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Psychological aptitude tests, which are highly suitable for securing the currently required levels of safety, contribute to the establishment of a safer railway environment. We carried out four new tests on 1,484 train operation staff (aged 18 - 63) and analyzed the correlation between the results of the current/new tests and staff members' history of causing railway accidents or transport disorder. A new set of tests was proposed based on the results of this analysis.

Previously we estimated the prevalence of essential hypertension (EH) as around 0.1% and suggested that male gender, obesity, and strong genetic background (hypertension in parents) were risk factors for EH in a young population aged less than 30 based on targeted screening for hypertension at a university health check-up. This study also revealed a high incidence of white coat hypertension (WCH) in university students, and thus, we continued this screening for four consecutive years, and examined the prognosis and clinical characteristics of young-onset WCH. Three occasions of casual blood pressure (BP) measurement and additional home BP measurement revealed 72 WCH and 15 EH students (all males) during the 4-year study period. None of the WCH students had elevated home BP to the level of hypertension during their stay at university, and 26 out of 38 WCH students participating screening in the following years showed normal casual BP. Although WCH students showed a significantly higher pulse rate than controls, WCH could not be fully differentiated from EH either by pulse rate or by correlation between casual BP value and pulse rate. These findings indicate the requirement of longer follow-up after graduation to determine the prognosis of young-onset WCH, though EH and WCH in the young population share the same risk factors and, possibly, autonomic nervous system dysfunction. Since diagnosis of WCH has limited importance for university students, screening of EH following a general health check-up would elevate the clinical validity of casual BP measurement at the university.

Difficulties have been associated with accurately diagnosing patients with thyroid dysfunction (PTD); however, measuring thyroid hormone levels in all individuals is challenging. We successfully constructed a prediction model for PTD by adopting pattern recognition methods using a combination of six routine laboratory tests, and identified 21 new PTD using our screening method, which was executed at two health check-up centers. In the present study, we newly introduced time-series variations in routine tests as additional parameters in order to develop the model by eliminating the influence of individual differences in routine tests. We constructed self-organizing maps (SOM) using the time-series traceable data of 13 PTD and 45 healthy individuals. We then investigated the locations of 140 projected false positives in our previous study on SOM and found that the number of false positives markedly decreased, thereby demonstrating the progression of our new model.

Study Objectives: To evaluate the morphological features of the mandible and the volume of the upper airway soft tissues in determining the anatomical risk factors for the upper airway in Japanese male patients with obstructive sleep apnea hypopnea syndrome (OSAHS). Methods: Five morphological parameters of the mandible at the mandibular base plane and three volumetric parameters of the upper airway soft tissue were analyzed using three-dimensional (3D) magnetic resonance imaging software in 31 OSAHS and 20 controls. Results: There were no significant differences between the two groups in mandibular internal width (the distance between the internal right and left gonia [IRG and ILG]) and mandibular bony thickness. However, the patients with OSAHS had a significantly wider mandibular divergence (the angle between the spina mentalis (SM)- IRG line and SM- ILG line), a smaller mandibular internal length (the perpendicular distance from SM to the RG- LG line), and a smaller area than the normal subjects at the mandibular base plane. There were no significant differences in these morphological parameters for the mandible between obese and nonobese OSAHS patients. The volumes of the tongue, soft palate, and lateral pharyngeal walls were not significantly different between the OSAHS and the control groups. Conclusions: Japanese male OSAHS patients had specific anatomical features in the bottom part of the mandible; however, obesity seemed to be a less significant risk factor. Investigators and clinicians must realize that ethnicity may modify the effects of obesity and abnormal craniofacial anatomy as risk factors for the pathogenesis of OSAHS.

