Patients with idiopathic pulmonary fibrosis and refractory cough have traction bronchiectasis and distorted airway architecture: a retrospective case review study.

Cough is a common and important sign/symptom in patients with idiopathic pulmonary fibrosis (IPF). However, there have been few reports focusing on cough, and the exact mechanisms for cough in patients with IPF have remained unclear. The objective of this study was to investigate the clinical features of IPF patients with refractory cough and to clarify mechanisms for cough in these patients. We retrospectively reviewed the files of patients with the diagnosis of IPF at Kanazawa University Hospital and compared the clinical features of IPF patients with refractory cough with the clinical features of IPF patients without refractory cough. Among a total of 23 patients with IPF, 10 patients (43.5%) had chronic cough. Of the ten patients, seven patients had concomitant conditions that could lead to cough. Of these seven patients, the cough of four patients was resolved after treatment of their concomitant condition. Finally, among the 23 patients there were 6 (26.1%) with refractory cough associated with IPF. Significant differences were seen between the following clinical features of IPF patients with or without refractory cough, respectively, as follows: lower body mass index (BMI; 18.8±2.5 vs. 22.8±2.5 kg/m2, P<0.01), lower forced vital capacity (FVC; 77.5%±30.4% predicted vs. 99.9%±0.53% predicted, P=0.046), and presence of traction bronchiectasis and distorted airway architecture on high-resolution computed tomography (HRCT; 83.3% vs. 11.8%, P<0.01). The difference between the proportions of patients with or without refractory cough with capsaicin cough sensitivity was not significant. Mechanical stress on the airways due to traction bronchiectasis and distorted airway architecture is a possible mechanism for cough in IPF patients.

Comparing region of interest selection and whole-field analysis for measurement of ciliary beat frequency in high-speed video analysis.

BACKGROUND: Ciliary beat frequency (CBF) is crucial in mucociliary clearance. High-speed video analysis (HSVA) is commonly used to measure CBF but lacks standardization. We compared visual observation and computer-assisted calculation using fast Fourier transformation (FFT) in freshly collected bronchial ciliary epithelial cells and cultured cells. METHODS: Bronchial epithelial cells were obtained from 12 patients who required bronchoscopic examination. Eighty-five videos of ciliary movement of freshly collected and cultured cells were recorded and used to calculate CBF using manual observation, region of interest (ROI) selection, and whole-field analysis. RESULTS: CBF measured by the ROI selection method strongly correlated with that measured using manual observation, especially in freshly collected cells. However, 27.8% of the manual observation method values were doubled in the ROI selection method, probably because a round trip of cilia was calculated as two cycles and needed to be corrected to 1/2 value. Upon increasing the number of ROIs, the results of the ROI selection method came closer to that of WFA. CONCLUSIONS: Computer-assisted calculation using FFT can aid in measuring CBF; however, current methods require visual confirmation. Further automated evaluation techniques are needed to establish more standardized and generalized CBF measurement methods using HSVA.

A feasibility study of provider-level implementation strategies to improve access to colorectal cancer screening for patients with schizophrenia: ACCESS2 (N-EQUITY 2104) trial.

BACKGROUND: People with schizophrenia have a lower colorectal screening rate than the general population. A previous study reported an intervention using case management to encourage colorectal cancer screening for patients with schizophrenia in psychiatric outpatient settings. In this feasibility study, we developed provider-level implementation strategies and evaluated the feasibility of conducting a definitive trial in terms of the penetration of the intervention assessed at the patient level. Additionally, we examined the fidelity of strategies to implement the intervention at the provider level in a routine clinical psychiatric setting. METHODS: This was a multicenter, single-arm feasibility study with medical staff at psychiatric hospitals in Japan. The provider-level implementation strategies developed in this study included three key elements (organizing an implementation team appointed by the facility director, interactive assistance using a clear guide that outlines who in the hospital should do what, and developing accessible educational materials) to overcome major barriers to implementation of the intervention and four additional elements (progress monitoring, joint meetings and information sharing among participating sites, adaptation of encouragement methods to specific contexts, and education of on-site staff), with reference to the elements identified in the Expert Recommendations for Implementing Change (ERIC). The feasibility of the strategies was evaluated by the proportion of patients who were eligible for encouragement (patients with schizophrenia aged 40, 50, or 60) who received encouragement. We set the goal of providing encouragement to at least 40% of eligible patients at each site. RESULTS: Two public and four private psychiatric hospitals in Okayama and Shimane prefectures participated in this study. Regarding fidelity, all elements of the strategies were conducted as planned. Following the procedures in the guide, each team prepared and provided encouragement according to their own facility and region. Penetration, defined as the proportion of eligible patients who received encouragement, ranged from 33.3 to 100%; five of the six facilities achieved the target proportion. CONCLUSIONS: The provider-level implementation strategies to implement encouragement were feasible in terms of penetration of the intervention assessed at the patient level. The results support the feasibility of proceeding with a future definitive trial of these strategies. TRIAL REGISTRATION: jRCT, jRCT1060220026 . Registered on 06/04/2022.

