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Background Rapid eye movement sleep -predominant sleep-disordered breathing (REM-SDB) is a condition in which sleep apneas or hypopneas predominantly occur during REM sleep. This study aimed to investigate the prevalence, clinical findings including daytime sleepiness or comorbid cardio-metabolic diseases, and detailed polysomnographic features of REM-SDB in Japanese population. Methods Total of 1458 patients diagnosed as SDB were selected for this study. Prevalence of REM-SDB was estimated in the groups of mild, moderate and severe SDB. Polysomnographic findings, daytime sleepiness self-measured with Epworth Sleepiness Scale (ESS) and history of comorbid cardio-metabolic diseases were obtained and compared between the groups with REM-SDB and non-stage specific SDB. Results Prevalence of REM-SDB according to the criteria #2 was 22.1% in total SDB subjects, 46,1% in mild SDB and 18.9% in moderate SDB. None was found in severe SDB. Patients with REM-SDB showed milder SDB, higher BMI and higher female predominance than those with non-stage specific SDB. They also showed lower arousal index, respiratory arousal index per total AHI, percentage of N1 sleep, total AHI, ODI, and higher sleep efficiency. Meanwhile, maximum event durations of obstructive apnea and hypopnea were significantly longer, and the nadir SpO2 was lower in REM-SDB. The ESS score and percentages of comorbid cardio-metabolic diseases were roughly equivalent between REM-SDB and non-stage specific SDB. Conclusion REM-SDB was associated with high obesity, female gender, and mild severity of SDB. They showed daytime sleepiness and comorbid cardio-metabolic diseases quite equally to patients with non-stage specific SDB in spite of their lower AHI and better sleep quality.

Purpose In 2-dimensional lateral cephalometric radiographs, patients with severe obstructive sleep apnea (OSA) exhibit a more crowded oropharynx in comparison with non-OSA. We tested the hypothesis that machine learning, an application of artificial intelligence (AI), could be used to detect patients with severe OSA based on 2-dimensional images. Methods A deep convolutional neural network was developed (n = 1258; 90%) and tested (n = 131; 10%) using data from 1389 (100%) lateral cephalometric radiographs obtained from individuals diagnosed with severe OSA (n = 867; apnea hypopnea index > 30 events/h sleep) or non-OSA (n = 522; apnea hypopnea index Results The sensitivity/specificity was 0.87/0.82 for full image, 0.88/0.75 for main region, 0.71/0.63 for head only, and 0.54/0.80 for the manual analysis. The area under the receiver-operating characteristic curve was the highest for main region 0.92, for full image 0.89, for head only 0.70, and for manual cephalometric analysis 0.75. Conclusions A deep convolutional neural network identified individuals with severe OSA with high accuracy. Future research on this concept using AI and images can be further encouraged when discussing triage of OSA.

Purpose In the treatment of obstructive sleep apnea (OSA), there is not yet a convenient tool for deciding whether a mandibular advancement oral appliance (OA) is adequately adjusted or when to perform post-treatment sleep-testing. We hypothesized that a gradual reduction in the STOP (snoring, tiredness during daytime, observed apnea, high blood pressure) score, i.e., fewer Yes responses in the STOP questionnaire, in patients undergoing OA treatment could be an indicator of better OA adjustment and, thus, the best timing for follow-up polysomnography.Methods The STOP score was recorded at every patient visit when the OA was adjusted ventrally as necessary (i.e., STOP group). We considered that the appropriate timing for follow-up polysomnography was when the STOP score stopped decreasing. A historical control group was established from consecutive patients without a STOP score.Results In the STOP group (n=57), the median (interquartile range) of STOP scores gradually decreased with OA treatment, from 3 (2-3) to 0 (0-1) (p

Pompe disease is an autosomal recessive disorder caused by deficiency of the acid α-glucosidase (GAA) enzyme. GAA deficiency induces progressive glycogen accumulation which leads to weakness of the respiratory muscle including the diaphragm. Pompe disease is one of the few myopathies, for which an established therapy is available. Thus, earlier detection of potential late-onset Pompe disease (LOPD) and earlier intervention would have a significant clinical impact. Our hypothesis is that sleep problems including sleep disordered breathing (SDB) and clinical symptoms may indicate an early stage of LOPD since decreased respiratory muscle activity generally first presents during sleep. Thus, the aims of this prospective, multicenter observational cohort study in Japan (PSSAP-J) are to demonstrate a higher prevalence of LOPD in a sleep lab–based population (primary outcome), and to identify predictive factors for LOPD from findings in diagnostic polysomnography (PSG) and clinical symptoms (secondary outcomes). The study design is a prospective multicenter observational cohort study. Consecutive patients who present to sleep labs due to suspected SDB for an overnight PSG will be enrolled. All patients will be measured for creatine kinase, GAA activity, and if necessary, genetic analysis of GAA. Furthermore, chest X-ray, pulmonary function test, and arterial blood gas analysis will be collected. Then, prevalence and specific findings of LOPD will be assessed. Congenital myopathy shows a shift from slow-deep to rapid-shallow breathing during transition from wakefulness to sleep accompanying a symptom of waking with gasping (actual further results are pending). The distribution in respiratory physiology between during wakefulness and sleep specific to LOPD may provide insights into early-stage detection. UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

