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In obstructive sleep apnea (OSA), the upper airway is obstructed during sleep due to obesity and/or posterior collapse of the tongue root. Maxillofacial morphological abnormalities increase the risk of OSA in the Asian population. This study sought to elucidate whether three-dimensional (3D) photogrammetry measurements correlate with the severity of OSA irrespective of sex and degree of obesity.A prospective pilot study was performed, in which 37 consecutive adult patients (M/F = 28/9) underwent polysomnography and 3D photogrammetry in the supine position for the diagnosis of OSA. Measurements obtained from 3D photogrammetry included mandibular width (Mw), mandibular length (Ml), mandibular depth (Md), mandibular width-length angle (Mwla), and mandibular area (Ma). The effects of sex and body mass index (BMI) on the measurements and their association with the apnea-hypopnea index (AHI) were statistically analyzed. The inter-rater reliability of the measurements was evaluated using intraclass correlation coefficients (ICC).Mwla (R = 0.73, p 0.01), Mw (R = 0.39, p 0.05), and Md (R = -0.34, p 0.05) were significantly correlated with the severity of OSA. On multivariate analysis, Mwla (p 0.01) and Md (p 0.05) remained independent factors for AHI after adjusting for sex, age, BMI, and neck circumference. In addition, diagnosability analysis revealed that Mwla was useful for identifying the presence of OSA (AHI ≥5) (cutoff: 78.6°, sensitivity: 0.938, specificity: 0.800, area under the curve: 0.931). The ICC was0.9, showing high reliability.This study suggests that Mwla measured using 3D photogrammetry can predict the presence of OSA and correlates with the severity of OSA, independent of obesity and sex.

The prevalence of sleep disordered breathing is high in patients with end-stage renal disease. Salt intake is related to the severity of obstructive sleep apnea in patients with resistant hypertension and hyperaldosteronism. We investigated the relationship between salt intake and sleep disordered breathing in patients on maintenance hemodialysis. We studied 128 dialysis outpatients (mean age 63 ± 11 years) who were followed at Kokura Daiichi Hospital. We estimated each patient's salt intake using an InBody S10 body composition analyzer and measured the 3% oxygen desaturation index (ODI) during sleep using a Pulsewatch: PMP-200 GplusX. The average estimated salt intake was 8.0 ± 2.6 g/day, and the median value of that was 7.5 g/day. Blood pressure (BP) before and after dialysis were 140 ± 18/78 ± 11 and 127 ± 13/72 ± 8 mmHg, respectively. The geometric average number of 3% ODI was 7.1, and sleep disordered breathing was detected in 30% of all subjects. The patients with ≥ 7.5 g/day salt intake were younger and more frequently male and had higher body mass index (BMI) and BP before dialysis compared to those with salt intakes

Yellow nail syndrome (YNS) is a rare disease comprising the clinical triad of yellow nail discoloration, pleural effusion, and lower limb lymphedema. We encountered a difficult-to-treat case of YNS in which the diagnosis was finally made based on intranodal lymphangiography. An 84-year-old man was admitted to our hospital with pleural effusion and yellow-green discoloration of the nails, accompanied by onychomycosis and limb lymphedema. Intranodal lymphangiography revealed a slow contrast flow and narrowing of the thoracic duct, suggesting lymphatic duct dysplasia and leading to the diagnosis of YNS.

Background: The vertical P-wave axis on electrocardiography (ECG) is a useful criterion for screening patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the clinical characteristics of patients with COPD with a vertical P-wave axis as they have not yet been elucidated. Methods: Keio University and its affiliated hospitals conducted an observational COPD cohort study over 3 years. We analyzed 201 patients using ECG and chest computed tomography. Results: The severity of airflow limitation was higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. Patients with a P-wave axis >75° exhibited significantly higher total COPD assessment test scores and increased St. George’s Respiratory Questionnaire total, activity, and impact scores than those with a P-wave axis ≤75°. The incidence of exacerbations over 1 and 3 years was significantly higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. The optimal cutoff for the P-wave axis for a percentage of the predicted forced expiratory volume in 1 s 75° than in those with a P-wave axis ≤75°. However, the ratio of the airway wall area did not differ between the 2 groups. Conclusions: Patients with COPD with a vertical P-wave axis exhibited severe airflow limitation and emphysema, a worse health status, and more frequent exacerbation than patients without a vertical P-wave. Detection of the vertical P-wave axis by ECG is beneficial for the management of patients with COPD.

Background Physical inactivity due to cachexia and muscle wasting is well recognized as a sign of poor prognosis in chronic obstructive pulmonary disease (COPD). However, there have been no reports on the relationship between trunk muscle measurements and energy expenditure parameters, such as the total energy expenditure (TEE) and physical activity level (PAL), in COPD. In this study, we investigated the associations of computed tomography (CT)-derived muscle area and density measurements with clinical parameters, including TEE and PAL, in patients with or at risk for COPD, and examined whether these muscle measurements serve as an indicator of TEE and PAL. Methods The study population consisted of 36 male patients with (n = 28, stage 1–4) and at risk for (n = 8) COPD aged over 50 years. TEE was measured by the doubly labeled water method, and PAL was calculated as the TEE/basal metabolic rate estimated by the indirect method. The cross-sectional areas and densities of the pectoralis muscles, rectus abdominis muscles, and erector spinae muscles were measured. We evaluated the relationship between these muscle measurements and clinical outcomes, including body composition, lung function, muscle strength, TEE, and PAL. Results All the muscle areas were significantly associated with TEE, severity of emphysema, and body composition indices such as body mass index, fat-free mass, and trunk muscle mass. All trunk muscle densities were correlated with PAL. The product of the rectus abdominis muscle area and density showed the highest association with TEE (r = 0.732) and PAL (r = 0.578). Several trunk muscle measurements showed significant correlations with maximal inspiratory and expiratory pressures, indicating their roles in respiration. Conclusions CT-derived measurements for trunk muscles are helpful in evaluating physical status and function in patients with or at risk for COPD. Particularly, trunk muscle evaluation may be a useful marker reflecting TEE and PAL.

