjustments for several covariates. RESULTS: Smokers with the CC genotype of CYP1A1 rs4646903 were significantly associated with increased risk of SLE (OR 9.72, 95% CI 2.73-34.6). Similarly, smokers with the combined CYP1A1 rs4646903/GSTM1 'at-risk' genotype were significantly associated with increased risk of SLE (OR 17.5, 95% CI 3.20-95.9). More than 60% of the excess risk for SLE in smokers with the CC genotype and smokers with the combined 'at-risk' genotype was due to an additive interaction. A lack of association of the GSTM1 genotypes with smoking was observed. CONCLUSIONS: Our results suggest that a combination of smoking and either the CYP1A1 rs4646903 genotype or the combined metabolic genotype plays an important role in SLE susceptibility in our Japanese population. Additional studies are warranted to confirm the metabolic polymorphism-smoking interaction suggested in the present study.

Evaluation of organ doses in CT examinations with an infant anthropomorphic phantom.

The aim of this study is to evaluate organ doses in infant CT examinations with multi-detector row CT scanners. Radiation doses were measured with radiophotoluminescence glass dosemeters set in various organ positions within a 1-y-old child anthropomorphic phantom and organ doses were evaluated from the measurement values. Doses for tissues or organs within the scan range were 28-36 mGy in an infant head CT, 3-11 mGy in a chest CT, 5-11 mGy in an abdominal-pelvic CT and 2-14 mGy in a cardiac CT. The doses varied by the differences in the types of CT scanners and scan parameters used at each medical facility. Compared with those for children of various ages, the doses in an infant CT protocol were found to be similar to or slightly smaller than those in a paediatric CT for 5- or 6-y-old children.