Modular knots, automorphic forms, and the Rademacher symbols for triangle groups.

É. Ghys proved that the linking numbers of modular knots and the "missing" trefoil K 2 , 3 in S 3 coincide with the values of a highly ubiquitous function called the Rademacher symbol for SL 2 Z . In this article, we replace SL 2 Z = Γ 2 , 3 by the triangle group Γ p , q for any coprime pair (p, q) of integers with 2 ≤ p < q . We invoke the theory of harmonic Maass forms for Γ p , q to introduce the notion of the Rademacher symbol ψ p , q , and provide several characterizations. Among other things, we generalize Ghys's theorem for modular knots around any "missing" torus knot K p , q in S 3 and in a lens space.

Respiratory sarcopenia: A position paper by four professional organizations.

We defined respiratory sarcopenia as a coexistence of respiratory muscle weakness and decreased respiratory muscle mass. Although respiratory muscle function is indispensable for life support, its evaluation has not been included in the regular assessment of respiratory function or adequately evaluated in clinical practice. Considering this situation, we prepared a position paper outlining basic knowledge, diagnostic and assessment methods, mechanisms, involvement in respiratory diseases, intervention and treatment methods, and future perspectives on respiratory sarcopenia, and summarized the current consensus on respiratory sarcopenia. Respiratory sarcopenia is diagnosed when respiratory muscle weakness and decreased respiratory muscle mass are observed. If respiratory muscle mass is difficult to measure, we can use appendicular skeletal muscle mass as a surrogate. Probable respiratory sarcopenia is defined when respiratory muscle weakness and decreased appendicular skeletal muscle mass are observed. If only respiratory muscle strength is decreased without a decrease in respiratory function, the patient is diagnosed with possible respiratory sarcopenia. Respiratory muscle strength is assessed using maximum inspiratory pressure and maximum expiratory pressure. Ultrasonography and computed tomography are commonly used to assess respiratory muscle mass; however, there are insufficient data to propose the cutoff values for defining decreased respiratory muscle mass. It was jointly prepared by the representative authors and authorized by the Japanese Society for Respiratory Care and Rehabilitation, Japanese Association on Sarcopenia and Frailty, Japanese Society of Respiratory Physical Therapy and Japanese Association of Rehabilitation Nutrition. Geriatr Gerontol Int 2023; 23: 5-15.

Effect of tiotropium/olodaterol on sedentary and active time in patients with COPD: post hoc analysis of the VESUTO® study.

Background: Patients with COPD are less physically active. This post hoc analysis of a randomized, double-blind, active-controlled, crossover trial assessed the efficacy of once-daily tiotropium/olodaterol combination therapy versus tiotropium monotherapy in Japanese patients with COPD. Patients and methods: Patients were provided with a three-axis accelerometer to measure sedentary and active behavior defined as 1.0-1.5 metabolic equivalents (METs), ≥2.0 METs, and ≥3.0 METs, respectively. Of the 182 patients enrolled, 131 satisfied the conditions for the present analysis and were randomized to tiotropium monotherapy (n=62) or tiotropium/olodaterol combination therapy (n=69). Results: Tiotropium/olodaterol combination therapy significantly reduced the duration of 1.0-1.5 MET activity by 8.64 mins (p=0.040) and significantly increased the duration of ≥2.0 MET and ≥3.0 MET activity by 6.51 mins (p=0.017) and 2.60 mins (p=0.008), respectively, compared with tiotropium alone. Subgroup analyses showed that better lung function, milder dyspnea, and higher levels of physical activity at baseline were associated with reduced sedentary time and increased duration of physical activity. Conclusion: Tiotropium/olodaterol combination therapy significantly reduced sedentary time and improved physical activity compared with tiotropium monotherapy. This trial was registered in ClinicalTrials.gov (NCT02629965).

Toward the harmonization of work with treatment and prevention for patients with chronic respiratory failure.