Development of Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome with Pembrolizumab for Lung Squamous Cell Carcinoma: A Case Report.

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs). There are a few case reports of remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE) as an irAE. We herein report a 49-year-old Japanese man who developed acute-onset polyarthralgia and edema of the back of both hands and bilateral lower legs after pembrolizumab administration for lung cancer. The patient's lung cancer was in complete remission, leading to the diagnosis of RS3PE induced by pembrolizumab rather than malignancy. When patients show RS3PE during ICI treatment, rheumatologists should consider the possibility of an irAE after excluding malignancy and systemic diseases.

Insulin Requirements During Severe COVID-19 Were Relatively Low in Japanese Patients With Type 2 Diabetes: Two Case Reports.

The global coronavirus disease 2019 (COVID-19) pandemic has caused myriad adverse effects on the pathology of other diseases. Numerous studies on COVID-19 have reported that, in patients with type 2 diabetes mellitus (T2DM) who have contracted severe COVID-19, glucose metabolism is exacerbated by multiple factors, such as severe inflammation, beta-cell dysfunction caused by the SARS-CoV-2 infection itself, corticosteroid therapy, vasopressor administration, and enteral or parenteral nutrition. Very high doses of insulin are often required in the acute phase of such patients; however, the factors that affect insulin requirements and to what extent remain unclear. A 50-year-old Japanese woman and a 67-year-old Japanese man, both with T2DM and obesity, were admitted to our hospital with severe COVID-19. Both patients required mechanical ventilation and were treated with dexamethasone and tocilizumab, an interleukin-6 (IL-6) receptor monoclonal antibody. Subcutaneous insulin injections failed to control the patients' hyperglycemia, requiring up to 1.83 and 1.81 units/kg/day of intravenous insulin, respectively. Insulin requirements were rapidly decreased with improvement of the respiratory condition, termination of dexamethasone, and discontinuation of tube feeding. Both patients were discharged with oral antidiabetic agents alone. We experienced two Japanese patients who achieved satisfactory glycemic control with a lower intravenous insulin dose than previous reports. Comparing the clinical factors with the previous literature, ethnic differences in insulin sensitivity and the administration of IL-6 receptor antibodies may have been related to the relatively low insulin requirements.

Influence of Chewing Gummy Jelly Containing Aroma Compound on Psychological Stress and Autonomic Nervous System Activity: A Randomized Crossover Trial.