Background: High density lipoprotein (HDL) exerts anti-atherogenic functions including cholesterol efflux capacity and anti-oxidative activities. Obstructive sleep apnea (OSA) is associated with increased risk for cardiovascular disease via inflammation and oxidative stress. However, HDL functions in patients with OSA remains to be elucidated. We therefore investigated cholesterol efflux capacity and anti-oxidative activity in order to assess whether OSA would affect HDL functions. Methods and Results: A total of 116 OSA patients who underwent polysomnography tests from April 2017 to April 2019 were enrolled in this cross-sectional study. Blood samples were obtained at the next day of polysomnography test. We measured cholesterol efflux capacity in OSA patients and found that CEC was significantly lower in SAS groups (apnea hypoxia index (AHI)≧5) compared with non-SAS groups.(AHI Conclusion: Obstructive sleep apnea syndrome attenuated cholesterol efflux capacity. Min SpO2 may be a good predictor of HDL dysfunction in OSA.

Chylothorax is reported as a postoperative complication, mainly in the field of thoracic surgery, but there are only 14 reports in the field of spinal surgery.A 64-year-old woman underwent spinal fusion surgery by the anterior and posterior approach for her scoliosis. She developed leg edema and right pleural effusion 2 months after the surgery. Laboratory findings showed decreased total protein and albumin levels in serum. The color of the thoracentesis sample was pinkish white, and the Triglyceride level in the pleural effusion was high. So, her leg edema was found to be associated with malnutrition and the pleural effusion was caused by chylothorax. The point of leakage from the lymph duct was confirmed in the right thoracic cavity of the slice that corresponded to that with the screw at Th11 by lymphatic scintigraphy. Her symptoms did not improve by diet restriction and lipidol lymphography, but her pleural effusion and albumin levels improved by the administration of octreotide. In the clinical course, serum albumin levels appeared to show an inverse correlation with the amount of pleural effusion, so it was thought that her serum albumin level decreased owing to leakage of protein, including albumin, into the thoracic cavity via the injured thoracic duct.We concluded that the chylothorax was owing to complications of the surgery. Although reports of chylothorax occurring as a complication of spinal fusion surgery are rare, when prolonged hypoalbuminemia or unilateral pleural effusion is observed, chylothorax should be considered as a differential diagnosis. Keywords: Chylothorax, Fusion, Complications of spinal surgery, Octreotide

Neutrophilic airway inflammation is one of the features of severe asthma. Neutrophil gelatinase-associated lipocalin (NGAL), or lipocalin-2, is a glycoprotein associated with neutrophilic inflammation and can be detected in blood. Recently, blood NGAL levels have been reported to be elevated in chronic obstructive pulmonary disease. However, the clinical significance of serum NGAL levels in patients with asthma has not been elucidated. The aim of this study was to explore the association between serum NGAL level and clinical parameters in patients with asthma. Sixty-one non-smoking people with stable asthma were enrolled in this study. All patients underwent blood collection and pulmonary function tests. The associations between serum NGAL levels and clinical parameters were analyzed retrospectively. Serum NGAL levels in patients with asthma and obstructive ventilatory defect were higher than those in patients with asthma without obstructive ventilatory defect (76.4±51.4 ng/mL vs. 39.3±27.4 ng/mL, P=0.0019). Serum NGAL levels were correlated with forced expired flow at 50% of vital capacity %predicted and forced expired flow at 75% of vital capacity %predicted (r=-0.3373, P=0.0078 and r=-0.2900, P=0.0234, respectively). Results of a multiple regression analysis demonstrated that serum NGAL level was independently associated with obstructive ventilatory defect. Serum NGAL levels were elevated in patients with asthma and obstructive ventilatory defect. NGAL may be involved in airway remodeling possibly mediated by neutrophilic inflammation in asthma.

Background: Neutrophilic airway inflammation is one of the features of severe asthma. Neutrophil gelatinase-associated lipocalin (NGAL), or lipocalin-2, is a glycoprotein associated with neutrophilic inflammation and can be detected in blood. Recently, blood NGAL levels have been reported to be elevated in chronic obstructive pulmonary disease. However, the clinical significance of serum NGAL levels in patients with asthma has not been elucidated. The aim of this study was to explore the association between serum NGAL level and clinical parameters in patients with asthma.Methods: Sixty-one non-smoking people with stable asthma were enrolled in this study. All patients underwent blood collection and pulmonary function tests. The associations between serum NGAL levels and clinical parameters were analyzed retrospectively. Results: Serum NGAL levels in patients with asthma and obstructive ventilatory disorder were higher than those in patients with asthma without obstructive ventilatory disorder (76.4 ± 51.4 ng/mL vs 39.3 ± 27.4 ng/mL, p=0.0019). Serum NGAL levels were correlated with forced expired flow at 50% of vital capacity %predicted and forced expired flow at 25% of vital capacity %predicted (r=-0.3373, p=0.0089 and r=-0.2900, p=0.0234, respectively). Results of a multiple regression analysis demonstrated that serum NGAL level was independently associated with obstructive ventilatory disorder.Conclusion: Serum NGAL levels were elevated in patients with asthma and obstructive ventilatory disorder. NGAL may be involved in airway remodeling possibly mediated by neutrophilic inflammation in asthma.