Home oxygen therapy (HOT), also known as long-term oxygen therapy, is prescribed to patients with chronic respiratory failure (CRF) due to advanced respiratory diseases, as it has been shown to improve the prognosis of patients with chronic obstructive pulmonary disease (COPD). However, the therapeutic impact of HOT does not fully reflect the "socialization" of patients, which is one of the final goals of "comprehensive pulmonary rehabilitation", proposed by the Japanese Respiratory Society. Since working is one form of socialization, we evaluated a 55-yr-old worker prescribed with HOT for the management of advanced COPD to elucidate and assess the social barriers experienced by HOT users. This case demonstrates a variety of factors affecting patients, respiratory physicians, occupational physicians, and management teams, which prevents patients from working. By elucidating these factors and seeking solutions, the promotion of the "harmonization of work with treatment and prevention" will both improve working environments and encourage CRF patients to continue working, leading to better socialization. Thus, the "harmonization of working with treatment and prevention" for CRF patients is a core goal for the promotion of both "health and productivity management" and "comprehensive pulmonary rehabilitation."

Efficacy of tiotropium/olodaterol on lung volume, exercise capacity, and physical activity.

Purpose: This study evaluated the efficacy of tiotropium/olodaterol vs tiotropium on lung function, exercise capacity, and physical activity in patients with COPD. Patients and methods: A total of 184 patients aged ≥40 years with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II-IV) received tiotropium/olodaterol for 6 weeks, then tiotropium for 6 weeks, or vice versa. The primary endpoint was inspiratory capacity (IC) at peak post-dose. Results: Adjusted mean IC after 6-week treatment was 1.990 L with tiotropium/olodaterol vs 1.875 L with tiotropium (difference: 115 mL; 95% CI: 77, 153; p<0.0001). Forced expiratory volume in 1 s (difference: 105 mL; 95% CI: 88, 123), forced vital capacity (difference: 163 mL; 95% CI: 130, 197), and slow vital capacity (difference: 134 mL; 95% CI: 91, 176) improved with tiotropium/olodaterol (all p<0.0001). Adjusted mean 6-min walk distance was similar between treatments in the overall population but was significantly increased with tiotropium/olodaterol in the subgroup with Global Initiative for Chronic Obstructive Lung Disease stage III/IV at baseline (difference: 18.1 m; 95% CI: 2.3, 33.9; p=0.0254). In a post hoc analysis, tiotropium/olodaterol improved the values for ≥2.0 metabolic equivalents (difference: 5.0 min; 95% CI: 0.4, 9.7; p=0.0337). Conclusion: Tiotropium/olodaterol significantly improved IC compared with tiotropium and potentially enhanced the exercise capacity in COPD patients. A slight improvement in physical activity of relatively more than moderate intensity was also seen with tiotropium/olodaterol.

Study Design of VESUTO®: Efficacy of Tiotropium/Olodaterol on Lung Hyperinflation, Exercise Capacity, and Physical Activity in Japanese Patients with Chronic Obstructive Pulmonary Disease.

INTRODUCTION: The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD. METHODS: A protocol is developed for the VESUTO® study that investigates the efficacy of tiotropium/olodaterol fixed-dose combination (FDC) compared with tiotropium alone on inspiratory capacity (IC, volume from functional residual capacity to total lung capacity), exercise capacity, and daily physical activity in Japanese patients with COPD. RESULTS: A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT® (Boehringer Ingelheim, Ingelheim, Germany) inhaler in the morning]. The primary endpoint is IC at rest measured at 60 min post-dose after 6 weeks treatment. The secondary endpoints include the 6-min walk distance (6MWD) at 90 min post-dose and physical activity measured by the activity monitor in the last 2 weeks of the 6-week treatment periods. Lung function tests will also be assessed after 6 weeks treatment. A mixed-effects model repeated measures approach will be used for the primary and secondary endpoints. CONCLUSION: The VESUTO® study is the first randomized interventional study to investigate exercise capacity (6MWD) and physical activity measured by a 3-axis accelerometer in Japanese patients with COPD. The study could provide additional evidence of long-acting muscarinic antagonist (LAMA) + long-acting ß2-agonist (LABA) combination therapy on patients' physical activities as well as lung function. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015). FUNDING: The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.