The aim of this randomized crossover trial was to clarify the effects of chewing gummy jelly containing a compound of decanoic acid, oligonol, methyl cellulose, and citral (DOMAC) on mental stress and autonomic nervous activity in facemask wearers. A placebo gummy jelly was used in conjunction with DOMAC. Eight healthy adults with no tooth loss (mean age: 35±5 yr) were included. The participants were required to chew one DOMAC or placebo gummy jelly for 5 min after wearing a facemask for 20 min in the laboratory, then the other gummy jelly after a washout period. Rate of change in salivary immunoglobulin A (IgA) as a marker of stress was compared between before and after chewing. Additionally, sympathetic and parasympathetic activity was compared at both time points. A significant difference was observed in the percentage change in salivary IgA from that at before wearing a facemask: 127±34% (mean±standard deviation) while wearing a facemask; 46±20% while chewing DOMAC gummies; and 47±26% while chewing placebo gummies (p<0.05). Parasympathetic nervous system activity was 971.2±1040.7 ms2 at 20 min after facemask wearing; 295.0±253.0 ms2 after DOMAC gummy chewing; and 1956.1±2798.0 ms2 after chewing a placebo gummy jelly; with significant differences only being found between 20 min after facemask wearing and after DOMAC gummy chewing (p<0.05). Sympathetic nervous system activity was 1.80±1.83 at 20 min after facemask wearing; 4.06±3.33 after DOMAC gummy chewing; and 4.95±7.02 after chewing a placebo gummy jelly; with significant differences only being found between 20 min after facemask wearing and after DOMAC gummy chewing. These results suggest that chewing gummy jellies containing DOMAC relieves stress caused by facemask wearing and activates sympathetic nervous system activity.

Bronchial Thermoplasty Attenuates Cough Reflex Sensitivity in Severe Asthma : A Single-Center Retrospective Study with 2-year Follow-up.

Despite the relatively short follow-up period in our previous study, we had reported that increased cough reflex sensitivity (CRS) may predict the efficacy of bronchial thermoplasty (BT) for treating asthma. Herein, we examined whether CRS predicts the efficacy of BT 2 years after the final BT treatment. We also investigated the influence of BT on CRS. We reviewed 10 patients 2 years after their final BT treatment. CRS, asthma-related symptoms, asthma exacerbations, and cough-related quality of life were assessed at baseline and 2 years after BT. Five patients responded positively to BT (BT responders) and their asthma control improved. No significant difference in CRS at baseline was detected between the BT responders and nonresponders. In contrast, BT responders exhibited significant improvements in CRS 2 years after BT. CRS at baseline could not predict the BT efficacy after 2 years. This is the first report demonstrating BT desensitized CRS in consecutive case series. J. Med. Invest. 70 : 271-275, February, 2023.

Molybdenum-Quinone-Catalyzed Deoxygenative Coupling of Aromatic Carbonyl Compounds.

In the presence of triphenylphosphine as a mild reductant, the use of catalytic amounts of Mo(CO)6 and an ortho-quinone ligand enables the intermolecular reductive coupling of aromatic aldehydes and the intramolecular coupling of aromatic ketones to produce functionalized alkenes. Diaryl- and diheteroaryl alkenes are synthesized with high (E)-selectivity and a tolerance toward bromide, iodide, and steric hindrance. Intramolecular coupling of dicarbonyl compounds under similar conditions affords mono- and disubstituted phenanthrenes.

Long-Term Survival of Patients With Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitor Monotherapy in Real-World Settings.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is more effective than cytotoxic chemotherapy in improving overall survival (OS) among patients with advanced-stage non-small cell lung cancer (NSCLC). Recently, chemotherapy combined with ICI has been found to yield good outcomes. However, ICI monotherapy is still considered an important treatment option. Data on long-term progression-free survival (PFS) and OS in real-world settings are limited. PATIENTS AND METHODS: This was a multicenter retrospective observational study. A total of 435 consecutive patients histologically diagnosed with advanced, metastatic, or recurrent NSCLC treated with ICI monotherapy were enrolled in this study from December 2015 to December 2018. Clinical data were collected from electronic medical records and pharmacy databases. RESULTS: The PFS and OS of the patients were 3.4 and 13.0 months, respectively. The objective response and disease control rates were 22.8% and 54.9%, respectively, and the 4-year survival rate was 17.9%. Multivariate analyses revealed that elder patients (>70 years), good Eastern Cooperative Oncology Group Performance Status (ECOG PS) score, programmed death-ligand 1 tumor proportion score (PD-L1 TPS) of ≥ 50%, absence of bone metastasis, and presence of immune-related skin toxicity, which is an immune-related adverse event, were correlated with good PFS. Moreover, good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good OS. CONCLUSIONS: The 4-year survival rate was 17.9%. Good ECOG PS score, PD-L1 TPS of ≥ 50%, absence of bone metastasis, and presence of skin toxicity were correlated with good PFS and OS.