Although weight loss suggests poor prognosis of COPD, only a few studies have examined total energy expenditure (TEE) or physical activity level (PAL) using the doubly labelled water (DLW) method. We evaluated TEE and PAL using the DLW method together with a triaxial accelerometer to elucidate the relationships between TEE, PAL and clinical parameters leading to a practical means of monitoring COPD physical status. This study evaluated 50- to 79-year-old male patients with mild to very severe COPD (n=28) or at risk for COPD (n=8). TEE, activity energy expenditure for 2 weeks and basal metabolic rate were measured by DLW, an accelerometer and indirect calorimetry, respectively. All patients underwent pulmonary function, chest-computed tomography, 6-min walk test, body composition and grip strength tests. Relationships between indices of energy expenditure and clinical parameters were analysed. Bland–Altman analysis was used to examine the agreement of TEE and PAL between the DLW method and the accelerometer. TEE and PAL using DLW in the total population were 2273±445 kcal·day−1 and 1.80±0.20, respectively. TEE by DLW correlated well with that from the accelerometer and grip strength (p, Although total energy expenditure and physical activity level in COPD patients were underestimated by an accelerometer, they can be predicted using indices of the accelerometer and clinical parameters such as the 6-min walk distance and grip strength. https://bit.ly/2OYbuaI

Emphysema is a major pathological change in chronic obstructive pulmonary disease (COPD). However, the annual changes in the progression of emphysematous have not been investigated. We aimed to determine possible baseline predicting factors of the change in emphysematous progression in a subgroup of COPD patients who demonstrated rapid progression. In this observational study, we analyzed patients with COPD who were followed up by computed tomography (CT) at least two times over a 3-year period (n = 217). We divided the annual change in the low attenuation area percentage (LAA%) into quartiles and defined a rapid progression group (n = 54) and a non-progression group (n = 163). Predictors of future changes in emphysematous progression differed from predictors of high LAA% at baseline. On multivariate logistic regression analysis, low blood eosinophilic count (odds ratio [OR], 3.22; P = 0.04) and having osteoporosis (OR, 2.13; P = 0.03) were related to rapid changes in emphysematous progression. There was no difference in baseline nutritional parameters, but nutritional parameters deteriorated in parallel with changes in emphysematous progression. Herein, we clarified the predictors of changes in emphysematous progression and concomitant deterioration of nutritional status in COPD patients.

Shingo Nakayama,1 Shotaro Chubachi,1 Kaori Sakurai,1 Hidehiro Irie,1 Akihiro Tsutsumi,1 Mizuha Hashiguchi,2 Yuji Itabashi,3 Mitsushige Murata,4 Hidetoshi Nakamura,5 Koichiro Asano,6 Koichi Fukunaga1 1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; 2Division of Pulmonary Medicine, Keiyu Hospital, Yokohama, Kanagawa 220-0012, Japan; 3Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan; 4Center for Preventive Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; 5Division of Pulmonary Medicine, Saitama Medical University Hospital, Saitama 350-0495, Japan; 6Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Isehara-Shi, Kanagawa 259-1193, JapanCorrespondence: Shotaro ChubachiDivision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo 160-8582, JapanTel +81-3-5363-3406Fax +81-3-3353-2502Email bachibachi472000@live.jpBackground: Pulmonary hypertension (PH) is a major comorbidity of chronic obstructive pulmonary disease (COPD). However, the association of PH detected by echocardiography and COPD-related outcome in longitudinal follow-up has not been elucidated. In this study, we aimed to investigate the relationship between clinical characteristics of COPD patients with PH detected by echocardiography and various outcome parameters such as COPD exacerbation and health status over a three-year observation period.Methods: In this observational study, we analyzed patients with COPD who underwent chest computed tomography and echocardiography at baseline (n = 183).Results: The prevalence of PH was 21.9% (40 patients). The median estimated systolic pulmonary artery pressure in patients with PH was 38.8 mmHg. COPD patients with PH were older, had a lower body mass index, scored worse in the COPD Assessment Test and St. George’s Respiratory Questionnaire, and exhibited a lower diffusing capacity of the lung for carbon monoxide in comparison to patients without PH. In computed tomography images, the percentages of low-attenuation areas (LAA%) and interstitial abnormalities were higher in COPD patients with PH than in those without PH. Higher values for LAA% (LAA ≥ 30%) and interstitial abnormalities independently increased the risk of PH. The ratio of main pulmonary diameter to aortic artery diameter was significantly correlated with estimated systolic pulmonary artery pressure. In the follow-up analysis, the frequency of exacerbations in three years was significantly higher in patients with PH compared to patients without PH.Conclusion: In this study, we identified the clinical characteristics of COPD patients with PH detected by echocardiography. The presence of PH assessed by echocardiography was related to future COPD exacerbations and closely related to radiographical emphysema.Keywords: comorbidity, COPD, echocardiography, pulmonary hypertension

Background and objectiveWeight loss and reduced fat-free mass are independent risk factors for mortality among patients with chronic obstructive pulmonary disease (COPD). These factors are important for determining diet therapy and examining the validity of assessment for energy intake (EI). We assessed the agreement of EI between a brief-type self-administered diet history questionnaire (BDHQ) and the doubly labelled water (DLW) method among male patients with stable/at risk for COPD.MethodIn this cross-sectional observational study, data for 33 male patients were analysed. At the first visit, EI was estimated using a BDHQ (EIBDHQ). Total energy expenditure (TEE) was measured during 13–15 days by the DLW method, while corrected EI was calculated using the TEE and weight change during the DLW period (EIDLW). The difference between EIBDHQ and EIDLW was evaluated by the Bland-Altman method. Multiple regression analysis was used to determine the proportion of variance in the difference between EIBDHQ and EIDLW, as determined by the patient’s characteristics.ResultsEIBDHQ was 2100 (95% CI: 1905 to 2295) kcal/day in the total population. A fixed bias was observed between EIBDHQ and EIDLW as −186 (95% CI: −422 to 50) kcal/day, while a proportional bias was not detected by the Bland-Altman analysis. Age, weight, anxiety and interleukin 6 were responsible for 61.7% of the variance in the difference between both EIs in a multiple regression model.ConclusionsThe BDHQ underestimated EI among male patients with stable/at risk for COPD, but this estimation error was within an acceptable range compared with previous studies. EIBDHQ precision might be improved by considering common COPD traits, including inflammatory condition and mental state.

