Usefulness of Computed Tomography for Evaluating the Effects of Bronchial Thermoplasty in Japanese Patients with Severe Asthma.

Background: Bronchial thermoplasty (BT) improves clinical outcomes and quality of life for patients with severe asthma and has shown sustained reductions in airway narrowing and air trapping in previous CT studies. However, there is a lack of a comprehensive analysis, including CT evaluation, of clinical outcomes in Japanese patients who have undergone BT for severe asthma. This study aimed to evaluate the impact of BT in Japanese asthma patients, with a focus on the CT metric "WA at Pi10" to assess airway disease. Methods: Twelve patients with severe persistent asthma who underwent BT were assessed using ACQ6, AQLQ, pulmonary function tests, FeNO measurement, blood sampling, and chest CT before BT and one year after the third procedure for the upper lobes. Results: The median age of the patient was 62.0 years, 7/12 (58.3%) were male, 4/12 (33.3%) used regular oral corticosteroids, and 8/12 (66.7%) received biologics. Median FEV1% was 73.6%, and median peripheral eosinophil count was 163.8/µL. After one year of BT, ACQ6 scores improved from 2.4 to 0.8 points (p = 0.007), and AQLQ scores improved from 4.3 to 5.8 points (p < 0.001). Significant improvements were also observed in asthma exacerbations, unscheduled visits due to exacerbations, FeNO, and √WA at Pi10 (p < 0.05). The baseline mucus score on the CT findings was negatively correlated with FEV1 (r = -0.688, p = 0.013) and with the maximum mid-expiratory flow rate (r = -0.631, p = 0.028), and positively correlated with the peripheral blood eosinophil count (r = -0.719, p = 0.008). Changes in √WA at Pi10 after one year were positively correlated with changes in the mucus score (r = 0.742, p = 0.007). Conclusion: This study has limitations, including its single-arm observational design and the small sample size. However, BT led to a symptomatic improvement in patients with severe asthma. The validated "√WA at Pi10" metric on CT effectively evaluated the therapeutic response in Japanese asthma patients after BT.

Pretreatment circulating MAIT cells, neutrophils, and periostin predicted the real-world response after 1-year mepolizumab treatment in asthmatics.

BACKGROUND: Mepolizumab treatment improves symptom control and quality of life and reduces exacerbations in patients with severe eosinophilic asthma. However, biomarkers that predict therapeutic effectiveness must be determined for use in precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical responsiveness to mepolizumab after 1-year treatment. METHODS: Twenty-seven patients with severe asthma were treated with mepolizumab for one year. Asthma control test scores, pulmonary function tests, fractional exhaled nitric oxide levels, and blood samples were evaluated. Additionally, we explored the role of CD69-positive mucosal-associated invariant T (MAIT) cells as a candidate biomarker for predicting treatment effectiveness by evaluating an OVA-induced asthma murine model using MR1 knockout mice, where MAIT cells were absent. RESULTS: The frequencies of CD69-positive group 1 innate lymphoid cells, group 3 innate lymphoid cells, natural killer cells, and MAIT cells decreased after mepolizumab treatment. The frequency of CD69-positive MAIT cells and neutrophils was lower and serum periostin levels were higher in responders than in non-responders. In the OVA-induced asthma murine model, CD69-positive MAIT cell count in the whole mouse lung was significantly higher than that in the control mice. Moreover, OVA-induced eosinophilic airway inflammation was exacerbated in the MAIT cell-deficient MR1 knockout mice. CONCLUSIONS: This study shows that circulating CD69-positive MAIT cells, neutrophils, and serum periostin might predict the real-world response after 1-year mepolizumab treatment. Furthermore, MAIT cells potentially have a protective role against type 2 airway inflammation.

Rationale and design of Juntendo Sarcopenia Registration to explore the predictors and prognosis of sarcopenia and frailty in the elderly in TOKYO (JUSTICE-TOKYO).