Cytotoxic activity of benzo[b]cyclohept[e][1,4]oxazines.

BACKGROUND: Although numerous articles have dealt with the biological activities of azulenes, studies of benzo[b]cyclohept[e][1,4]oxazines are limited. In the present study, we investigated a total of 14 newly-synthesized benzo[b]cyclohept[e][1,4]oxazines for their growth stimulation at low concentrations (so-called 'hormesis'), cytotoxicity at higher concentrations and apoptosis-inducing activity. MATERIALS AND METHODS: Cytotoxicity of these compounds against human normal gingival fibroblast (HGF) and human oral squamous cell carcinoma cell lines derived from gingival tissue (Ca9-22), was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The tumor specificity (TS) was determined by the ratio of the 50% cytotoxic concentration (CC50) value for HGF cells to that for Ca9-22 cells. Apoptosis induction was evaluated by DNA fragmentation and caspase-3 activation. RESULTS: Compounds 10-(2-methoxyethylamino)benzo[b] cyclohept[e][1,4]oxazine and 10-(3-methoxypropylamino) benzo[b]cyclohept[e][1,4] oxazine, but not other compounds, induced hormesis only in HGF cells. Compound 10-(6-hydroxyhexylamino)benzo[b] cyclohept[e][1,4]oxazine [4] showed the highest cytotoxicity against Ca9-22 cells, followed by 10-(4-hydroxybutylamino) benzo[b]cyclohept[e] [1,4]oxazine and 10-(5-hydroxypentylamino)benzo[b]cyclo-hept[e][1,4]oxazine. Compound [4] did not induce apoptosis markers, but rather induced necrotic cell death (characterized by a smear pattern of DNA fragmentation). CONCLUSION: The present study suggests that the OH group and a certain length of methylene group are necessary for maximal cytotoxicity, and substitution of fluoride in the benzene ring enhances cytotoxicity.

Anti-UV activity of newly-synthesized water-soluble azulenes.

BACKGROUND: We have previously reported that azulene-related compounds can protect cells from UV-induced cytotoxicity. However, due to their high water insolubility, their anti-UV activity could not be accurately determined. In the present study, we newly-synthesized a total of nine derivatives with higher water solubility, and re-investigated their anti-UV activity. MATERIALS AND METHODS: Cytotoxicity of these compounds against three human normal oral and three human oral cells squamous cell carcinoma cell lines (OSCCs) was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The concentration that reduced the viable cell number by 50% (CC(50)) and the concentration that increased the viability of UV-irradiated cells to 50% (EC(50)) were determined by the dose-response curves. Anti-UV activity (SI) was determined by the ratio of CC(50) to EC(50). The tumor specificity was determined by the ratio of the mean CC(50) value for the normal cells to that for OSCC cells. Apoptosis induction was evaluated by DNA fragmentation and caspase activation. RESULTS: All compounds except one (sodium 7-isopropyl-3-ethylazulene-1-sulfonate) were new compounds, and showed some tumor specificity (TS value=1.4 to 3.5), without induction of hormesis or apoptosis at lower and higher concentrations, respectively. Sodium 3-methylazulene-1-sulfonate showed the highest tumor specificity and potent anti-UV activity, approximately one half that of sodium ascorbate, the positive control. CONCLUSION: These data suggest the possible applicability of newly-synthesized water-soluble azulenes as skin care products protecting from UV irradiation.

Pulmonary rehabilitation program including respiratory conditioning for chronic obstructive pulmonary disease (COPD): Improved hyperinflation and expiratory flow during tidal breathing.