Aim To evaluate the association between periodontal disease and pneumonia mortality in haemodialysis patients. Materials and methods This prospective cohort study included 211 patients (mean age, 64.4 years) undergoing haemodialysis at a single medical centre. The patients underwent a baseline clinical dental examination in 2008 and were then followed up until July 2015. Periodontal disease was defined as the presence of clinical attachment loss of ≥4 mm in ≥30% of the probed sites. The primary endpoint, that is death from pneumonia, was determined by reviewing death certificates and was analysed using the competing-risks regression model. Results At baseline, 92 patients (43.6%) had periodontal disease. The median follow-up period was 84 months (interquartile range, 36-86 months). Of the 68 deaths that occurred, 21 were from pneumonia. The multivariable competing-risks regression model showed that periodontal disease was significantly associated with death from pneumonia (adjusted subhazard ratio, 3.49; 95% confidence interval, 1.14-10.64), after adjusting for other baseline health characteristics. Conclusions The results of this study suggest that periodontal disease is independently associated with pneumonia mortality in haemodialysis patients. Future studies evaluating the potential effect of oral interventions for periodontal health improvement on pneumonia in haemodialysis patients would be of great interest.

Background The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a subjective measure of quality of life. The aim of this study was to examine the characteristics of COPD patients with increasing CAT scores within 3 years. Methods Keio University and its affiliate hospitals conducted an observational COPD cohort study over 3 years. St. George's Respiratory Questionnaire (SGRQ) and CAT were completed at baseline and annually thereafter. Patients who had at least 3 CAT scores were included (n = 315). The ΔCAT score/year and ΔSGRQ score/year were calculated by the slope between each of the measures and the date of measurement. Results The median ΔCAT score/year was 0.4, and ΔCAT score/year was significantly correlated with ΔSGRQ total score/year. Using an annual cut-off CAT score of +2 points, patients who deteriorated (n = 79) were older, had lower %FEV 1 , and more severe emphysema on computed tomography scan at baseline than patients who did not deteriorate. The baseline value was not a determinant of subsequent changes in the CAT score. Longitudinal changes in the CAT score were positively correlated with those in the SGRQ score. Conclusions Old age and severe COPD, not the CAT score at one time point, predicted worsening quality of life.

Shotaro Chubachi,1 Saeko Takahashi,1 Akihiro Tsutsumi,1 Naofumi Kameyama,1 Mamoru Sasaki,1 Katsuhiko Naoki,1 Kenzo Soejima,1 Hidetoshi Nakamura,2 Koichiro Asano,3 Tomoko Betsuyaku1 On behalf of the Keio COPD Comorbidity Research Group 1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, 2Department of Respiratory Medicine, Saitama Medical University, Irima-gun, Saitama, 3Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Isehara-shi, Kanagawa, Japan Background: Only a few studies have evaluated the radiologic features of pre-existing structural abnormalities where lung cancer may develop. This study aimed to analyze the computed tomography (CT) images of lung areas where new cancer developed in chronic obstructive pulmonary disease (COPD) patients. Patients and methods: We conducted a multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research, to assess the incidence of lung cancer. Emphysema and interstitial abnormalities were evaluated in 240 COPD patients who had baseline CT scans applicable for further digital analyses. For patients who developed lung cancer during the 3-year follow-up period, the local spherical lung density of the precancerous area was individually quantified. Results: Lung cancer was newly diagnosed in 21 participants (2.3% per year). The percentage of low attenuation area in patients who developed lung cancer was higher than that of the other patients (20.0% vs 10.4%, P=0.014). The presence of emphysema (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.0–29.0, P=0.049) or interstitial lung abnormalities (OR 15.6, 95% CI 4.4–65.4, P

Periodontitis is common among dialysis patients. The current cross-sectional study aimed to explore associations between periodontitis and health-related quality of life (HRQoL) among hemodialysis patients. Data from 188 dentate patients undergoing hemodialysis between May and July 2008 at a medical center in Kitakyushu city, Japan, were analyzed while applying modified Centers for Disease Control and Prevention/American Academy of Periodontology periodontitis case definitions to categorize the participants into the following three groups: severe, moderate, and no/mild periodontitis, respectively. HRQoL was assessed by the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) where a higher score indicates better health status. Associations between periodontitis groups and the eight health domains of SF-36 were evaluated using general linear models that were adjusted for age, sex, underlying cause of dialysis, duration of dialysis, comorbidities, serum biomarkers, body mass index, smoking status, and alcohol use. Among the 188 participants, 18 (9.6%) had severe periodontitis, 100 (53.2%) had moderate periodontitis, and the remaining 70 (37.2%) had no/mild periodontitis. Compared with the participants with no/mild periodontitis, those with severe periodontitis had worse scores in the following five of eight SF-36 health scales: physical functioning, role physical, vitality, social functioning, and mental health (P

Background and objectives Patients with chronic obstructive pulmonary disease (COPD) frequently suffer from various comorbidities. Recently, cluster analysis has been proposed to examine the phenotypic heterogeneity in COPD. In order to comprehensively understand the comorbidities of COPD in Japan, we conducted multicenter, longitudinal cohort study, called the Keio COPD Comorbidity Research (K-CCR). In this cohort, comorbid diagnoses were established by both objective examination and review of clinical records, in addition to self-report. We aimed to investigate the clustering of nineteen clinically relevant comorbidities and the meaningful outcomes of the clusters over a two-year follow-up period. Material and Methods The present study analyzed data from COPD patients whose data of comorbidities were completed (n = 311). Cluster analysis was performed using Ward's minimum-variance method. Results Five comorbidity clusters were identified: less comorbidity; malignancy; metabolic and cardiovascular; gastroesophageal reflux disease (GERD) and psychological; and underweight and anemic. FEV 1 did not differ among the clusters. GERD and psychological cluster had worse COPD assessment test (CAT) and Saint George's respiratory questionnaire (SGRQ) at baseline compared to the other clusters (CAT: p = 0.0003 and SGRQ: p = 0.00046). The rate of change in these scores did not differ within 2 years. The underweight and anemic cluster included subjects with lower baseline ratio of predicted diffusing capacity (D L co/V A ) compared to the malignancy cluster (p = 0.036). Conclusions Five clusters of comorbidities were identified in Japanese COPD patients. The clinical characteristics and health-related quality of life were different among these clusters during a follow-up of two years.