AIM: This study aimed to clarify the prevalence, predictors, and prognosis of frailty and sarcopenia in both cross-sectional and longitudinal study of the real world. METHODS: The JUSTICE-TOKYO study is a single-center, prospective observational study of elderly patients. Patients aged ≥65 years who regularly visited our center were enrolled and followed up for 4 years (n = 1042). The diagnosis of sarcopenia and frailty in the enrolled patients was based on the criteria established by the Asian Working Group for Sarcopenia and Japanese version of the Cardiovascular Health Study criteria, respectively. The primary end point is the incidence of all-cause mortality and hospitalization for treatment. The secondary end points are clinically significant bleeding, cardiovascular events, strokes, malignancies, incidence of falling, fractures, pneumonia, and the onset of new dementia cases. RESULTS: A total of 1042 patients were enrolled in this study. The mean age of the cohort at baseline was 78.2 years, with 56% being women. Among the enrolled patients, 223 (21.4%) diagnosed with sarcopenia, 172 (16.5%) exhibited frailty, and 541 (51.9%) fell into the prefrailty category. CONCLUSIONS: The JUSTICE-TOKYO study provides valuable insights into the prevalence of sarcopenia and frailty among older adult outpatients in a real-world context and contributes to measures aimed at extending healthy life expectancy. Geriatr Gerontol Int 2024; 24: 168-172.

Cross-Sectional Study on the Association between Dietary Patterns and Sarcopenia in Elderly Patients with Chronic Kidney Disease Receiving Conservative Treatment.

Sarcopenia is a poor prognostic factor in patients with chronic kidney disease (CKD). Adequate dietary patterns are important for preventing sarcopenia; however, evidence regarding the underlying association between sarcopenia and diet is insufficient. Therefore, in this study, we aimed to investigate the association between sarcopenia and dietary patterns in CKD patients receiving conservative treatment. In this cross-sectional study, 441 patients with conservative CKD were examined using the Asian Working Group for Sarcopenia diagnostic criteria. CKD was defined as an eGFR of <60 mL/min/1.73 m2 present for >3 months. The participants were divided into sarcopenia and non-sarcopenia groups, and dietary patterns were compared between the two groups using the dietary variety score, a simple dietary survey method that investigates the weekly frequency of consumption of 10 food groups. Logistic regression analysis for CKD G3 showed that female sex (odds ratio (OR): 0.166, 95% confidence interval (CI): 0.086-0.320), increased body mass index (OR: 0.663, 95% CI: 0.590-0.745), and almost daily consumption of green/yellow vegetables (OR: 0.350, 95% CI: 0.176-0.695) were positively associated with non-sarcopenia. Although further prospective studies are required, the results suggest that low frequent consumption of vegetables is associated with sarcopenia in patients with CKD.

MAP3K19 Affects TWEAK-Induced Response in Cultured Bronchial Epithelial Cells and Regulates Allergic Airway Inflammation in an Asthma Murine Model.

The mitogen-activated protein kinase (MAPK) signaling pathway is involved in the epithelial-mesenchymal transition (EMT) and asthma; however, the role of mitogen-activated protein kinase kinase kinase 19 (MAP3K19) remains uncertain. Therefore, we investigated the involvement of MAP3K19 in in vitro EMT and ovalbumin (OVA)-induced asthma murine models. The involvement of MAP3K19 in the EMT and the production of cytokines and chemokines were analyzed using a cultured bronchial epithelial cell line, BEAS-2B, in which MAP3K19 was knocked down using small interfering RNA. We also evaluated the involvement of MAP3K19 in the OVA-induced asthma murine model using Map3k19-deficient (MAP3K19-/-) mice. Transforming growth factor beta 1 (TGF-ß1) and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) induced the MAP3K19 messenger RNA (mRNA) expression in the BEAS-2B cells. The knockdown of MAP3K19 enhanced the reduction in E-cadherin mRNA and the production of regulated upon activation normal T cell express sequence (RANTES) via stimulation with TWEAK alone or with the combination of TGF-ß1 and TWEAK. Furthermore, the expression of MAP3K19 mRNA was upregulated in both the lungs and tracheas of the mice in the OVA-induced asthma murine model. The MAP3K19-/- mice exhibited worsened eosinophilic inflammation and an increased production of RANTES in the airway epithelium compared with the wild-type mice. These findings indicate that MAP3K19 suppressed the TWEAK-stimulated airway epithelial response, including adhesion factor attenuation and RANTES production, and suppressed allergic airway inflammation in an asthma mouse model, suggesting that MAP3K19 regulates allergic airway inflammation in patients with asthma.

Pretreatment Frequency of Circulating Th17 Cells and FeNO Levels Predicted the Real-World Response after 1 Year of Benralizumab Treatment in Patients with Severe Asthma.