BACKGROUND: Pulmonary rehabilitation has generally relieved symptoms, strengthened exercise endurance and improved health-related quality of life (QOL) in patients with COPD, but recovery of pulmonary function remains questionable. This analysis of our innovative rehabilitation program is directed at documenting changes in patients' expiratory airflow limitation, pulmonary symptoms and QOL. This program is designed to provide "respiratory conditioning", a physical therapist-assisted intensive flexibility training that focuses on stretching and rib cage mobilization. METHODS: Thirty-one patients with COPD who attended rehabilitation sessions at Juntendo University Hospital from 1999 to 2006 were analyzed. Pulmonary function, expiratory flow limitation during tidal breathing, six minute walk distance (6MWD), respiratory muscle strength, and St. George Respiratory Questionnaire (SGRQ) were measured before and after pulmonary rehabilitation. RESULTS: In participants ages 68±7 years, the FEV(1)% predicted was 39.3±15.7%. 6MWD, SGRQ and respiratory muscle strength were significantly improved after pulmonary rehabilitation. Although neither FEV(1)% predicted nor FEV(1)/FVC was affected to a significant extent, indicating little effect on airflow limitation, expiratory flow limitation in supine as well as seated during tidal breathing improved significantly. Moreover, rehabilitation significantly diminished TLC% predicted, FRC% predicted, RV% predicted and RV/TLC values, thus indicating a reduction of hyperinflation of the lungs at rest. CONCLUSIONS: The present results suggest that our rehabilitation program with respiratory conditioning significantly lowered the hyperinflation of lungs at rest as well as the expiratory flow limitation during tidal breathing. In patients with COPD, overall pulmonary function improved, exercise endurance increased and health-related QOL was enhanced.

Hormetic and UV-protective effects of azulene-related compounds.

BACKGROUND: We have previously reported a possible anti-inflammatory activity of azulene-, tropolone- and azulenequinone-related compounds. To further pursue the newly discovered biological activity of these compounds, five compounds that inhibited nitric oxide production by activated macrophages were investigated for their possible hormetic and anti-radiation effects. MATERIALS AND METHODS: Viable cell number of human oral normal cells (gingival fibroblast, pulp cell and periodontal ligament fibroblast) and three oral squamous cell carcinoma cell lines on treatment with various concentrations of each azulene-related compound was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Apoptosis induction was monitored by caspase-3 activation and DNA fragmentation. RESULTS: Among five compounds, only benzo[b]cyclohepta[e][1,4]thiazine slightly stimulated the growth of all three normal cell types, but not tumor cell lines, at concentrations slightly higher than cytotoxic concentrations. Using a newly established evaluation system for UV-induced cellular damage, we found that this compound slightly but significantly protected the cells from UV-induced cellular injury, and its effect was synergistically enhanced by sodium ascorbate. CONCLUSION: These data suggest the possible application of benzo[b]cyclohepta[e][1,4]thiazine in UV protection therapy.

Ultrasonographic evaluation of the diaphragm in patients with amyotrophic lateral sclerosis.

Real-time diaphragmatic movement was evaluated with ultrasonography in three patients with amyotrophic lateral sclerosis (ALS). The initial complaint of two patients was weakness of the extremities followed by dyspnoea later in the disease course, while the third patient had dyspnoea as the initial symptom. Ultrasonographic analyses revealed that the contractile function of the diaphragm was not maintained during maximum inspiratory effort, with unsatisfactory diaphragmatic excursion and no change in diaphragmatic thickness during respiration, indicating diaphragmatic paralysis. Ultrasonography may be useful for the diagnosis and follow up of diaphragmatic involvement with amyotrophic lateral sclerosis and other motor-neuron diseases.

Binary vectors and super-binary vectors.

A binary vector is a standard tool in the transformation of higher plants mediated by Agrobacterium tumefaciens. It is composed of the borders of T-DNA, multiple cloning sites, replication functions for Escherichia coli and A. tumefaciens, selectable marker genes, reporter genes, and other accessory elements that can improve the efficiency of and/or give further capability to the system. A super-binary vector carries additional virulence genes from a Ti plasmid, and exhibits very high frequency of transformation, which is valuable for recalcitrant plants such as cereals. A number of useful vectors are widely circulated. Whereas vectors with compatible selectable markers and convenient cloning sites are usually the top criteria when inserting gene fragments shorter than 15 kb, the capability of maintaining a large DNA piece is more important for consideration when introducing DNA fragments larger than 15 kb. Because no vector is perfect for every project, it is recommended that modification or construction of vectors should be made according to the objective of the experiments. Existing vectors serve as good sources of components.