STUDY OBJECTIVES: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the combination of cerebellar ataxia, parkinsonism, and autonomic disturbance. Patients with MSA frequently have sleep-disordered breathing. In some patients with MSA, central sleep apnea manifests during the disease's natural course or as a treatment effect. Breathing instability may be involved in the development of obstructive sleep apnea (OSA); therefore, we investigated whether breathing instability affects the severity of OSA in patients with MSA. METHODS: Patients with MSA and a control group of individuals who were matched for age, body mass index (BMI), and supine apnea-hypopnea index (AHI) were recruited. Breathing instability was evaluated by using polysomnography to determine the irregular pattern with approximate entropy (ApEn) of chest respiratory movements during wakefulness before sleep onset. The ApEn values were compared between the groups. The severity of OSA was evaluated with background parameters and ApEn values by regression analysis. RESULTS: Twenty patients with MSA (9 men; mean age, 61 years; BMI, 24.1 kg/m(2); supine AHI, 37.9 events/h) were compared to the control group. The ApEn values were higher in the patients with MSA than those in the control group (1.28 versus 1.11; P < .05). Multiple regression analysis showed that supine AHI was associated with ApEn values but not with BMI in patients with MSA and associated with BMI but not with ApEn values in the individuals in the control group. CONCLUSIONS: Patients with MSA had more breathing irregularity. In patients with MSA, breathing instability may be a more influential factor for OSA than BMI. COMMENTARY: A commentary on this article appears in this issue on page 1641. CITATION: Nakayama H, Hokari S, Ohshima Y, Matsuto T, Shimohata T. Breathing irregularity is independently associated with the severity of obstructive sleep apnea in patients with multiple system atrophy. J Clin Sleep Med. 2018;14(10):1661–1667.

Background In this study, we aim to estimate the prevalence of heated tobacco product (HTP) smokers three years after the launch of HTPs in Japan. Methods Our study, performed in February 2018 in Japan, had a cross-sectional population-based design. A total of 4,628 adult participants (2,121 men and 2,507 women) were randomly sampled from all regions of Japan. The response rate was 57.9%. Interviews were conducted by trained investigators who visited participants' homes. A survey on current (past 30 days) and lifetime tobacco use (including e-cigarettes and HTPs), as well as numerous sociodemographic factors, was conducted. Results The age-adjusted rates (95% confidence interval) and estimated number of lifetime-HTP smokers were 14.1% (12.5-15.6%; 7.11 million men) and 3.7% (2.9-4.4%; 1.99 million women). The age-adjusted rates (95% confidence interval) for current HTP smokers were 8.3% (7.1-9.6%; 4.21 million men) and 1.9% (1.3-2.4%; 1.02 million women). Multiple variables were found to be associated with a higher prevalence of current HTP use, including being male, aged 20-39 years old, a current Internet user, a risky drinker, or a heavy episodic drinker. HTP use was also higher among men with 10 years or more of education, women with 15 years or less of education, and men with middle- or high-level household incomes. Conclusion We concluded that HTP use has increased substantially in Japan. However, regulations for HTPs are weaker than those for combustible cigarettes in Japan. Thus, HTPs should be subjected to the same regulations as combustible tobacco products.

Objective/background Multiple system atrophy (MSA) frequently results in the development of sleep-disordered breathing (SDB). Few reports have described the natural course of this phenomenon. The aim of the present study was to determine the natural course of SDB and prognostic factors associated with such conditions in MSA. Patients/methods Twenty-four consecutive patients were recruited with probable MSA, who had not been treated with continuous positive airway pressure (CPAP) and had undergone overnight polysomnography (PSG) more than once following the development of snoring or stridor. Based on changes in the apnea-hypopnea index (AHI) over the course of the disease, patients were divided into two groups (AHI-maintained and AHI-deteriorated) and the clinical findings were compared. Results Mean duration between the first and last PSG was 2.4 ± 1.5 years, and patients underwent PSG assessment an average of 2.5 ± 0.6 times during this period. During this interval, AHI increased from 19.4 ± 22.8/hour to 34.4 ± 30.1/hour ( p = 0.006), although spontaneous improvement was observed in 29% of patients. Following the first PSG, all patients were diagnosed with obstructive sleep apnea; however, the SDB type changed from obstructive sleep apnea to central sleep apnea in 3 of the 24 (13%) patients during the period between the first and last PSG. Conclusions Although SDB associated with MSA exacerbates with disease progression, spontaneous improvement in AHI may occur in some patients. Earlier development of snoring or stridor may predict rapid progression of SDB in MSA.

Positional obstructive sleep apnea (P-OSA) is a clinically common phenotype of OSA, which can be treated effectively with mandibular advancement devices (MADs). We hypothesized that the efficacy of an MAD is comparable to that of nasal continuous positive airway pressure (nCPAP) in P-OSA patients.Among patients diagnosed with OSA at a single sleep center from January 2008 to May 2014, male subjects with moderate OSA were recruited and stringently categorized as having P-OSA when the ratio of their lateral apnea-hypopnea index (AHI) to supine AHI was ≤ 0.5, their lateral sleep time was60 minutes, and their lateral REM sleep time was longer than 10 minutes. Treatment efficacy was compared between P-OSA subjects with an MAD (n = 34) and those with nCPAP (n = 34) after matching for age, body-mass index, and baseline AHI.There were no significant differences in baseline AHI (MAD: nCPAP = 20.6 ± 3.9/h: 21.3 ± 1.7/h, p = 0.35) or in follow-up AHI (MAD: nCPAP = 4.7 ± 3.5/h: 3.4 ± 3.7/h, p = 0.12) between the 2 treatment groups, and hence MADs lowered the AHI to the same extent as nCPAP.These findings suggest that an MAD is as efficacious as nCPAP for P-OSA patients. MAD treatment for this specific phenotype may be a promising patient-tailored and first-line approach to OSA.A commentary on this article appears in this issue on page 1079.