Methicillin-resistant Staphylococcus aureus Necrotizing Bronchitis after Radiotherapy in Combination with Axitinib.

A 38-year-old man with renal cell carcinoma was referred to our hospital because of a productive cough. He had received radiotherapy for lung metastasis and been treated with axitinib. Bronchoscopy revealed necrosis in the bronchi of the right middle and lower lobes. Culture of the necrotic bronchial specimen revealed methicillin-resistant Staphylococcus aureus (MRSA). Although radiotherapy in combination with axitinib carries a risk of causing airway toxicity, MRSA necrotizing bronchitis has not been reported. Physicians should consider the possibility of infectious necrotizing bronchitis if irradiated patients show prolonged respiratory symptoms.

Rat peri-implant soft tissue specifically expressed CXCL2 on titanium implant during wound healing.

Many of genes specifically expressed in peri-implant soft tissue (PIST) selected by microarray analysis are involved in the inflammatory response. This study investigated the gene expression and localization of PIST-specific inflammatory markers in PIST during wound healing. Pure titanium implants were implanted into the rat upper mandibular socket to create PIST. Samples were harvested from PIST as an experimental group, and tooth extracted area of oral mucosa tissue (OMT) and healthy periodontal tissue (PT) as control groups. The gene expressions of four standard inflammatory markers and nine PIST-specific inflammatory markers including chemokine (C-X-C motif) ligand 2 (CXCL2) during wound healing were examined. Immunoreactions of CXCL2 and immune cells in PIST and control tissues were compared. During wound healing, gene expression of PIST-specific inflammatory markers was higher in PIST than in OMT (p < .05), but there were no significant differences in the expression of standard inflammatory markers. The molecule CXCL2 was expressed locally at the implant-connective tissue interface, and localization of immune cells closely matched the CXCL2 expression pattern. In PIST, seven of PIST-specific inflammatory markers were expressed specifically and strongly during wound healing and their expression was maintained until the end of healing. Furthermore, CXCL2 expression was due to the creation of the implant-connective tissue interface, and it established a unique defense mechanism in PIST that was not apparent in OMT or PT.

Implant Body Displacement into Medullary Cavity of Mandible: A Case Report.

One serious complication in implant surgery is displacement of the implant body into the surrounding tissue. This occurs only rarely in the mandible, however. This report describes a case of an implant body displacing into the medullary cavity of the mandible and discusses this in reference to the literature. The patient was a 72-year-old woman who was referred to our department at Tokyo Dental College Chiba Hospital (now Chiba Dental Center) by her regular dentist after an implant inserted in the left mandible in 2010 showed loosening in October 2016. Panoramic X-rays obtained at the initial examination revealed that 2 implants had been inserted into the left mandible, one on top of the other. Removal of both was recommended to prevent infection at the implant site and any potential effects on the alveolar nerve. In the absence of subjective symptoms other than implant loosening, however, the patient did not consent to this proposal. Therefore, only the broken abutment was removed. The patient was instructed to contact us immediately should infection or any other symptoms appear once the mucosa had healed, and the dental clinic that had referred her to us was requested to make her a set of dentures. To our knowledge, only 11 reports have been published to date describing displacement of an implant body into the mandible, and these address a total of just 20 cases. The possibility that an implant body in the mandible may become displaced must be kept in mind during treatment.

Synthesis of 6-epi-tuberiferin and the biological activities of tuberiferin, dehydrobrabrachylaenolide, 6-epi-tuberiferin, and their synthetic intermediates.

