Characteristics of the nocturnal desaturation waveform pattern of SpO2 in COPD patients: an observational study.

BACKGROUND: Nocturnal desaturation is common in patients with chronic obstructive pulmonary disease (COPD) and impacts disease exacerbation and prognosis. In our previous study, we developed a diagnostic algorithm to classify nocturnal desaturation from SpO2 waveform patterns based on data from patients receiving home oxygen therapy. In this study, we aimed to investigate nocturnal desaturation in patients with COPD based on SpO2 waveform patterns and the associations between the waveforms and clinical data. METHODS: We investigated patients diagnosed with COPD and measured SpO2 and nasal airflow with a type 4 portable long-term recordable pulse oximeter. Then, we classified the SpO2 waveforms with the algorithm and compared the clinical data. RESULTS: One hundred fifty-three patients (136 male and 17 female) were analysed. One hundred twenty-eight of the 153 (83.7%) patients had nocturnal desaturation, with an intermittent pattern (70.6%), sustained pattern (13.1%) and periodic pattern (68.0%). Intriguingly, desaturation with an intermittent pattern was associated with the apnoea-hypopnea index obtained with the portable monitor, and desaturation with a sustained pattern was associated with the cumulative percentage of time at a SpO2 below 90%. CONCLUSIONS: We found that nocturnal desaturation was frequently observed in patients with COPD and could be classified into 3 types of waveform patterns.

[A Case of Multiple Brain Tumors Successfully Diagnosed with Liquid Biopsy and Treated with Osimertinib].

A seventy‒year‒old man complaining of left arm weakness and gait disturbance was diagnosed with multiple tumors and severe edema in the brain as well as right lung mass lesion, suggesting brain metastases. He started whole brain radiation therapy but had to discontinue it since his neurological symptoms were worsened including paralysis, aphasia, and coma. These symptoms made it difficult to perform tumor biopsy for cancer diagnosis as well as oncogene mutations. Liquid biopsy, which examines EGFR gene mutations in plasma sample, revealed EGFR L858R point mutation. Treatment with osimertinib improved his symptoms, resulting in discharge to home. Even a patient severely ill with metastatic brain tumors can benefit from the molecular‒targeted therapy using liquid biopsy to diagnose EGFR‒mutated lung cancer, suggesting an important differential diagnosis in such patients.

Occupational respiratory allergy to lettuce in lettuce farmers.

BACKGROUND: Lettuce-associated respiratory allergy has never been reported before. The aim of this study was to clarify the clinical condition of lettuce-associated respiratory allergy and to identify the lettuce antigen which induces allergic symptoms. METHODS: We distributed questionnaires to 1168 lettuce farmers and performed medical examinations in those who exhibited respiratory symptoms related to occupational exposure to lettuce. We analysed specific IgE-binding proteins in the sera of patients through immunoblotting analysis and determined molecular characterization of the IgE-binding bands using liquid chromatography-mass spectrometry. RESULTS: A total of 932 farmers (80%) responded to the questionnaire. Of those, 7% exhibited lettuce-associated respiratory symptoms, during harvesting and packaging. Thirteen patients were diagnosed with allergy to lettuce and agreed to undergo further examinations. The percentage of activated basophils in these patients was significantly higher compared with that reported in negative controls (P < .05). Lettuce-specific IgE (ImmunoCAP® ) and skin prick testing was positive in 46% and 62% of patients, respectively. Notably, occupational lettuce-allergic asthma was detected in one patient through specific bronchial provocation testing. The IgE-binding bands recognized in the sera of >50% of patients were identified as epidermis-specific secreted glycoprotein EP1-like (51 kDa). CONCLUSION: The present analysis identified a novel lettuce allergen. This allergen may have clinically useful applications, such as specific IgE testing and allergen-specific immunotherapy.

Phospholipase Cε plays a crucial role in neutrophilic inflammation accompanying acute lung injury through augmentation of CXC chemokine production from alveolar epithelial cells.