The spherical micro-cells are a semi-transparent photovoltaic (PV) technology which can contribute to improve the sustainability of greenhouse systems. Previous prototypes were tested in laboratory conditions, but the size was not suitable for the greenhouse roof application. In this work, a new prototype has been developed and tested on a real greenhouse roof. The semi-transparent PV module (STM) was composed by 4800 spherical silicon micro-cells (1.2 mm diameter) sandwiched between glass plates and integrated on a greenhouse roof with 26.5° slope. The STM was 910 mm long and 610 mm wide to match the size of the greenhouse framework. The percentage of the STM area covered with micro-cells was 2.3%, reaching 9.7% considering the metallic conductors. The cell density was 2 cells cm−2 and the measured perpendicular light transmissivity of the semi-transparent area was 73%. The characteristics of the prototype were compared with those of a conventional planar multi-crystalline silicon module (CPM). The module conversion efficiency was steadily around 0.2% over wide incident sunlight angle. The micro-cells never completely eclipse the incident sunlight when observed from more than 1 m distance from the roof, keeping the eclipsing level at 9.7%. The yield factor of the STM was slightly higher than the CPM because of the isotropic properties of the spherical cells, which are able to use both the sky-incident and the ground-reflected irradiation for energy production, irrespective of the module slope. The prototype STM is promising for greenhouse roof applications and its performance can be improved by increasing the conversion efficiency.

Rationale Various determinants of osteoporosis have been previously identified. However, only a few longitudinal studies have examined related factors. We aimed to investigate factors predicting and modifying rapid decline of bone mineral density in patients with chronic obstructive pulmonary disease. Methods We analyzed patients with chronic obstructive pulmonary disease whose bone mineral density were measured at least three times over three years (n = 111). We divided annual per cent changes of bone mineral density in different body parts into tertiles. Rapid decliners (n = 33) were defined as those with the largest decline in at least two parts; all other participants were defined as non-rapid decliners (n = 78). Results At enrollment, bone mineral density did not differ between the two groups. However, rapid decliners had a significantly greater rate of new vertebral fractures over 3 years compared with non-rapid decliners. On multivariate logistic regression analysis, age, moderate to severe emphysema, no daily exercise habits, and anemia increased the likelihood of rapid decliners. Furthermore, patients who newly started and continued bisphosphonate exhibited higher annual per cent changes of bone mineral density than did those without bisphosphonate use. Conclusions A rapid decline in bone mineral density correlates to a higher likelihood of vertebral fracture. We clarified the predictors of bone mineral density decline and demonstrated that bisphosphonate use might modify bone mineral density in patients with chronic obstructive pulmonary disease.

Background Neutrophil-to-lymphocyte ratio (NLR) is a biomarker of inflammation in chronic obstructive pulmonary disease (COPD) patients. But, a meaningful threshold and the longitudinal changes are unknown. We aimed to investigate the association between NLR and the clinical characteristics of COPD patients and to determine a meaningful threshold and the longitudinal changes for NLR. Methods Keio University and its affiliate hospitals conducted an observational COPD cohort study over 3 years. We performed a blood examination and a pulmonary function test. Blood examination was completed at baseline and annually thereafter, at a time when the disease was stable. Two hundred seventy-four patients who had at least 3 blood examinations over 3 years were included. Results Baseline NLR was correlated with baseline C-reactive protein (CRP) (r = 0.18, p = 0.003) and SAA (r = 0.34, p

Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation with endothelial dysfunction. Cadherins are adhesion molecules on epithelial (E-) and vascular endothelial (VE-) cells. Soluble (s) cadherin is released from the cell surface by the effects of proteases including matrix metalloproteinases (MMPs).The aim of this study was to examine the associations of sE-/sVE-cadherin levels in plasma with the development of COPD.Plasma sE-/VE-cadherin levels were measured by an enzyme-linked immunosorbent assay in 115 patients with COPD, 36 symptomatic smokers (SS), 63 healthy smokers (HS) and 78 healthy non-smokers (HN). sE-cadherin and MMP-7 levels in epithelial lining fluid (ELF) were measured in 24 patients (12 COPD and 12 control).Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios were significantly higher in COPD and SS than in HS and HN groups, while plasma sVE-cadherin levels were lower in COPD than in HS and HN groups (p 0.0001). sE-cadherin levels paralleled the severity of airflow limitation in both plasma (p 0.01) and ELF (p 0.05), while plasma sVE-cadherin levels were inversely correlated with the extent of emphysema (p 0.05). MMP-7 levels were correlated with sE-cadherin levels in ELF.Plasma sE-cadherin levels and sE-cadherin/sVE-cadherin ratios are potential biomarkers for COPD.

We have examined the noncontact respiration measurement by applying the active stereo for realizing easy screening of chronic obstructive pulmonary disease COPD. In this study, we apply the self-organizing map SOM for classification of unforced respiratory waveform. The automatic classification of the respiratory waveform is based on the difference in the undulating pattern of respiratory waveform between the COPD patients and the healthy subjects. As the result of the experiment, it became clear that the classification by SOM is almost equivalent to the classification by respiratory specialists.