Tuberiferin, 6-epi-tuberifelin, dehydrobrachylaenolide and two series of eudesmanolides, eudesmane-12,6 α-lactones and eudesmane-12,6ß-lactones, were synthesized for the studies of the structure-activity relationships to explore novel anti-inflammatory, anti-cancer and crop disease prevention agents. The anti-inflammatory activities were tested by the inhibitory on the induction of inter-cellular adhesion molecule (ICAM-1), the permeation of leucocyte into inflammatory air pouch of murine, the killing function of cytotoxic T-lymphocytes (CTL), production of IL-1; The anti-cancer activities were established on the cytotoxic activities to six kinds of cell lines (P388, CCRF-CEM, VA-13, HepG2, QG-56, and WI-38). Results showed that Dehydrobrachylaenolide (an exo-endo cross conjugated dienone and α-methylene γ-lactone) was the most effective compound inhibiting ICAM-1 (IC50 3.0 µM) and the cell line VA-13 (IC50 0.45 µM); Compound 20 with an α-bromo-ketone moiety embraced the most potent inhibitory activity towards the permeation of leucocyte into inflammatory air pouches of murine in vivo (inhibitory ratio 54% at 10 mg); Compound 25 with an α-bromo-ketone and α-methylene trans-γ-lactone) showed the most significant inhibitory activity on the killing function of CTL (IC50 18 µM), as well as the cell lines of CCRF-CEM (IC50 1.1 µM) and P388 (IC50 1.21 µM) ; Tuberiferin (an α,ß-unsaturated ketone and α- methylene γ-lactone) was on the top effective inhibitory on the production of IL-1; Compounds 19 with an α-bromo-ketone and α-methylene cis-γ-lactone exhibited the most potent inhibitory of QG-56 (IC50 12.5 µM); Compound 29 with an α-bromo-α,ß-unsaturated ketone and α-methylene γ-lactone) showed significant inhibitory for HepG2 (IC50 1.23 µM) , though potently inhibited WI 38 (IC50 0.31 µM) as well. A conclusion may be reached that the α-Methylene γ-lactone moiety, exo-endo cross conjugated dienone moiety, and α-bromo-ketone withα-methylene moiety might be essential for eudesmanolides in the expression of their anti-inflammatory, anti-tumour biological activities. Similarly, the above mentioned key moieties are also responsible for the preventive activity of crop disease controlling.

The characteristic regulation of gene expression Lbp and Sod3 in peri-implant connective tissue of rats.

The aim of this study was to investigate the characteristic gene expression profile and localization of peri-implant connective tissue (PICT) compared with those of periodontal connective tissue (PCT) and oral mucosal connective tissue (OMCT). Upper first molar of 5-week-old rats were extracted and titanium implant were placed for PICT group. PCT and OMCT were used as control. Laser microdissected connective tissue at 4 weeks used for microarray analysis. The expression and localization of selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Approximately, 1000 genes of upregulated and downregulated in PICT compared with PCT and OMCT were recognized. Based on the results of microarray analysis and qRT-PCR were demonstrated lipopolysaccharide binding protein (Lbp) as a specific upregulated gene and superoxide dismutase 3 (Sod3) as a specific downregulated gene in PICT. Immunoreaction of LBP and F4/80 as macrophage marker localized to subepithelial and implant facing connective tissue in PICT. SOD3 expression was not observed in PICT, reactive oxygen species, a target of superoxide dismutase, was strongly and locally expressed in all three tissues. Our data suggested that the upregulation of Lbp and downregulation of Sod3 are as characteristic gene expression pattern in PICT.

The prevalence and clinical features of asthma-COPD overlap (ACO) definitively diagnosed according to the Japanese Respiratory Society Guidelines for the Management of ACO 2018.

Background Asthma-COPD overlap (ACO) is a disease that shares clinical features of both asthma and COPD. The purpose of this study is to investigate the prevalence and clinical features of ACO. Methods We retrospectively reviewed data for 170 patients with persistent airflow limitation and diagnosed them according to "The Japanese Respiratory Society Guidelines for the Management of ACO 2018". Results Of the 170 patients, 111 were diagnosed as follows : COPD (74 patients, 66.6%), ACO (34 patients, 30.6%), and asthma (3 patients, 2.8%). There was no significant difference in clinical features between ACO and COPD patients. The following pulmonary function tests were significantly lower in ACO than in COPD patients : forced expiratory volume in 1 second/forced vital capacity, peak expiratory flow, maximal mid-expiratory flow, and the maximum expiratory flow at 50%and75%. The following respiratory impedance parameters were significantly higher in ACO than in COPD patients : respiratory resistance (Rrs) at 5 Hz (R5), Rrsat 20 Hz (R20), R5-R20, and low-frequency reactance area. Conclusions About 30% of patients with persistent airflow limitation were diagnosed with ACO. ACO patients had lower lung function and higher respiratory impedance compared with COPD patients. J. Med. Invest. 66 : 157-164, February, 2019.