BACKGROUND: We have shown that phospholipase Cε (PLCε), an effector of Ras and Rap1 small GTPases, plays pivotal roles in inflammation and inflammation-associated carcinogenesis by augmenting proinflammatory cytokine production from epithelial cells of various organs. The purpose of this study is to analyze its role in neutrophilic alveolar inflammation accompanying acute lung injury (ALI), focusing on that in alveolar epithelial cells (AECs), which are known to make a major contribution to the pathogenesis of ALI. METHODS: We examine the effect of the PLCε genotypes on the development of ALI induced by intratracheal administration of lipopolysaccharide (LPS) to PLCε wild-type (PLCε+/+) and knockout (PLCεΔX/ΔX) mice. Pathogenesis of ALI is analyzed by histological examination of lung inflammation and measurements of the levels of various cytokines, in particular neutrophil-attracting chemokines such as Cxcl5, by quantitative reverse transcription-polymerase chain reaction and immunostaining. Primary cultures of AECs, established from PLCε+/+ and PLCεΔX/ΔX mice, are used to analyze the roles of PLCε, protein kinase D (PKD) and nuclear factor-κB (NF-κB) in augmentation of LPS-induced Cxcl5 expression. RESULTS: Compared to PLCε+/+ mice, PLCεΔX/ΔX mice exhibit marked alleviation of lung inflammation as shown by great reduction in lung wet/dry weight ratios, accumulation of inflammatory cells in the alveolar space and thickening of alveolar walls as well as the number of neutrophils and the protein concentration in bronchoalveolar lavage fluid. Also, LPS-induced expression of the CXC family of chemokines, in particular Cxcl5, is substantially diminished in the total lung and AECs of PLCεΔX/ΔX mice. Moreover, LPS-induced Cxcl5 expression in primary cultured AECs is markedly suppressed on the PLCεΔX/ΔX background (p < 0.05 versus PLCε+/+ AECs), which is accompanied by the reduction in phosphorylation of inhibitor κB (IκB), PKD and nuclear translocation of NF-κB p65. Also, it is suppressed by the treatment with inhibitors of PKD and IκB kinase, suggesting the involvement of the PLCε-PKD-IκB-NF-κB pathway. CONCLUSIONS: PLCε-mediated augmentation of the production of the CXC family of chemokines, in particular Cxcl5, in AECs plays a crucial role in neutrophilic alveolar inflammation accompanying ALI, suggesting that PLCε may be a potential molecular target for the treatment of acute respiratory distress syndrome.

Crucial Role of Extracellular Vesicles in Bronchial Asthma.

Extracellular vesicles (EVs) are circulating vesicles secreted by various cell types. EVs are classified into three groups according to size, structural components, and generation process of vesicles: exosomes, microvesicles, and apoptotic bodies. Recently, EVs have been considered to be crucial for cell-to-cell communications and homeostasis because they contain intracellular proteins and nucleic acids. Epithelial cells from mice suffering from bronchial asthma (BA) secrete more EVs and suppress inflammation-induced EV production. Moreover, microarray analyses of bronchoalveolar lavage fluid have revealed that several microRNAs are useful novel biomarkers of BA. Mesenchymal stromal cell-derived EVs are possible candidates of novel BA therapy. In this review, we highlight the biologic roles of EVs in BA and review novel EV-targeted therapy to help understanding by clinicians and biologists.

Effect of Bronchial Thermoplasty on Air Trapping Assessed by Xenon Ventilation Computed Tomography.

Objective Bronchial thermoplasty (BT) is a bronchoscopic procedure for patients with severe asthma. Although it has been suggested that BT works by reducing airway smooth muscle, the detailed mechanism underlying its effects is still unknown. Methods We performed xenon ventilation computed tomography (Xe-CT) before each BT procedure and six weeks after the third treatment to assess the improvement in lung ventilation at each separate lung region. The air trapping index in each lobe was defined as the mean trapping value (0: none, 1: mild, 2: moderate, and 3: severe) of the included segments. Patients and Materials Four patients were included. Results Asthma symptoms were improved after BT. The comparison of the scores at baseline with those after the third treatment showed that the air trapping index was improved in both the treated and untreated regions. However, neither the pulmonary function nor the exhaled nitric oxide was improved. Conclusion Using Xe-CT, we successfully evaluated the air trapping in patients who underwent BT. The improvement in asthma symptoms by BT may be related to the amelioration of peripheral lung ventilation in both the treated and untreated regions.