Benralizumab treatment reduces exacerbations and improves symptom control and quality of life in patients with severe eosinophilic asthma. However, the determination of biomarkers that predict therapeutic effectiveness is required for precision medicine. Herein, we elucidated the dynamics of various parameters before and after treatment as well as patient characteristics predictive of clinical effectiveness after 1 year of benralizumab treatment in severe asthma in a real-world setting. Thirty-six patients with severe asthma were treated with benralizumab for 1 year. Lymphocyte subsets in peripheral blood samples were analyzed using flow cytometry. Treatment effectiveness was determined based on the ACT score, forced expiratory volume in 1 s (FEV1), and the number of exacerbations. Benralizumab provided symptomatic improvement in severe asthma. Benralizumab significantly decreased peripheral blood eosinophil and basophil counts and the frequencies of regulatory T cells (Tregs), and increased the frequencies of Th2 cells. To our knowledge, this is the first study to show benralizumab treatment increasing circulating Th2 cells and decreasing circulating Tregs. Finally, the ROC curve to discriminate patients who achieved clinical effectiveness of benralizumab treatment revealed that the frequency of circulating Th17 cells and FeNO levels might be used as parameters for predicting the real-world response of benralizumab treatment in patients with severe asthma.

Thyroid storm induced by combined nivolumab and ipilimumab immunotherapy in advanced non-small cell lung cancer.

Thyroid storm is a rare and life-threatening condition associated with excess thyroid hormones. Early detection of thyroid storm is the key to decreasing the morbidity and mortality associated with this condition. We present a rare case of thyroid storm induced by combination therapy with nivolumab and ipilimumab in a patient with advanced non-small cell lung cancer (NSCLC). Because of prominent hyperthyroidism with gastrointestinal symptoms and signs of heart failure, the patient was diagnosed with thyroid storm 3 weeks after initiating this combination immunotherapy. The patient had no history of thyroid disease but was positive for antithyroid antibodies. This case report suggests that thyroid function and symptoms of suspected thyroid storm should be evaluated routinely within 3 weeks from the initiation of therapy when combination therapy is administered in patients with NSCLC positive for antithyroid antibodies.

Chitin induces steroid-resistant airway inflammation and airway hyperresponsiveness in mice.

BACKGROUND: Previous reports have shown that pathogen-associated patterns (PAMPs) induce the production of interleukin (IL)-1ß in macrophages. Moreover, studies using mouse models also suggest that chitin, which acts as a PAMP, induces adjuvant effects and eosinophilic infiltration in the lung. Thus, we investigated the effects of inhaled chitin in mouse models. METHODS: We developed mouse models of inhaled chitin particle-induced airway inflammation and steroid-resistant ovalbumin (OVA)-induced airway inflammation. Some experimental groups of mice were treated additionally with dexamethasone (DEX). Murine alveolar macrophages (AMs), which were purified from bronchoalveolar lavage (BAL) fluids, were incubated with chitin, and treated with or without DEX. RESULTS: The numbers of total cells, AMs, lymphocytes, eosinophils, and neutrophils among BAL-derived cells, as well as the IL-1ß levels in BAL fluids and the numbers of IL-1ß-positive cells in lung, were significantly increased by chitin stimulation. Airway hyperresponsiveness (AHR) was aggravated in mice of the chitin inflammation model compared to control animals. The production of IL-1ß was significantly increased in murine AMs by chitin treatment, but DEX administration did not inhibit this chitin-induced IL-1ß production. Furthermore, in mouse models, DEX treatment inhibited the OVA-induced airway inflammation and AHR but not the airway inflammation and AHR induced by chitin or the combination of OVA and chitin. CONCLUSIONS: These results suggest that inhaled chitin induces airway inflammation, AHR, and the production of IL-1ß. Furthermore, our findings demonstrate for the first time that inhaled chitin induces steroid-resistant airway inflammation and AHR. Inhaled chitin may contribute to features of steroid-resistant asthma.

Difference between two exhaled nitric oxide analyzers, NIOX VERO® electrochemical hand-held analyzer and NOA280i® chemiluminescence stationary analyzer.