Obstructive bronchiolitis (OB) is an intractable disease causing stenosis in the surrounding bronchiolar region and bronchiolar lumen obstruction. Causes of OB are lung and hematopoietic stem-cell transplantation, collagen diseases, infections, and foods, but there are very few reports of drug-induced OB [1]. Imatinib is a drug used for the treatment of leukemia, gastrointestinal stromal tumors, etc. Although there are some reports of imatinib-induced lung injury as a complication (Ohnishi et al., 2006; Ma et al., 2003; Yamasawa et al., 2008; Koide et al., 2011) [[2], [3], [4], [5]], OB has not been reported. We have encountered a patient with OB related to imatinib administered for chronic myelogenous leukemia, who we have followed for 10 years. Drug-induced OB is very rare, but our case demonstrates the importance of considering the possibility of airway lesions by evaluating pulmonary function and expiratory computed tomography in patients with respiratory symptoms despite no shading on imaging.

The upper airway (UA) anatomical collapsibility, UA muscle responsiveness, breathing control, and/or arousability are important contributing factors for obstructive sleep apnea (OSA). Differences in clinical manifestations of OSA are believed to reflect interactions among these factors. We aimed to classify OSA patients into subgroups based on polysomnographic (PSG) variables using cluster analysis and assess each subgroup’s characteristics. Men with moderate or severe OSA and without any concomitant heart or psychosomatic disease were recruited. A hierarchical cluster analysis was performed using variables including fraction of apnea, respiratory event duration, minimum oxygen saturation, arousal rate before termination, and frequency of respiratory events in the supine position. The impact of sleep stages or body position on PSG variables was also evaluated in each cluster. A total of 210 men (mean age, 50.0 years, mean body mass index, 27.4 kg/m2) were studied. The three subgroups that emerged from the analysis were defined as follows: cluster 1 (high fraction of apnea and severe desaturation (20%)), cluster 2 (high fraction of apnea and long event duration (31%)), and cluster 3 (low fraction of apnea (49%)). There were differences in the body mass index and apnea type between the three clusters. Sleep stages and/or body position affected PSG variables in each cluster. Patients with OSA could be divided into three distinct subgroups based on PSG variables. This clustering may be used for assessing the pathophysiology of OSA to tailor individual treatment other than continuous positive airway pressure therapy.

Background Several multifactorial risk indexes have been proposed by Western countries for identifying patients at a high risk of developing postoperative pulmonary complications (PPC). However, there is no consensus on how to evaluate the risk of PPC and what multifactorial risk index should be adapted for Japanese patients. This study aimed at clarifying the utility of risk indexes to predict PPC following digestive surgeries in Japanese patients. Methods We retrospectively analyzed 892 patients who underwent digestive surgeries under general anesthesia in Niigata University Medical and Dental Hospital between January 2009 and March 2011. PPC was defined as postoperative respiratory failure and postoperative pneumonia. We calculated three risk indexes (respiratory failure risk index (RFRI), postoperative pneumonia risk index, and PPC risk score), and compared them between the PPC group and the non-PPC group. A receiver operating characteristic (ROC) curve analysis was employed to compare the usefulness of each index. Results PPC developed in 55 patients (6.2%). All risk indexes were significantly higher in the PPC group than the non-PPC group. The category classification of the risk scores demonstrated a significant tendency to increase the incidence rate of PPC. In the ROC analysis, the area under the curve for RFRI was 0.762 (95% CI 0.697–0.826), which was the highest value observed among these indexes. Conclusions Multifactorial risk indexes are useful tools for identifying Japanese patients at a high risk of developing PPC following digestive surgeries. Of the risk indexes evaluated in this study, RFRI is potentially the most accurate in predicting PPC.

Intestinal epithelial cells are the first targets of ingested mycotoxins, such as ochratoxin A, citrinin and deoxynivalenol. It has been reported that paracellular permeability regulated by tight junctions is modulated by several mycotoxins by reducing the expression of specific claudins and integral membrane proteins in cell-cell contacts, accompanied by increase in phosphorylation of mitogen-activated protein kinases, including extracellular signal-related kinase (ERK) 1/2, p38 and c-Jun NH2-terminal protein kinase. Claudin-2 is expressed in the deep crypt cells, but not in the villus/surface cells in vivo. While Caco-2, T84 and IPEC-J2 cells, which are widely used intestinal epithelial cell lines to assess the influence of mycotoxins, do not express claudin-2, CMT93-II cells express claudin-2. We previously reported that inhibition of the ERK pathway reduced claudin-2 levels in cell-cell contacts in CMT93-II cells. In this study, we examined whether ochratoxin A, citrinin and deoxynivalenol affect claudin-2 expression and ERK1/2 phosphorylation in CMT93-II cells. We found that all mycotoxins reduced claudin-2 expression in cell-cell contacts, with reduction (by citrinin and deoxynivalenol) or no change (by ochratoxin A) in phosphorylated ERK1/2. All mycotoxins increased transepithelial electrical resistance, but did not affect flux of fluorescein. While ochratoxin A and citrinin are known to be nephrotoxic, only deoxynivalenol reduced claudin-2 expression in MDCK II cells derived from the renal tubule. These results suggest that claudin-2 expression is regulated not only by the ERK pathway, but also by other pathways in an organ-specific manner.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL; however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.