[Measurement of diffusing capacity by the intrabreath method].

The diffusing capacity of the lung for carbon monoxide (DLco) is usually measured by the single breath method with a 10-second breath hold. With the introduction of rapid gas analyzers, an alternative method for measurement of DLco, the intrabreath method, has been developed. The intrabreath method does not depend upon length of time or other conditions during either breath holding or expiration. The aim of this study was to compare the single breath method and intrabreath method of DLco measurement. DLco measured by the intrabreath method (DLco IB) was compared with DLco measured by the single breath method (DLco SB) in 32 normal subjects, 88 patients with obstructive impairment and 39 patients with restrictive impairment. DLco SB could not be measured in 2 patients with obstructive impairment and 7 patients with restrictive impairment, while in all except one patient with severe restrictive impairment, DLco IB was able to be measured. There was an excellent correlation between DLco IB and DLco SB in normal subjects (rho = 0.942, p < 0.0001). There was no difference in the mean value between DLco IB (21.0 +/- 5.4 ml/min/mmHg) and DLco SB (20.9 +/- 4.9 ml/min/mmHg). In the obstructive impairment group there was also an excellent correlation between DLco IB and DLco SB (rho = 0.922, p < 0.0001). In the mild or moderate obstructive impairment group (%FEV1 > 50%), no difference between DLco IB (11.8 +/- 5.80 ml/min/mmHg) and DLco SB (12.4 +/- 4.68 ml/min/mmHg) was found. In the severe obstructive impairment group (%FEV1 < 50%), the DLco IB (7.29 +/- 3.61 ml/min/mmHg) was lower than the DLco SB (8.58 +/- 3.24 ml/min/mmHg) (p < 0.0001). The relation between DLco SB and DLco IB was equally strong in patients with restrictive impairment (rho = 0.742, p < 0.0001). There was an excellent correlation between DLco IB and DLco SB in normal subjects, the obstructive impairment group and the restrictive impairment group. The intrabreath method therefore seems to be a useful and reliable alternative to the single breath method for clinical measurement of DLco.

Elicitor-induced activation of phospholipases plays an important role for the induction of defense responses in suspension-cultured rice cells.

Biphasic generation of reactive oxygen species (ROS) induced by N-acetylchitooligosaccharide elicitor in rice cells was associated with the activation of phopholipase C (PLC) and phospholipase D (PLD). The activation of both enzymes was observed for the first phase of ROS generation, but only the activation of PLD was evident for the second response. Activation of PLD was associated with its recruitment to the membrane. Enzymatic products of these phospholipases, diacylglycerol (DG) and phosphatidic acid (PA), could induce ROS generation by themselves. Moreover, the addition of these lipids compensated the inhibition of the second phase of ROS generation by cycloheximide, indicating the involvement of the synthesis of PLD or related proteins in the second phase of ROS generation. DG and PA also induced the expression of elicitor-responsive genes in the absence of the elicitor. They could not induce phytoalexin biosynthesis by themselves but greatly enhanced the elicitor-induced phytoalexin accumulation. Further, the inhibition of PLD by 1-butanol inhibited the elicitor-induced phytoalexin accumulation, indicating the involvement of PLD and its reaction product, PA, in the induction of phytoalexin biosynthesis. These results indicated the importance of phospholipid signaling, especially by PLD and its product PA, in plant defense responses.

[Questionnaire on the attitude of the physicians in educating the elderly patients with chronic obstructive pulmonary disease about smoking cessation].