BACKGROUND: Fractional exhaled nitric oxide (FENO) is useful for the evaluation of eosinophilic airway inflammation, including that seen in asthma. Although a new electrochemical hand-held FENO analyzer, the NIOX VERO® (Aerocrine AB, Solna, Sweden), is clinically convenient to use, it has not been fully compared with the chemiluminescence stationary electrochemical analyzer NOA280i® (Sievers Instruments, Boulder, CO, USA) in terms of the level of measured FENO. The aim of this study was to determine whether there is a difference between the two analyzers. METHODS: The FENO levels measured with both NIOX VERO® and NOA280i® were evaluated in 1,369 adults at Juntendo University Hospital from May 2016 to October 2016. RESULTS: The median FENO level measured with the NIOX VERO® was significantly lower than that measured with the NOA280i® (41 ppb, range 5-368 ppb vs. 29 ppb, range 5-251 ppb; p < 0.001). There was a strong positive correlation in the measurement of FENO level between the NOA280i® and the NIOX VERO® (r = 0.942, p < 0.001). The following conversion equation was calculated: FENO (NOA280i®) = 1.362 (SE, 0.661) + 1.384 (SE, 0.021) × FENO (NIOX VERO®). CONCLUSIONS: To our best knowledge, we have provided the first report showing that the measured FENO level with the NIOX VERO® was approximately 30% lower than that with the NOA280i® and that there was a significant correlation between the measurements of these two devices. The correction equation that we provided may help assess the data obtained by these two analyzers. Abbreviations ATS American Thoracic Society BMI Body mass index ERS European Respiratory Society FENO Fractional exhaled nitric oxide GINA Global Initiative for Asthma NO Nitric oxide ppb Parts per billion ROC Receiver operating characteristic SD Standard deviation.

Characterization of tenascin-C as a novel biomarker for asthma: utility of tenascin-C in combination with periostin or immunoglobulin E.

BACKGROUND: Extracellular matrix proteins tenascin-C (TNC) and periostin, which were identified as T-helper cell type 2 cytokine-induced genes in human bronchial epithelial cells, accumulate in the airway basement membrane of asthmatic patients. Although serum periostin has been accepted as a type 2 biomarker, serum TNC has not been evaluated as a systemic biomarker in asthma. Therefore, the objective of this study was to evaluate whether serum TNC can serve as a novel biomarker for asthma. METHODS: We evaluated 126 adult patients with mild to severe asthma. Serum TNC, periostin, and total IgE concentrations were quantified using enzyme-linked immunosorbent assays. RESULTS: Serum TNC levels were significantly higher in patients with severe asthma and high serum total IgE levels. Patients with both high serum TNC (> 37.16 ng/mL) and high serum periostin (> 95 ng/mL) levels (n = 20) or patients with both high serum TNC and high serum total IgE (> 100 IU/mL) levels (n = 36) presented higher disease severity and more severe airflow limitation than patients in other subpopulations. CONCLUSIONS: To our knowledge, this is the first study to show that serum TNC levels in asthmatic patients are associated with clinical features of asthma and that the combination of serum TNC and periostin levels or combination of serum TNC and total IgE levels were more useful for asthma than each single marker, suggesting that serum TNC can serve as a novel biomarker for asthma.

Combination of TWEAK and TGF-ß1 induces the production of TSLP, RANTES, and TARC in BEAS-2B human bronchial epithelial cells during epithelial-mesenchymal transition.

AIM OF THE STUDY: In patients with asthma, chronic inflammatory processes and the subsequent remodeling of the airways contribute to the symptoms and the pathophysiological changes. Epithelial-mesenchymal transition (EMT) is thought to play an important role in tissue remodeling. Previous reports show that tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a cytokine of the TNF superfamily, exerts pro-inflammatory effects, and enhances transforming growth factor (TGF)-ß-induced EMT in bronchial epithelial cells. In this study, we investigated the TWEAK-induced cytokine and chemokine production in the human bronchial epithelial cell line BEAS-2B during EMT. MATERIALS AND METHODS: Quantitative real-time RT-PCR, enzyme-linked immunosorbent assays, western blotting, and immunohistochemistry were used to define the production of cytokines and chemokines. RESULTS: We found that TWEAK increases mRNA and protein levels of thymic stromal lymphopoietin (TSLP), monocyte chemoattractant protein -1 (MCP-1), regulated upon activation normal T cell express sequence (RANTES), and IL-8 in BEAS-2B bronchial epithelial cells. Moreover, co-treatment with TWEAK and TGF-ß1 induces not only features of EMT but also enhances the production of TSLP and RANTES. Thymus- and activation-regulated chemokines (TARC) production is induced by the co-treatment of TWEAK and TGF-ß1 but not by TWEAK or TGF-ß1 stimulation alone. Furthermore, the increased mRNA expression of TSLP and RANTES after co-treatment with TWEAK and TGF-ß1 is prevented by inhibitors of Smad-independent signaling pathways. CONCLUSIONS: In the present study, we have revealed a novel mechanism for the production of asthma-related cytokines and chemokines in EMT driven by the co-stimulation with TWEAK and TGF-ß1. We conclude that cellular EMT processes caused by TWEAK and TGF-ß1 may contribute to chronic airway inflammation and remodeling.