Randomized cross-over trial of demand oxygen delivery system.

INTRODUCTION: Long-term oxygen therapy is reported to improve hypoxemia and survival in patients with respiratory failure. The demand oxygen delivery system (DODS) saves oxygen and extends the usable time of an oxygen cylinder 2- to 3-fold. A portable oxygen concentrator with an auto-DODS has been developed to switch its sensitivity among 3 levels (standard, high, and extra high) and to supply pulsed-flow oxygen when it detects apnea. The aim of this study is to evaluate the efficacy of this newly developed portable oxygen concentrator with auto-DODS compared to the efficacy of conventional DODS in oxygenation. METHODS AND ANALYSIS: Twenty-six patients with chronic obstructive pulmonary disease or interstitial pneumonia will be randomized to use auto-DODS or conventional DODS at rest and during a 6-minute walk test. Primary endpoints are mean oxygen saturation (SpO2) at rest and during the 6-minute walk test. Secondary endpoints are the ratios of the times during which the oxygen concentrator operates at each sensitivity mode (standard, high, and extra high) and at a constant pulse rate to the examination time, the ratio of the times during which SpO2 fall below 90% to the examination time, the lowest value of SpO2 during the examination time, the mean and highest pulse rates during the examination time, 6-minute walking distance, recovery time, Borg scale, comfort, and reliability, which are measured by a numerical rating scale and a questionnaire, respectively. ETHICS AND DISSEMINATION: The study was conducted in accordance with the Declaration of Helsinki and was registered on Aug 23, 2019 (https://jrct.niph.go.jp/en-latest-detail/jRCTs052190041). The results of the study will be presented at academic conferences and submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTs052190041.

Randomized cross-over trial of demand oxygen delivery system in nocturnal hypoxemia.

BACKGROUND: It has not been determined that demand valve oxygen therapy is effective for nocturnal hypoxia. A portable oxygen concentrator with an auto-demand oxygen delivery system (auto-DODS; standard, high, and extra high) has recently been developed to improve oxygenation and comfort. This oxygen concentrator can supply a pulsed flow when it detects apnoea. The aim of this study is to demonstrate that this newly developed portable oxygen concentrator with an auto-demand function is non-inferior to a continuous-flow oxygen concentrator for nocturnal hypoxemia. METHODS: Twenty patients with chronic obstructive pulmonary disease or interstitial pneumonia will be randomized to receive a portable oxygen concentrator with an auto-DODS or a continuous-flow oxygen concentrator during sleep. The primary endpoint is mean oxygen saturation (SpO2) during the total sleep time. The secondary endpoints are the ratios of time that the oxygen concentrator spends in each sensitivity mode (standard, high, and extra-high) and at a constant pulse rate to the total sleep time, the total time and ratio of time for which SpO2 is less than 90% during the total sleep time, the lowest value of SpO2 during the total sleep time, the mean and highest pulse rate during the total sleep time, the apnoea index during the total sleep time, the total sleep duration itself, and comfort and reliability as measured by numerical rating scale and questionnaires. DISCUSSION: If the auto-DODS demonstrates non-inferiority to continuous flow in oxygenation during sleep, the auto-DODS can be used even at night, and the patient will need only 1 device. TRIAL REGISTRATION: The study was registered on Aug 23, 2019 (jRCTs052190042).

Novel cancer therapy targeting microbiome.