Drug-induced lung injury (DLI) results from the specific use of a drug, including prescription drugs, over-the-counter drugs, and supplements. A DLI is an adverse drug reaction that occurs in the pulmonary system including the lungs, bronchi, and pulmonary vessels. The following diagnostic criteria are generally used: (1) history of ingestion of a drug known to induce lung injury, (2) the clinical manifestation reported to be induced by a drug, (3) exclusion of other causes of the clinical manifestation, (4) improvement of the clinical manifestations after drug discontinuation, and (5) exacerbation of the clinical manifestations after resuming the drug. Pathogenetic mechanisms of DLI have not been precisely elucidated, but two possible mechanisms have been suggested. First, there are cytotoxic effects of drugs on alveolar type II and airway epithelial cells or vascular endothelial cells. The cytotoxic effects may be mediated by reactive oxygen species, proteases, and cytokines. Second, activation of immune cells may promote the development of DLI through acquisition of immunogenicity by binding of a drug or its metabolite to cytoplasmic proteins as a hapten. These two mechanisms may be involved in the pathogenesis of DLI independently or in combination, and they may be modified by a variety of host and environmental factors, such as genetic predisposition, age, underlying lung diseases, and interactions with concomitant drugs.

To investigate the relationship between small pulmonary vessels and extent of emphysema on CT in individual lungs with chronic obstructive pulmonary disease (COPD).Forty-nine patients were included. The percentage of cross-sectional area of vessels5mmLess than half of the COPD patients demonstrated an inverse correlation between %CSA5 and percentage of low attenuation area (LAA%). In the remaining patients, %CSA5 was homogeneously distributed.Not all patients with COPD demonstrated an inverse correlation of the distributions between %CSA5 and LAA% in individual lungs.

Background and objective Osteoporosis is an important systemic comorbidity of chronic obstructive pulmonary disease (COPD). However, neither its mechanisms nor its risk factors have been fully elucidated. With regard to genetic factors, low-density lipoprotein receptor-related protein 5 (LRP5) A1330V is known to be associated with osteoporosis in the general population, but the influence of this polymorphism in COPD is unknown. The aim of this study was to investigate the potential risk factors of COPD-related bone loss and fracture. Methods Keio University and affiliated hospitals have enrolled an observational cohort to investigate the management of COPD comorbidities. To assess risk factors for osteopenia and osteoporosis, bone mineral density (BMD) of the hip and lumbar spine, presence of vertebral fracture, quantitative data on emphysema and airway wall on computed tomography, as well as LRP5 genotype were analysed in patients with or at risk for COPD (n = 270). Results The percentage of subjects with osteoporosis (T-score ≤ −2.5), osteopenia (T-score between −1 and −2.5) and a normal BMD (T-score ≥ −1) was 15.2%, 35.9% and 48.9%, respectively. T-score was significantly decreased in subjects with LRP5 TT genotype (n = 15) compared with that in those with CC/CT genotype (n = 255) (−1.83 vs. −0.98, P = 0.0167). On multivariate logistic regression analysis, female gender (odds ratio (OR) 10.4; P

This study aimed to determine how much time can be saved with the use of unit-of-use packaging for prescription drugs as compared with bulk packaging in community pharmacies as well as to determine the number of errors. In a simulation, mock prescriptions were dispensed either in unit-of-use packages or by transferring medication from a bulk container, and a time study was conducted to measure the time spent on dispensing and prescription auditing by pharmacists. Pharmacists' and patients' degree of satisfaction was also surveyed. The time saved with unit-of-use packaging was 66.25 s per prescription. The sole dispensing error that was found in the study occurred with bulk dispensing. Among both pharmacists and patients, many were of the opinion that dispensing with unit-of-use packaging was preferable to bulk dispensing. Unit-of-use packaging shortens the time that pharmacists spend on dispensing activities and increases the efficiency of their work. Unit-of-use packaging is also thought to reduce the number of counting errors.

The standard technique to evaluate the proteins present in epithelial lining fluid (ELF) is bronchoalveolar lavage (BAL). Bronchoscopic microsampling (BMS) method has been developed for humans as a less invasive alternative. We establish the usefulness of a rat bronchial microsampling (rBMS) to evaluate various proteins in ELF in lipopolysaccharide (LPS)-induced lung injury models in rats. In the first experiment of this study, we validate that whether the rBMS can obtain information from ELF in place of BAL. Tumor necrosis factor (TNF)-α concentrations were increased in the rBMS samples similar to BAL 1 and 3 h after LPS instillation. In the second part of this study, a proteomic analysis of the rBMS, using the Protein Chip R system, revealed the presence of proteins whose molecular weights corresponded to TNF-related proteins in the LPS-treated rats. In rats treated with a TNF-α converting enzyme inhibitor, the concentrations of these proteins in rBMS decreased or disappeared. In the third experiment, rBMS was performed without tracheostomy at 6 and 24 h after instillation of LPS, and a rat multiple cytokines assay system detected heterogeneous variations in the concentrations of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-αand interferon (IFN)-γ in ELF. The cytokine profile was significantly modified by pre-treatment with dexamethasone. This new rBMS technique could be used to measure TNF-α in LPS-induced acute lung injury (ALI) as well as for proteomic analysis, without sacrificing the rats. Furthermore, this procedure enables the serial collection of ELF, which would allow the examination of time-dependent cytokine variations in rat ALI model.

Purpose. This study aimed to examine whether plasma levels of cathepsin S or its inhibitor, cystatin C, may serve as biomarkers for COPD.Patients and Methods. We measured anthropometrics and performed pulmonary function tests and chest CT scans on 94 patients with COPD and 31 subjects with productive cough but no airflow obstruction (“at risk”; AR). In these subjects and in 52 healthy nonsmokers (NS) and 66 healthy smokers (HS) we measured plasma concentrations of cathepsin S and cystatin C using an ELISA. Data were analyzed using simple and logistic regression and receiver operating characteristic analyses.Results. Cathepsin S and cystatin C plasma levels were significantly higher in the COPD and AR groups than in the NS and HS groups (p<0.01). Among the COPD patients and AR subjects, plasma cathepsin S levels and cathepsin S/cystatin C ratios, but not cystatin C levels, were negatively related to severe airflow limitation (% FEV1predicted < 50%;p=0.005) and severe emphysema as assessed by low attenuation area (LAA) score on chest CT scans (LAA≥8.0;p=0.001).Conclusion. Plasma cathepsin S and cathepsin S/cystatin C ratios may serve as potential biomarkers for COPD.