Treatment of autoimmune pulmonary alveolar proteinosis (aPAP) by subcutaneous injection or inhaled therapy of granulocyte-macrophage colony-stimulating factor (GM-CSF) has been demonstrated to be safe and efficacious in several reports. However, some reports of subcutaneous injection described transient benefit in most instances. The durability of response to inhaled GM-CSF therapy is not well characterized.To elucidate the risk factors for recurrence of aPAP after GM-CSF inhalation, 35 patients were followed up, monitoring for the use of any additional PAP therapies and disease severity score every 6 months. Physiologic, serologic, and radiologic features of the patients were analyzed for the findings of 30-month observation after the end of inhalation therapy.During the observation, 23 patients remained free from additional treatments, and twelve patients required additional treatments. There were no significant differences in age, sex, symptoms, oxygenation indexes, or anti-GM-CSF antibody levels at the beginning of treatment between the two groups. Baseline vital capacity (% predicted, %VC) were higher among those who required additional treatment (P.01). Those patients not requiring additional treatment maintained the improved disease severity score initially achieved. A significant difference in the time to additional treatment between the high %VC group (%VC≥80.5) and the low %VC group was seen by a Kaplan-Meier analysis and a log-rank test (P.0005).These results demonstrate that inhaled GM-CSF therapy sustained remission of aPAP in more than one-half of cases, and baseline %VC might be a prognostic factor for disease recurrence.ISRCTN Register and JMACCT Clinical Trial Registry; No.: ISRCTN18931678 and JMAIIA00013; URL: http://www.isrctn.org and http://www.jmacct.med.or.jp.

In 2007, we reported a large cohort of autoimmune pulmonary alveolar proteinosis (n=248, PAP) in Japan, and showed the incidence and prevalence were 0.24 - 0.49/million/year and 2.04 - 6.2/million (AJRCCM 2007), and 1.4%, 1.4%, and 5.7% of patients had interstitial lung diseases (ILD), autoimmune diseases, and infections. The aims of this study are; (1) To establish a nationwide consecutive registration system for PAP, updating the incidence and prevalence, and (2) To show the usefulness of the system via a surveillance of intractable cases. Methods: (1) All patients, who received the serum anti-GM-CSF autoantibodies tests and were definitely diagnosed, were annually consecutively registered to our database (2011-2014). Three institutes (Niigata, Kinki-Chuo, Aichi) measured the antibodies. (2) Surveillance for the intractable cases (dead, complications such as ILD, infection, etc.) was conducted via the system. Results: (1) Total 903 cases were registered. 88 cases/year have been newly diagnosed in average. The incidence and the prevalence were 0.69/million/year and 6.11/million. 92.9, 6.1, 0.4, and 0.6% were autoimmune, secondary, congenital, and unclassifiable PAP. (2)50% of the institutes responded, providing the data of 579 cases (64% of total patients). 14, 11.2, 10.2, 3.8, 6.7, and 7.9% had dead, respiratory failure, ILD, autoimmune diseases, infections, extra-pulmonary complications. Conclusions: We established a simple consecutive nation-wide registration system for PAP in Japan, providing updated annual epidemiological data and effective surveillance data. This study was granted from AMED (#15652554 , YI).

Summary Background Autoimmune pulmonary alveolar proteinosis (aPAP) is caused by granulocyte/macrophage-colony stimulating factor (GM-CSF) autoantibodies in the lung. Previously, we reported that GM-CSF inhalation therapy improved alveolar-arterial oxygen difference and serum biomarkers of disease severity in these patients. It is plausible that inhaled GM-CSF improves the dysfunction of alveolar macrophages and promotes the clearance of the surfactant. However, effect of the therapy on components in bronchoalveolar lavage fluid (BALF) remains unclear. Objectives To figure out changes in surfactant clearance during GM-CSF inhalation therapy. Methods We performed retrospective analyses of BALF obtained under a standardized protocol from the same bronchus in each of 19 aPAP patients before and after GM-CSF inhalation therapy (ISRCTN18931678, JMA-IIA00013; total dose 10.5–21 mg, duration 12–24 weeks). For evaluation, the participants were divided into two groups, high responders with improvement in alveolar-arterial oxygen difference ≥13 mmHg ( n = 10) and low responders with that n = 9). Results Counts of both total cells and alveolar macrophages in BALF did not increase during the therapy. However, total protein and surfactant protein-A (SP-A) were significantly decreased in high responders, but not in low responders, suggesting that clearance of surfactant materials is correlated with the efficacy of the therapy. Among 94 biomarkers screened in bronchoalveolar lavage fluid, we found that the concentration of interleukin-17 and cancer antigen-125 were significantly increased after GM-CSF inhalation treatment. Conclusions GM-CSF inhalation decreased the concentration of total protein and SP-A in BALF, and increase interleukin-17 and cancer antigen-125 in improved lung of autoimmune pulmonary alveolar proteinosis.