In the human intestinal tract, there are more than 100 trillion symbiotic bacteria, which form the gut microbiota. Approximately 70% of the human immune system is in the intestinal tract, which prevents infection by pathogenic bacteria. When the intestinal microbiota is disturbed, causing dysbiosis, it can lead to obesity, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, autism spectrum disorder and cancer. Recent metabolomics analyses have also made the association between the microbiota and carcinogenesis clear. Here, we review the current evidence on the association between the microbiota and gastric, bladder, hepatobiliary, pancreatic, lung and colorectal cancer. Moreover, several animal studies have revealed that probiotics seem to be effective for the prevention of carcinogenesis to some extent. In this review, we focused on this relationship between the microbiota and cancer, and considered how to prevent cancer using strategies involving the gut microbiota.

Eosinophilic Pneumonia Associated With Natalizumab In A Patient With Multiple Sclerosis: A Case Report And Literature Review.

We herein report the case of a 39-year-old Japanese female with eosinophilic pneumonia associated with natalizumab. The patient with bronchial asthma had multiple sclerosis and was treated using natalizumab. The patient was referred to our department because of a persistent cough. A chest computed tomography (CT) scan revealed bilateral patchy consolidation surrounded by ground-glass opacity. A bronchoalveolar lavage (BAL) was performed. Eosinophil levels in the BAL fluid were increased and the patient was consequently diagnosed as eosinophilic pneumonia associated with natalizumab. Therefore, natalizumab treatment was discontinued. Subsequent chest CT findings showed a remarkable improvement without any treatment.

Questionnaire Survey for Bronchial Asthma in Elderly Care Facilities.

In developed countries such as North America, the decline in mortality from bronchial asthma has ceased since 2006. The decline in mortality rate is also decreasing in Japan, where about 1,500 asthma deaths have been reported. Among these, elderly people aged 65 years or over account for about 90% of cases. Therefore, the treatment of elderly patients with asthma is an important subject. However, few studies have been conducted on asthma in elderly patients. In this survey, we distributed a questionnaire to 253 elderly care facilities in Kobe, Japan. Ninety facilities responded, and 223 patients in 70 out of 90 facilities were diagnosed with asthma. Dry powder inhaler was the most commonly used dosage form of inhaled corticosteroids. Many facilities have patients who need some assistance during inhalation: only 60% of facilities reported that inhalation is performed accurately. While 31 facilities had patients with a history of hospitalization for asthma attacks, only 14 of these facilities were able to provide appropriate initial treatment. Many facilities have difficulty providing assistance with inhalation to elderly patients whose cognitive function has deteriorated. This survey highlights challenges experienced by care facilities in treating asthma in the elderly.

Tenosynovitis Induced by an Immune Checkpoint Inhibitor: A Case Report and Literature Review.

A 51-year-old man underwent second-line treatment for non-small-cell lung cancer (NSCLC) with the immune checkpoint inhibitor (ICI) pembrolizumab. On day 2 after two cycles of pembrolizumab, he presented with edema limited to the left third, fourth, and fifth fingers. Based on symptoms, laboratory results, and contrast-enhanced magnetic resonance imaging (MRI) findings, we diagnosed him with tenosynovitis. We prescribed oral prednisolone (0.5 mg/kg/day), and pembrolizumab was continued. Prednisolone immediately relieved the symptoms, and the tumor was still shrinking on day 21 after eight cycles of pembrolizumab. ICI-induced tenosynovitis was managed while continuing ICI usage, suggesting that 0.5 mg/kg/day prednisone might be effective for tenosynovitis without ICI cessation.

Synergistic interaction of gemcitabine and paclitaxel by modulating acetylation and polymerization of tubulin in non-small cell lung cancer cell lines.