The development and wide usage of interferon (IFN)-γ release assays (IGRAs) brought remarkable advances in the diagnosis of tuberculosis (TB). QuantiFERON®-TB Gold In-Tube (QFT-GIT), one of the IGRAs, employs three TB antigens, ESAT-6, CFP-10, and TB7.7, to which cell-mediated immune responses are measured in a single tube. In this regard, the QFT-GIT in patients with active TB was hypothesized to detect TB positivity for a longer period after the initiation of treatment. The change of IFN-γ values in patients with pulmonary TB serially registered to the study was examined with QFT-GIT before initiating anti-TB drugs, after completion of treatment and 12 months after the cessation of treatment. The data demonstrates that the IFN-γ levels remained consistently positive for a period of one year after treatment.

Background Although the age range of chronic obstructive pulmonary disease (COPD) patients is broad, few studies have focused on the effects of age on disease characteristics. Methods Keio University and affiliated hospitals established an observational COPD cohort. Patients were assessed using high resolution computed tomography (CT) to quantify emphysema, health status using the COPD assessment test (CAT) and the St. George’s Respiratory Questionnaire (SGRQ), spirometry, echocardiogram, dual X-ray absorption of bone, biomarkers and comorbid diagnoses. We examined the characteristics of COPD patients aged 75 and over compared with patients below 75. Results A total of 443 patients comprising 252 patients aged

Dialysis-related amyloidosis is a serious complication of long-term hemodialysis. Its pathogenic mechanism involves accumulation of β2-microglobulin in the blood, which then forms amyloid fibrils and is deposited in tissues, leading to inflammation and activation of osteoclasts. Lixelle, a direct hemoperfusion column for adsorption of β2-microglobulin, has been available since 1996 to treat dialysis-related amyloidosis in Japan. However, previous studies showing the therapeutic efficacy of Lixelle were conducted in small numbers of patients with specific dialysis methods. Here, we report the results of a nationwide questionnaire survey on the therapeutic effects of Lixelle. Questionnaires to patients and their attending physicians on changes in symptoms of dialysis-related amyloidosis by Lixelle treatment were sent to 928 institutions that had used Lixelle, and fully completed questionnaires were returned from 345 patients at 138 institutions. The patients included 161 males and 184 females 62.9 ± 7.7 years age, who had undergone dialysis for 25.9 ± 6.2 years and Lixelle treatment for 3.5 ± 2.7 years. Based on self-evaluation by patients, worsening of symptoms was inhibited in 84.9-96.5% of patients. Of the patients, 91.3% felt that worsening of their overall symptoms had been inhibited, while attending physicians evaluated the treatment as effective or partially effective for 72.8% of patients. Our survey showed that Lixelle treatment improved symptoms or prevented the progression of dialysis-related amyloidosis in most patients.

The objective of this study was to clarify differences in oral health status between patients who needed haemodialysis (HD) owing to diabetic nephropathy (DN) and chronic glomerulonephritis (CGN).Ninety-eight HD patients who were 50-70 years old were selected as the study subjects [DN group (29 subjects) and CGN group (69 subjects)] to compare with 106 control subjects (control group) not undergoing HD. All HD subjects underwent oral- and systemic-related examination just before HD therapy.The mean number of teeth present in the DN group was significantly less than in the CGN and control groups. The mean percentage of sites with bleeding on probing in the DN group was greater than in the CGN and control groups. The mean salivary flow rate in the DN and CGN groups was significantly lower compared with the control group.The patients undergoing HD for DN were found to have fewer teeth and worse periodontal health compared with those undergoing HD for CGN and with the control subjects not undergoing HD. Furthermore, the dental and periodontal health of the patients undergoing HD for CGN was comparable to that of the controls.For effective measures of prevention and improvement of oral health in HD patients, clinicians should be aware of the differences in the characteristics of the oral health between patients undergoing HD for DN and CGN.

Previous family studies suggested that genetic variation contributes to COPD susceptibility. The only gene proven to influence COPD susceptibility is SERPINA1, encoding α1-antitrypsin. Most studies on COPD candidate genes except SERPINA1, have not been consistently replicated. However, longitudinal studies of decline in lung function, meta-analyses of candidate gene studies, and family-based linkage analyses suggested that variants in EPHX1, GST, MMP12, TGFB1, and SERPINE2 were associated with susceptibility to COPD. A genome-wide association (GWA) study has recently demonstrated that CHRNA3/5 in 15q25 was associated with COPD compared with control smokers. It was of interest that the CHRNA3/5 locus was associated with nicotine dependence and lung cancer as well. The associations of HHIP on 4q31 and FAM13A on 4q22 with COPD were also suggested in GWA studies. Another GWA study has shown that BICD1 in 12p11 was associated with the presence or absence of emphysema. Although every genetic study on COPD has some limitations including heterogeneity in smoking behaviors and comorbidities, it has contributed to the progress in elucidating the pathogenesis of COPD. Future studies will make us understand the mechanisms underlying the polygenic disease, leading to the development of a specific treatment for each phenotype.

The standard computer-tomography-based method for measuring emphysema uses percentage of area of low attenuation which is called the pixel index (PI). However, the PI method is susceptible to the p...

In this study, we try to develop a new head injury criterion in the automotive crash accident, which is evaluated by the hydrostatic pressure. Main subject of this study is to find the threshold value of the functional injury of the brain nerve cell, which is obtained by the impact loading experiment. PC-12 cultured nerve cell is employed to imitate the human's nerve cell and measure the critical pressure value for the occurrence of damage. We observed the cytoskeleton injury, and evaluated the decreasing ratio of fluoro-area caused by hydrostatic pressure loading. The disappearance area of fluorescence is caused by the creation of the actin rods and which means F-actin structural disorder. It reveals that the cytoskeleton injury depends on the hydrostatic pressure loading, and the injury threshold value, such as the critical pressure, is obtained. Finally, an availability of our new head injury criterion based on the nerve cell injury is confirmed.