Smoking status, the extent of recognition of the relationship between smoking and COPD, and actual nature of education for smoking cessation by physicians have not yet been fully elucidated. To investigate perceptions about education for smoking cessation in the elderly by physicians who work in the clinic, questionnaires were sent to the 1,012 physicians who belong to the Yokohama City Medical Association. Of these, 311 respond and their data (31%) were included in the analysis. The questionnaire included questions on the importance of smoking cessation in the elderly, on the perception about the relationship between smoking and various diseases, and actual education for smoking cessation. The smoking status of the physicians themselves was also investigated. The distribution of current smokers, ex-smokers, and non-smokers among the physicians was 13%, 33%, and 54%, respectively. Seventy-five percent of ex-smokers answered that their experience of smoking cessation influenced their patient education for smoking cessation, and 39% of smokers answered that their smoking status did not influence it. Only 53% of the physicians replied that they actually performed education for smoking cessation to the elderly, and 8% of them replied that they hardly perform any or do not perform it. Smoking cessation is thought to be the only way to prevent the development of COPD. However, only a half of physicians recognized the importance of smoking cessation for the treatment and control of COPD in the elderly. In addition, less than one third of physicians perform nicotine replacement therapy for smoking cessation. Enlightenment for physicians should be needed to make them perform education for smoking cessation more aggressively.

[Chronic obstructive pulmonary disease (COPD) in the elderly: analysis from questionnaire about attitudes to the COPD guideline of the Japanese Respiratory Society and actual therapy for COPD used by physicians].

We have conducted a survey of attitudes to chronic obstructive pulmonary disease (COPD) in the elderly, a survey of attitudes to the COPD guideline prepared by the Japanese Respiratory Society, and a survey of the therapies actually used for this disease among physicians belonging to the Yokohama Medical Association. The results showed that most respondents thought that physicians, mainly except for respiratory physicians, miss the COPD patients because of failure to recognize COPD. The spread of the COPD guideline among physicians and the amount of therapy conducted according to this guideline were also insufficient. However, most physicians who know this guideline have used it well, and have also appreciated the contents. Thus, the results of our surveys suggested that this COPD guideline, with its step-by-step pharmacologic therapy, should be more widely disseminated, mainly among clinics and physicians that are not respiratory specialists. This would enable them to follow the guideline and improve their treatment of COPD. In addition, it was also supposed that the comprehensive respiratory rehabilitation should be more executed in the hospitals.

Gastric carcinoid tumors without autoimmune gastritis in Japan: a relationship with Helicobacter pylori infection.

In Japan, most cases of gastric carcinoid tumor (GCT) are unassociated with either autoimmune gastritis (AIG) showing type-A chronic atrophic gastritis (CAG-A) or Zollinger-Ellison syndrome (ZES). However, the pathogenesis of this tumor remains unknown. Recent studies have determined that Helicobacter pylori infection induces gastric carcinoid in Mongolian gerbils and that H. pylori lipopolysaccharide exerts a mitogenic effect on ECL cells. We examined five patients with histologically diagnosed GCT, 40 patients with H. pylori-positive gastric ulcer (Hp+GU), 24 patients with H. pylori-positive duodenal ulcer (Hp+DU), and 12 patients with AIG showing CAG-A topographically. We compared the prevalence of H. pylori infection, and the levels of gastrin and pepsinogen (PG) in the serum of patients with GCT with those of patients with Hp+GU, or Hp+DU, and AIG. We also investigated the histological characteristics of the tumor and the gastric corpus mucosa in the GCT patients. The levels of serum gastrin and PG I and II were measured using an RIA kit. In all five (100%) patients with GCT, H. pylori infection was present, without any evidence of AIG or ZES. The serum levels of gastrin in the GCT patients were higher than those in either Hp+GU or Hp+DU patients and lower than those in the AIG patients. In contrast, serum PG I levels and the PG I/II ratio were lower in the GCT group than in the Hp+GU or Hp+DU groups. Histologically, all GCTs were ECL cell tumors and peritumoral corporal mucosal atrophy was observed in four of the five patients with GCT. In conclusions, H. pylori infection and hypergastrinemia were found in the patients with GCT without AIG. This finding suggests that H. pylori infection may induce corporal mucosal atrophy and hypergastrinemia that can produce a GCT with time.