Background: The purpose of this study was to investigate whether heart rate variability parameters can be useful for evaluating cardiac autonomic dysfunction in multiple system atrophy patients. Methods: Both the time and frequency domains of heart rate variability were investigated among 17 multiple system atrophy patients and 27 normal control subjects. Results: All time- and frequency-domain measures, except the low- to high-frequency ratio, were significantly lower in multiple system atrophy patients than in controls. In multiple system atrophy patients, there were significant inverse correlations between heart rate variability parameters and disease duration, as well as disease severity, but heart rate variability parameters were not affected by other autonomic dysfunctions. Conclusions: The cardiac autonomic state of multiple system atrophy was characterized by decreases in both sympathetic and parasympathetic tones. Because heart rate variability parameters were not affected by other autonomic dysfunctions, this may be a useful method for evaluating cardiac autonomic dysfunction in multiple system atrophy. © 2012 Movement Disorder Society

Background Sudden death in multiple system atrophy (MSA) usually occurs during sleep and was therefore attributed to suffocation resulting from vocal cord abductor paralysis, a characteristic laryngeal finding of MSA. This led to the use of tracheostomy and noninvasive positive pressure ventilation (NPPV) for the prevention of sudden death. However, neither method has been able to prevent sudden death, and both have occasionally precipitated treatment-related complications, including central sleep apneas and exacerbation of floppy epiglottis. Therefore, it is important to determine the mechanisms and prevention of sudden death in MSA. Methods We reviewed the literature on the mechanisms and prevention of sudden death in patients with MSA. Results Sudden death in MSA is hypothesized to be a consequence of disordered central respiration, suffocation caused by sputum and food, upper airway obstruction from NPPV acting on a floppy epiglottis, cardiac autonomic disturbance, or a combination of these factors. Conclusion Various factors may be involved in the mechanism of sudden death in MSA. A multidisciplinary approach is needed to prevent sudden death, and this requires an organized system of several medical specialties. Neurologists require a cooperative network that includes experts in otorhinolaryngology, sleep medicine, dysphagia rehabilitation, and cardiology.

Objective Continuous positive airway pressure (CPAP) is used for the management of sleep-disordered breathing in patients with multiple system atrophy (MSA). However, the long-term outcome after CPAP treatment is yet to be ascertained. Methods A retrospective study was performed to investigate the frequency and causes of CPAP treatment discontinuation, and to ascertain the determinations of CPAP treatment duration in Japanese patients diagnosed with probable MSA based upon the consensus diagnostic criteria, who were admitted to our hospital from 2001 to 2012. Results Twenty-nine consecutive patients treated with CPAP were analyzed. During the observation period, 19 patients (66%) discontinued CPAP treatment. The median CPAP treatment duration was 13.0 months (range, 1–53 months). The major causes for discontinuation were pulmonary infection, respiratory insufficiency of undetermined origin, and CPAP intolerance. On comparing the clinical characteristics of the groups subjected to short- and long-term CPAP treatment, floppy epiglottis was more frequently observed in the short-term group than in the long-term group (64% vs 15%; P = 0.015). Conclusion The CPAP treatment duration in MSA patients was not long, and floppy epiglottis may be a determinant of the duration of CPAP treatment.

We tested the hypothesis that fasting affects hypoxic ventilatory responses through metabolic changes via histamine H1 receptors. Wild-type (WT) and histamine H1 receptor knockout (H1RKO) mice were studied in fed and fasted states. In the fed WT, hypoxic-gas exposure elicited an increase and a subsequent decline in ventilation (hypoxic ventilatory decline or HVD). HVD was influenced by fasting in breathing pattern with metabolic rate. Fasting elicited hypoglycemia, a drop in R, and increases in free fatty acid and ketone bodies in the serum. In H1RKO, HVD was blunted in the fed state, but it appeared in the fasted state. There was a minimal drop in R following fasting and a low triglyceride concentration. Thus, fasting affects HVD through a change in energy mobilization from glucose to lipid metabolism. Histamine H1 receptors are involved in HVD during fed and fasted states, resulting in adaptation to the environmental conditions.

To determine whether tremulous arytenoid movements predict the severity of glottic stenosis in patients with multiple system atrophy (MSA), 28 MSA patients and 14 age-matched controls underwent fiberoptic laryngoscopy with video monitoring during wakefulness and under anesthesia induced by intravenous injection of propofol. Presence or absence of tremulous arytenoid movements was recorded during wakefulness. The ratio of glottic stenosis (%), which represents the extent of airway narrowing under anesthesia, was obtained by measuring the inspiratory glottic angle during wakefulness and under anesthesia. The median ratio of glottic stenosis was significantly higher in patients with MSA (57.5%) than in control subjects (0.5%). Tremulous arytenoid movements were characterized by shaking movements of the arytenoid region including the vocal folds, which are most apparent in the arytenoid cartilage. In this study, tremulous arytenoid movements were observed in 18 (64.2%) of 28 patients with MSA, who displayed a significantly higher median ratio of glottic stenosis (71.2%) than other patients (34.9%). None of the control subjects exhibited tremulous arytenoid movements. A clear correlation existed between the ratio of glottic stenosis and disease duration. Our observations indicate that tremulous arytenoid movements are a marker of the severity of glottic stenosis, which confers an increased risk of upper airway obstruction in patients with MSA.