Masaki Miyazaki,1 Hidetoshi Nakamura,1,2 Saeko Takahashi,1 Shotaro Chubachi,1 Mamoru Sasaki,1 Mizuha Haraguchi,1 Hideki Terai,1 Makoto Ishii,1 Koichi Fukunaga,1 Sadatomo Tasaka,1 Kenzo Soejima,1 Koichiro Asano,3 Tomoko Betsuyaku1 On behalf of the Keio COPD Comorbidity Research (K-CCR) group 1Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, 2Department of Respiratory Medicine, Saitama Medical University, Saitama, 3Division of Pulmonary Medicine, Department of Medicine, Tokai University School of Medicine, Kanagawa, Japan Background: Triple combination therapy involving long-acting muscarinic antagonists long-acting β2 agonists, and inhaled corticosteroids has recently become an option for maintenance treatment of COPD. Some add-on clinical trials have reported the benefits of these combinations. However, the process to step up to triple therapy varies for individual cases.Methods: Keio University and affiliated hospitals conducted an observational COPD cohort study, recruiting patients diagnosed as having COPD by pulmonary physicians and those referred for investigation of possible COPD. Their prescription history and clinical course were retrospectively analyzed based on the physicians’ medical records and patient questionnaires. This study was registered with UMIN (UMIN000003470, April 10, 2010).Results: A total of 95 of the 445 COPD patients (21%) were treated with inhaled corticosteroids/long-acting β2agonists/long-acting muscarinic antagonists as maintenance therapy, including 12 in COPD Grade I, 31 in Grade II, 38 in Grade III, and 14 in Grade IV, based on the Global Initiative for Chronic Obstructive Lung Disease spirometric grading. For more than half of the patients on triple therapy, the treatment had been intensified due to unsatisfactory improvement of symptoms, and 32% were treated with triple therapy due to comorbid asthma. In contrast, there were COPD patients whose therapy was maintained after starting with triple therapy because of their serious conditions or concurrent exacerbation at diagnosis (8%).Conclusion: Triple therapy was often prescribed in the real-life management of COPD, even in patients whose airflow limitation was not severe. To better control symptoms was the major reason for choosing triple therapy, regardless of the severity of COPD, in Japan. Keywords: chronic obstructive pulmonary disease, inhaled corticosteroids, long-acting muscarinic antagonists, long-acting β2 agonists, triple therapy&nbsp

Background Underdiagnosis is a critical problem in the management of chronic obstructive pulmonary disease (COPD). It is important to screen patients at risk for COPD among those with lifestyle-related diseases such as hypertension, diabetes mellitus, and dyslipidemia, since these diseases promote the development of cardiovascular diseases closely associated with increased COPD mortality. Methods Thirteen primary care clinics in a suburb of Tokyo participated in the current study. A total of 950 patients from these clinics were enrolled in the study between 2010 and 2012; the patients ranged in age from 40 to 79 years, and they had no diagnosed respiratory diseases at the time of enrollment. Patients fulfilling the selection criteria were recruited to undergo spirometry and then completed a self-report questionnaire about comorbid diseases and smoking habits. Spirometry was performed 15min after inhalation of 200μg of salbutamol sulfate. Results The prevalence of airflow limitation was 12.7% in the 950 primary care clinic patients. Lifelong cigarette consumption was the most significant risk factor for airflow limitation, e.g., patients who smoked 60 pack-years or more had a 40% likelihood of airflow limitation. Among common lifestyle-related diseases, hypertension was associated with the severity of airflow limitation ( p =0.03), whereas dyslipidemia appeared to be inversely correlated with the severity of airflow limitation ( p =0.004) on multiple regression analysis including lifelong cigarette consumption as a factor. Conclusions Undiagnosed airflow limitation was detected in 12.7% of outpatients at the primary care clinics. Since most patients with lifestyle-related diseases are treated by primary care physicians, it is essential for the physicians to obtain an accurate history of smoking and comorbid diseases to screen patients for COPD.

The whole gene deletion CYP2A6*4 , the defect of the main nicotine oxidase, contributes to limiting lifelong and daily cigarette consumption. However, the effects on smoking habits of CYP2A6*7 and *9 , two major functional polymorphisms common in Asian populations, have not been reported. The present study examined the relationship between polymorphisms *4 , *7 and *9 with the smoking habits of 200 Japanese smokers who visited the Keio University Hospital (Tokyo, Japan). The allele frequencies of *1 (wild type), *4 , *7 and *9 were 52, 17, 11 and 20%, respectively. When the three polymorphisms were considered simultaneously, the percentages of homozygous wild type, heterozygote, and homozygous mutants and compound heterozygotes were 26.0, 52.5 and 21.5%, respectively. Homozygous mutants and compound heterozygotes (n = 43) smoked fewer cigarettes daily than heterozygotes (n = 105) and homozygous wild-type individuals (n = 52). Smokers with *7 / *7 , *9/*9 or *7 / *9 had lower daily cigarette consumption than smokers with *1/*1 . In conclusion, polymorphisms *4 , *7 and *9 of CYP2A6 were detected in approximately three out of four Japanese smokers, and their daily cigarette consumption was genetically modulated by these functional polymorphisms.

Our understanding of asthma severity was advanced by the identification of biomarkers which account for differences in lung function impairment. We tried to examine the effects of corticosteroid treatment on known correlates of asthma severity including peripheral eosinophil counts, total IgE, IL-5, and eotaxin Levels in plasma. We compared these biomarkers among groups of stable asthmatics categorized by the dose of corticosteroid (N: steroid-free, n = 25; L: low-dose inhaled, n = 27; MH: medium or high-dose inhaled, n= 19; O: inhaled plus oral, n= 8). Next we compared these markers and peak expiratory flow rate (PEFR) in unstable asthmatics before and after treatment with steroids (n = 22). Eotaxin levels in the O group were higher than those in the N and MH groups (P0.05). Logistic regression analysis demonstrated that plasma eotaxin level was correlated with the severity of asthma defined by treatment intensity (P = 0.01) and % FEV1 (P = 0.04) while the other markers were not. Eotaxin levels did not change after steroid treatment in unstable patients, whereas eosinophil counts decreased in parallel with PEFR. Among biomarkers of asthma severity studied, plasma eotaxin level was not significantly affected by corticosteroid treatment, and was associated with the severity even in the presence of steroid therapy.