Implant-supported Prostheses in Patient with Sjögren's Syndrome: Clinical Report with 3-year Follow-up.

Sjögren's syndrome (SS), an autoimmune disorder, affects the exocrine glands, including the lacrimal and salivary glands. It is characterized by symptoms of dry eye and dry mouth. As secretion of saliva decreases, patients with SS experience rampant caries, pain in the oral mucosa, inflammation and hardening of the salivary glands, abnormal taste, dysphagia, and loss of teeth earlier than healthy individuals. A removable partial denture is often used as a prosthesis after tooth loss. Compromised salivary lubrication, however, can produce traumatic ulceration of the mucosa, making use of a removable prosthesis in SS patients painful. In such cases, a dental implant is likely to be requested as an alternative. This report describes dental implant treatment in an SS patient, a 50-year-old woman who presented with the chief complaint of masticatory dysfunction and pain due to a removable partial denture. Eight implants were placed in the maxillary and mandibular first molar tooth and second molar tooth regions. Following a 4-month non-loading period, second-stage surgery and provisional restoration with a screwretained implant temporary crown were performed. Screw-retained superstructures were fitted by means of a customized titanium abutment and zirconia crown as the final restoration. No complications, including inflammation of peri-implant soft tissue or resorption of peri-implant bone, were observed at 3 years following placement of the superstructures.

5´-UTR introns enhance protein expression in the yeast Saccharomyces cerevisiae.

Saccharomyces cerevisiae is one of the most suitable microorganisms for recombinant protein production. To enhance protein production, various expression systems have been intensively studied. However, the effect of introns on protein expression has not been examined deeply in S. cerevisiae. In this study, we analyzed the effect of some introns on protein expression. RPS25A, RPS26A, and RPS26B contain single introns within the 5´-untranslated regions (5´-UTRs), and RPS24A has an intron just downstream of the initiation codon. Expression activity of the promoter regions containing introns (intron promoters) were analyzed by luciferase reporter assays. These intron promoters showed higher expression than the TDH3 promoter (TDH3p), which is one of the strongest promoters in S. cerevisiae. Deletion of the introns from these promoters decreased luciferase expression, indicating that introns have a role in enhancing protein expression. To develop artificial strong intron promoters, several chimeric promoters were constructed using the TDH3p and the RPS25A intron promoter. A construct containing the entire TDH3p followed by the RPS25A intron showed about 50-fold higher expression than the TDH3p alone. Inducible expressions driven by the GAL10 promoter and the CUP1 promoter were also enhanced by the RPS25A intron. However, enhancement of mRNA accumulation by the TDH3p and the GAL10 promoter with the RPS25A intron was lower than the effect on luciferase activity, suggesting that the intron affects post-transcriptionally. The chimeric promoter, TDH3p-RPS25A-intron, enhanced expressions of some, but not all proteins examined, indicating that 5'-UTR introns increase production of a certain type of recombinant proteins in S. cerevisiae.

Two cases of acute respiratory distress syndrome with high values of Chlamydophila pneumoniae-specific antibodies.

We herein report two cases of acute respiratory distress syndrome (ARDS) with high values of Chlamydophila pneumoniae-specific antibodies. In the first case (a 65-year-old man), high levels of anti-C. pneumoniae antibodies (IgG and IgA) were detected on admission, and the anti-C. pneumoniae IgA level rose by Day 30. The patient was successfully treated with quinolone and steroids. In the second case (an 85-year-old man), abnormally high levels of anti-C. pneumoniae IgM were detected on admission. The patient did not recover, despite receiving treatment with several antibiotics and anti-inflammatory agents. Neither of the patients displayed other pathogen-specific antigens or antibodies. Chlamydophila pneumonia is usually mild, although it can cause severe interstitial pneumonia and ARDS in reinfected patients and the elderly.