Ventilation oscillates throughout a day in parallel with oscillations in metabolic rate. Histamine affects ventilation and the balance of the energy metabolism via H1 receptors in the brain. We tested the hypothesis that the ventilatory response to hypoxia varies between light and dark periods and that histamine H1 receptors are required for the circadian variation, using wild-type (WT) and histamine H1 receptor knockout (H1RKO) mice. Mice were exposed to hypoxic gas (7% O2 + 3% CO2 in N2) during light and dark periods. Ventilation initially increased and then declined. In WT mice, minute ventilation (V̇e) during hypoxia was higher in the dark period than in the light period, which was an upward shift along with the baseline ventilation. Hypoxia decreased the metabolic rate, whereas O2 consumption (V̇o2) and CO2 excretion were higher in the dark period than in the light period. However, in H1RKO mice, changes in V̇e during hypoxia between light and dark periods were minimal, because V̇e was increased relative to V̇o2, particularly in the light period. In H1RKO mice, the HCO3− concentration and base excess values were increased in arterial blood, and the level of ketone bodies was increased in the serum, indicating that metabolic acidosis occurred. Respiratory compensation takes part in the V̇e increase relative to V̇o2 during hypoxia. These results suggested that changes in V̇e during hypoxia vary between light and dark periods and that H1 receptors play a role in circadian variation in V̇e through control of the acid-base status and metabolism in mice.

Information on obstructive sleep apnea-hypopnea syndrome (OSAHS) in Japan has been limited. The purposes of this clinical study were to evaluate the demographic characteristics of Japanese OSAHS patients and to assess how demographic factors are associated with OSAHS severity. We analyzed 3,659 OSAHS patients who underwent polysomnographic evaluation between January 2000 and December 2004 at 11 hospitals in Niigata Prefecture, Japan. Data consisted of apnea-hypopnea index (AHI) and demographic characteristics, including sex, age, and body-mass index, for statistical analysis. Levels of obesity were classified according to the WHO criteria. The male-to-female patient ratio for OSAHS was 4.6, and male patients presented more severe OSAHS than female patients. High AHI and a high proportion of moderate to serious OSAHS (AHI > or = 15) were found among the patients in their 30s, as well as female patients in their 70s and male patients in their 80s. The AHI and the proportion of moderate-to-serious OSAHS (AHI > or = 15) were greater in patients classified as underweight than in normal weight patients. In conclusion, there is a higher male predominance in the prevalence of OSAHS, and in both sexes, the results suggest different pathophysiological mechanisms of deteriorating OSAHS between adults under age 55 and adults 55 years or over. In addition, underweight patients exhibit more severe OSAHS than normal weight patients.

Fatigue tests were conducted on adhesively-bonded CFRP/aluminum double-cantilever beam (DCB) specimens to investigate the effect of adherend thickness on the fatigue crack growth rate. Components of the specimens were unidirectional composite, aluminum plate and a film-type epoxy adhesive. The experimental results indicate that the increase in the aluminum plate thickness lowers the fatigue threshold value and steepens the slope in the Paris region. To elucidate the effect of the adherend thickness on the fatigue crack propagation behavior, a finite element analysis was conducted to investigate the mode ratio, and stress and strain distributions near the crack tip, where the coefficient of thermal expansion mismatch between the aluminum and the CFRP plates was taken into account. The effect of the adherend thickness on the crack propagation rate has been tentatively explained in terms of stress distributions near the crack tip and crack propagation path.

Background: Obstructive sleep apnoea (OSA) syndrome is thought to be induced pathophysiologically by the interactions of upper airway collapsibility, control of breathing and/or arousability. The withdrawal of excitatory noradrenergic and serotonergic inputs to upper airway motor neurons during REM sleep increases the propensity for upper airway (UA) collapse. Aims: To evaluate the features of respiratory events by UA collapsibility estimated during REM sleep. Methods: Types (apnoea or hypopnoea) and duration of respitatory events, the degree of desaturation, occurrence and timing of arousals were determined with the diagnostic polysomnography. The proportion of apnoeas per total events (A ratio) in supine position during REM sleep was considered as UA collapsibility and three groups were categorized; mild(M, 0.7). Results: 78 male OSA patients with more than 15 per hour of AHI and without heart diseases and/or psychiatric disorders (Age 48±10 years, BMI 27.5 ± 5.1 kg/m2, AHI 38.6± 22.9 /h) were studied. There were no significant differences in age and BMI except AHI(M 24.9, Mo 27.2, S 42.6/h, median) among three groups (M 14, Mo 23, S 41 pts). In M group, no differences were seen in A ratio and the proportion of arousals per events between each sleep stage. There was more proportion of arousals per events during REM sleep in S group than other groups ( S 0.636 vs Mo 0.449, M 0.309, p Conclusion: UA collapsibility estimated during REM sleep affects types of respiratory events and the proportion of arousals during sleep stages. Granted by Japanese society for the promotion of science.