Background: The combination of gemcitabine (GEM) and paclitaxel (PTX) was appealing for clinical exploration due to different mechanisms of action and partially non-overlapping toxicities. Purpose: The aim of this study was to elucidate a potential effect of this combination on the proliferation of two non-small cell lung cancer (NSCLC) cell lines, A549 and H520. Materials and methods: Cell lines were treated with GEM and PTX for 48 hours to evaluate the half maximal inhibitory concentration (IC50). To determine the combination index (CI), cell lines were exposed to GEM and PTX, in a constant ratio of IC50, by various combination treatments. GEM`s effect on tubulin was assessed by western blotting and immunofluorescent staining. GEM was combined with nanoparticle albumin-bound-paclitaxel (NP) in evaluating tumor growth inhibition. Results: The IC50 of GEM and PTX in A549 and H520 were 6.6 nM and 46.1 nM, and 1.35 nM and 7.59 nM, respectively. Among the sequences explored (GEM→PTX, PTX→GEM, and GEM plus PTX simultaneously [GEM+PTX]), GEM→PTX produced a mean CI <1 in both cell lines. Western blotting and immunofluorescent staining revealed the intention expressions of acetylated tubulin protein and enhancement of tubulin polymerization within GEM→PTX group. A combination order GEM→NP also worked synergistically to suppress tumor growth. Conclusion: The GEM→PTX sequence may represent a promising candidate regimen for the treatment of NSLCL.

Role of S1P/S1PR3 axis in release of CCL20 from human bronchial epithelial cells.

BACKGROUND: Sphingosine kinase phosphorylates sphingosine to generate sphingosine 1 phosphate (S1P) following stimulation of the five plasma membrane G-protein-coupled receptors. The objective of this study is to clarify the role of S1P and its receptors (S1PRs), especially S1PR3 in airway epithelial cells. METHODS: The effects of S1P on asthma-related genes expression were examined with the human bronchial epithelial cells BEAS-2B and Calu-3 using a transcriptome analysis and siRNA of S1PRs. To clarify the role of CCL20 in the airway inflammation, BALB/c mice were immunized with ovalbumin (OVA) and subsequently challenged with an OVA-containing aerosol to induce asthma with or without intraperitoneal administration of anti-CCL20. Finally, the anti-inflammatory effect of VPC 23019, S1PR1/3 antagonist, in the OVA-induced asthma was examined. RESULTS: S1P induced the expression of some asthma-related genes, such as ADRB2, PTGER4, and CCL20, in the bronchial epithelial cells. The knock-down of SIPR3 suppressed the expression of S1P-inducing CCL20. Anti-CCL20 antibody significantly attenuated the eosinophil numbers in the bronchoalveolar lavage fluid (P<0.01). Upon OVA challenge, VPC23019 exhibited substantially attenuated eosinophilic inflammation. CONCLUSIONS: S1P/S1PR3 pathways have a role in release of proinflammatory cytokines from bronchial epithelial cells. Our results suggest that S1P/S1PR3 may be a possible candidate for the treatment of bronchial asthma.

Renal embolism as a primary manifestation of Streptococcus dysgalactiae subspecies equisimilis endocarditis in a patient with chronic aortic dissection.

We report a case of renal embolism as an initial manifestation of Streptococcus dysgalactiae subspecies equisimilis (SDSE) endocarditis in a patient with chronic aortic dissection. A 37-year-old man who underwent total aortic arch replacement owing to aortic dissection, presented with a 3-h history of fever, chills, and acute right-sided flank pain. The endocarditis affected the native aortic valve and was complicated by a renal embolism. Blood culture results were positive for SDSE. Intravenous penicillin resulted in satisfactory clinical and echocardiographic recovery.

Antithyroid drug-induced agranulocytosis complicated by pneumococcal sepsis and upper airway obstruction.

Streptococcus pneumoniae is a rare pathogen of sepsis in patients with antithyroid drug-induced agranulocytosis. We herein describe a case of antithyroid drug-induced agranulocytosis complicated by pneumococcal sepsis and upper airway obstruction. A 27-year-old woman who was previously prescribed methimazole for nine months presented with a four-day history of a sore throat. She nearly choked and was diagnosed with febrile agranulocytosis. She was successfully treated with intubation, intravenous antibiotics and granulocyte colony-stimulating factor. Her blood cultures yielded S. pneumoniae. Emergency airway management, treatment of sepsis and the administration of granulocyte colony-stimulating factor can improve the clinical course of antithyroid drug-induced pneumococcal sepsis in patients with airway obstruction.