In comparison with neutrophil-mediated lung diseases, such as acute respiratory distress syndrome, the involvement of IL-8 in lymphocyte-mediated lung diseases has not been fully investigated. Several reports have shown a slight increase in bronchoalveolar lavage fluid (BALF) IL-8 in patients with hypersensitivity pneumonitis (HP) and sarcoidosis (SAR), but the source of the IL-8 has not been clarified. In the present study, the in vivo production of IL-8 by alveolar macrophages (AMs) is examined in these patients by analyzing the cell-associated IL-8, using the flow cytometric method adopted previously. The IL-8 levels in the epithelial lining fluid (ELF) were also assessed. Initially, slight, but significant, increased levels of ELF IL-8 in HP and SAR were confirmed. Using flow cytometric analysis, a significant increase was found in the cell-associated IL-8 of the freshly isolated AMs in HP, but not in SAR, indicating in vivo production of IL-8 by AMs in HP. The cell-associated IL-8 of the AMs cultured with or without lipopolysaccharide was also analyzed. However, in contrast to previous findings in patients with idiopathic pulmonary fibrosis, no differences were found between SAR and HP patients and control subjects. Based on these findings, it is speculated that ELF IL-8 levels are slightly increased in HP and SAR, and they may contribute to the accumulation of neutrophils and possibly lymphocytes. However, the source of IL-8 may be different and AMs are the candidate source of IL-8 in HP, but not in SAR. The flow cytometric method may be useful in assessing cytokines production by AMs.

Background and Purpose— The slowdown of a steeply declining trend in cardiovascular mortality has been reported in Japan, but precise reasons for this trend are uncertain. Methods— We established 3 study cohorts of Hisayama residents aged ≥40 years without a history of stroke or myocardial infarction in 1961 (1618 subjects, first cohort), 1974 (2038 subjects, second cohort), and 1988 (2637 subjects, third cohort). We followed up with each cohort for 12 years, comparing the incidence, mortality, and survival rate of cardiovascular disease. Results— The age-adjusted incidence of cerebral infarction significantly declined by 37% for men and by 32% for women from the first to the second cohort. It continued to decline by 29% for men, but the decline decelerated for women in the third cohort. The incidence of cerebral hemorrhage steeply declined by 61% from the first to the second cohort in men only, while it was sustained for both sexes in the third cohort. Stroke mortality continuously declined as a result of these incidence changes and significant improvement of survival. In contrast, the incidence and mortality rate of coronary heart disease were unchanged except for the increasing incidence in the elderly. The prevalence of severe hypertension and current smoking significantly decreased, while that of glucose intolerance, hypercholesterolemia, and obesity greatly increased among the cohorts. Conclusions— Our data suggest that the decline in stroke incidence is slowing down and that the incidence of coronary heart disease has been increasing in the elderly in recent years. Insufficient control of hypertension and the increase in metabolic disorders may contribute to these trends.

Although neutrophil depletion can reduce the level of acute lung injury (ALI) induced by Escherichia coli endotoxin, that induced by live E coli cannot be attenuated even in neutropenia. This suggests that live E coli cause ALI by way of an mechanism independent of circulating neutrophil. Tumor necrosis factor-α (TNF-α), which is released from monocytes and macrophages, is a proinflammatory cytokine that is recognized as a central mediator of several forms of inflammation. In this controlled experimental study, we examined the effects of an adenosine-receptor agonist, 2-chloroadenosine (2CA), that has suppressive effects on various cell types and TNF-α, on endotoxin plus latex particles, and on ALI induced by live E coli in the neutropenic state. We studied 42 guinea pigs rendered neutropenic by means of intraperitoneal cyclophosphamide administration. Experimental groups consisted of (1) a saline-solution control group; (2) an endotoxin (0.2 mg/kg)-treated group; (3) a group treated with endotoxin plus 2CA (10 μg/kg); (4) a group treated with latex (2 × 10 9 /kg); (5) a group exposed to endotoxin and latex; (6) a group exposed to endotoxin, latex, and 2CA; (7) a group exposed to E coli (2 × 10 9 /kg); and (8) a group exposed to E coli and 2CA. The injection of endotoxin alone in neutropenic animals did not increase the indexes of ALI (lung tissue/plasma ratio [T/P] and lung wet weight/dry weight ratio [W/D], calculated with the use of iodine 125-labeled albumin). In contrast, these indexes were increased in the endotoxin-and-latex groups compared with those of the control group. ALI in the endotoxin-and-latex group was attenuated by intravenous 2CA. The intravenous injection of live E coli also caused increases in T/P, W/D, and plasma TNF-α, but thse were limited by 2CA. In summary, ALI induced by latex particles added to endotoxin and live E coli in the neutropenic state was attenuated by 2CA, suggesting a partial contribution of various cell types or humoral mediators as a neutrophil-independent pathway in its pathogenesis.

Nicotine is responsible for smoking dependence and is mainly metabolised by CYP2A6. Several types of genetic polymorphism of CYP2A6 have been reported, but their relation to smoking habit and chronic obstructive pulmonary disease (COPD) phenotypes has not been fully clarified.203 current or ex-smokers (lifelong cigarette consumption (CC)/=10 pack years) with subclinical and established COPD phenotypes were clinically evaluated and pulmonary function tests and a chest CT scan were performed (smoker group). The non-smoker group consisted of 123 healthy volunteers. CYP2A6 genotypes were determined in both groups.The percentage of subjects with a CYP2A6del allele (genotype D) was lower in heavy smokers (20.5%, n=88, CC/=60 pack years) than in light smokers (37.4%, n=115, CC 10-59 pack years, chi(2)=6.8, p=0.01) or non-smokers (36.1%, n=122, chi(2)=6.0, p=0.01); lower in ex-smokers (20.7%, n=111) than in current smokers (41.3%, n=92, chi(2)=10.1, p0.01); and lower in smokers with a high LAA (low attenuation area) score on the chest CT scan (18.4%, n=76, LAA/=8.0) than in those with a low LAA score (37.0%, n=127, LAA8.0, chi(2)=7.8, p0.01).Subjects with the CYP2A6del allele tend not to be heavy habitual smokers but can be light habitual smokers. The CYP2A6del polymorphism may inhibit smokers from giving up smoking, but appears to function as a protective factor against the development of pulmonary emphysema independent of smoking habit.