Thrombotic thrombocytopenic purpura (TTP) is a rare complication of mixed connective tissue disease (MCTD). In this report, we describe the case of a 73-year-old Japanese woman with MCTD who developed fever, thrombocytopenia, and microangiopathic hemolytic anemia and was diagnosed with MCTD together with TTP. The activity of von Willebrand factor (vWF) cleaving metalloprotease ADAMTS13 was low and considered to have contributed to the disease activity of TTP. The patient died despite intensive treatment of plasma exchange (PEX) and steroid pulse therapy. Autopsy results revealed that the kidneys had platelet and fibrin thrombi, which occluded capillaries and arterioles. These findings were compatible with TTP and the decreased activity of ADAMTS13 was considered to be associated with the disease activity of TTP.

Background The importance of smoking in bronchial asthma has been thoroughly investigated. Although a high smoking rate has been recognized in Japan, there have been few studies of the relationship between active smoking and bronchial asthma, and little analysis of the gender difference in this relationship. The aims of this study were to examine the contribution of active smoking to asthma and to clarify any gender difference. Methods For 8 weeks from September through October 2000, a smoking questionnaire survey was performed on adult patients with bronchial asthma, and their attending physicians, in Niigata Prefecture, Japan. The questionnaire surveyed asthma control, asthma-related emergencies and satisfaction in daily life. The attending physicians were questioned about patient profiles and medications. Patients were classified into three groups: non-smokers (NS), ex-smokers (ES) and current smokers (CS). For examination of gender differences, the CS group was compared with the NS group, due to variable duration of smoking and of cessation of smoking in the ES group. Results Complete data were received from 2947 cases. Of the male patients, 340 (23.0%) were in the CS group, 325 (22.0%) were in the NS group and 812 were in the ES group. Of the female patients, 109 (7.4%) were in the CS group, 1132 (77.4%) were in the NS group, and 229 (7.4%) were in the ES group. The male CS group had more severe asthma-related symptoms in the morning and at night, more sputum and cough in the morning, and more severe sleep disturbance than the male NS group. In the female patients, these differences were not detected. A logistic and multiple regression analysis confirmed these significant differences between male and female asthma patients. Conclusions The gender differences in the susceptibility of asthma to smoking suggests the need for gender-specific strategies for smoking cessation, although further investigation is required.

Sleep unmasks a highly sensitive hypocapnia-induced apnoeic threshold, whereby apnoea is initiated by small transient reductions in arterial CO2 pressure (PaCO2) below eupnoea and respiratory rhythm is not restored until PaCO2 has risen significantly above eupnoeic levels. We propose that the ‘CO2 reserve’ (i.e. the difference in PaCO2 between eupnoea and the apnoeic threshold (AT)), when combined with ‘plant gain’ (or the ventilatory increase required for a given reduction in PaCO2) and ‘controller gain’ (ventilatory responsiveness to CO2 above eupnoea) are the key determinants of breathing instability in sleep. The CO2 reserve varies inversely with both plant gain and the slope of the ventilatory response to reduced CO2 below eupnoea; it is highly labile in non-random eye movement (NREM) sleep. With many types of increases or decreases in background ventilatory drive and PaCO2, the slope of the ventilatory response to reduced PaCO2 below eupnoea remains unchanged from control. Thus, the CO2 reserve varies inversely with plant gain, i.e. it is widened with hyperventilation and narrowed with hypoventilation, regardless of the stimulus and whether it acts primarily at the peripheral or central chemoreceptors. However, there are notable exceptions, such as hypoxia, heart failure, or increased pulmonary vascular pressures, which all increase the slope of the CO2 response below eupnoea and narrow the CO2 reserve despite an accompanying hyperventilation and reduced plant gain. Finally, we review growing evidence that chemoreceptor-induced instability in respiratory motor output during sleep contributes significantly to the major clinical problem of cyclical obstructive sleep apnoea.

Patients with OSAS (obstructive sleep apnoea syndrome) demonstrate renal signs such as proteinuria, glomerular hypertrophy and focal glomerular sclerosis. We performed a clinical study to investigate the glomerular function in OSAS patients and the short-term effect of CPAP (continuous positive airway pressure) on it. OSAS patients underwent a sodium thiosulphate and p-aminohippurate double clearance test, polysomnography and ambulatory blood pressure monitoring before and a week after the induction of CPAP. Twenty-seven consecutive patients (24 males) with moderate-to-severe OSAS admitted to our hospital for the induction of CPAP, and 32 healthy donors for renal transplantation as controls participated in the study. Before treatment, the glomerular filtration rate, estimated by the sodium thiosulphate clearance test, was within normal range, and the renal plasma flow was significantly lower than normal in the OSAS patients, thus the FF (filtration fraction) value was much higher than normal. FF before CPAP was not significantly correlated with age, body mass index or blood pressure; however, indices of increased hypoxaemia correlated with increased FF values. Polysomnographic variables after CPAP showed significant improvements in all patients, and only the nocturnal blood pressures were slightly lower than before CPAP. In 21 patients who underwent the clearance test after CPAP, FF significantly decreased from 0.26±0.04 to 0.23±0.03 (P