Pulmonary Intravascular Large B-cell Lymphoma (IVLBCL) Disguised as an Asthma Exacerbation in a Patient with Asthma.

A 62-year-old man with asthma presented with a 1-month history of wheezing and exertional dyspnea. Although the wheezing symptoms disappeared after systemic corticosteroid therapy, the exertional dyspnea and hypoxemia did not improve. A diagnosis of intravascular large B-cell lymphoma (IVLBCL) with pulmonary involvement was suspected because of the increased serum lactic dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) level, increased alveolar-arterial oxygen difference (AaDO2), decreased pulmonary diffusing capacity for carbon monoxide (DLCO) and scintigraphic, computed tomography (CT) and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT findings. The patient was diagnosed as having IVLBCL with pulmonary involvement based on a pathological analysis of a random skin biopsy and a transbronchial lung biopsy. IVLBCL should be considered in patients with symptoms of asthma that are refractory to corticosteroid treatment.

Circulating activated innate lymphoid cells and mucosal-associated invariant T cells are associated with airflow limitation in patients with asthma.

BACKGROUND: A variety of innate subsets of lymphoid cells such as natural killer (NK) cells, several populations of innate lymphoid cells (ILCs), and mucosal-associated invariant T (MAIT) cells as innate-like T lymphocytes are involved in asthma and may have important effector functions in asthmatic immune responses. In the present study, we investigated whether NK cells, ILCs, and MAIT cells in the peripheral blood of patients with asthma would be associated with clinical asthma parameters. METHODS: We recruited 75 adult patients with mild to severe asthma. The peripheral blood mononuclear cells in peripheral venous blood samples from the patients were purified and stained with different combinations of appropriate antibodies. The cells were analyzed by flow cytometry. RESULTS: The percentage of activated (i.e., CD69+) NK cells in the total NK cell population was negatively correlated with FEV1% which is calculated by the forced expiratory volume in 1 s (FEV1)/the forced vital capacity (FVC). The percentages of CD69+ ILC1s and ILC2s were negatively correlated with FEV1% and %FEV1. The percentage of CD69+ ILC3s was positively correlated with BMI, and the percentage of CD69+ MAIT cells was negatively correlated with FEV1%. Moreover, the percentage of CD69+ NK cells, ILC1s, ILC2s, ILC3s, and MAIT cells were positively correlated with each other. CONCLUSIONS: For the first time, our data showed that activated NK cells, ILC1s, ILC2s, ILC3s, and MAIT cells were positively correlated with each other and may be associated with airflow limitation in patients with asthma.

Ultrastructural analysis between fetal and adult wound healing process of marsupial opossum skin.

The opossum delivers a newborn baby equivalent to tremature fetus state by postpregnancy. The peculiarity is advantageous for studies of fetus, because operations to take out fetus from the uterus of a mother are not necessary. When mammalian skin is wounded by full-thickness excision, fetal and adult wound healing processes differ. Fetal-type wound healing does not leave a scar. However, studies of how the fetal wound healing process differs in detail from the adult type are not advanced. We first observed the normal skin development of the gray short-tailed opossum (Monodelphis domestica) using an electron microscope. As for normal skin, an epidermis became multi-layered, and thickened from birth through to 7 days after birth. The quantity of extracellular matrix of the dermis increased thereafter, and several types of cells were found in the dermis. To examine the wound healing, we used material from a 1 day-old newborn baby, and from another 15 days after birth, and compared the wound healing style morphologically. Differences in the constitution of cells and fine structures of the skin were observed, it was obviously suggested that change in the wound healing style from fetal-type to adult-type occurred between 1 to 15 days after birth.