Objective: To clarify the prevalence and clinical characteristics of obesity-hypoventilation syndrome (OHS) in a large number of patients with moderate to severe obstructive sleep apnea syndrome (OSAS). Methods: Subjects comprised 611 patients with OSAS registered from 7 sleep centers and clinics and analyzed according to the definitions of the Respiratory Failure Research Group of the Japanese Ministry of Health and Welfare. Baseline characteristics, polysomnographic data during sleep, laboratory blood examinations, excessive daytime sleepiness, pulmonary functions, and arterial blood gases were compared between OHS and non-OHS patients. Determinants of daytime hypercapnia were also examined in OHS patients. Results: OHS was identified in 55 of the 611 patients with OSAS (9%). OHS patients were younger, heavier, and more somnolent than non-OHS patients and displayed more severe OSAS, liver dysfunctions, higher total cholesterol, and impaired pulmonary function. However, these differences were resolved except for pulmonary function after correction for obesity. Daytime hypercapnia was associated with impaired pulmonary function. Percent vital capacity (%VC) was most closely correlated with PaCO2 in OHS. Conclusion: OHS patients display numerous abnormalities due to obesity compared with non-OHS patients. Impaired pulmonary function, particularly %VC, may play an important role in the development of daytime hypercapnia independent of obesity in OHS patients.

Heme oxygenase 1 (HO-1) catalyzes heme breakdown, eventually releasing iron, carbon monoxide, and bilirubin IXalpha. HO-1 is induced by its substrate heme and various environmental factors, which represents a protective response against oxidative stresses. Here we show that hypoxia represses HO-1 expression in three human cell types but induces it in rat, bovine, and monkey cells, indicating the inter-species difference in the hypoxic regulation of HO-1 expression. The hypoxia-mediated repression of HO-1 expression is consistently associated with the induction of Bach1, a heme-regulated transcriptional repressor, in human cells. Bach1 is a basic leucine zipper protein, forming a heterodimer with a small Maf protein. Expression of HO-1 was also reduced in human cells when exposed to interferon-gamma or an iron chelator desferrioxamine, each of which induced Bach1 expression. In contrast, induction of HO-1 expression by CoCl(2) is associated with reduced expression of Bach1 mRNA. Thus, expression of HO-1 and Bach1 is inversely regulated. We have identified a Maf recognition element in the human HO-1 gene that is required for repression of a reporter gene by hypoxia and targeted by Bach1. Therefore, Bach1 functions as a hypoxia-inducible repressor for the HO-1 gene, thereby contributing to fine-tuning of oxygen homeostasis in human cells.

本研究は, 人間ドック受診者における慢性閉塞性肺疾患 (chronic obstructive pulmonary disease: COPD) の有病率と喫煙習慣について検討し, 有病者の実態を明らかにすることを目的とした。対象は, 仙台市にあるエスエスサーティ健康管理センターにおいて, 2001年1月～12月に人間ドックを受診した6, 967名 (男性4, 722名, 女性2, 245名; 平均年齢46.9±8.0歳; 年齢分布30～73歳; 喫煙率38.8%) とした。解析は, COPDの診断基準を1秒率 (1秒量/肺活量×100) ≦70%として, 年齢階級別および喫煙習慣別 (非喫煙者, 元喫煙者, 現喫煙者) に実施した。全対象者におけるCOPDの有病率は3.8%を示した。喫煙習慣別の有病率は, 非喫煙者, 元喫煙者, 現喫煙者のいずれも50歳代以降に増加した。特に現喫煙者の有病率の増加が著明であった。各年齢階級内における喫煙習慣別の有病率については, 30歳代, 40歳代において有意差が認められなかった。しかし, 50歳代および60歳以上の有病率は, 非喫煙者, 元喫煙者, ブリンクマン指数 (BI)

This study was aimed to examine the short- and long-term effects of nasal continuous positive airway pressure (CPAP) on the chemosensitivity to hypoxia and hypercapnia in the patients with obstructive sleep apnea (OSA). Awake ventilatory responses to hypoxia and hypercapnia were examined in 28 patients (3 female) with moderate to severe OSA. All these tests were examined before and after 2 weeks of nasal CPAP. In 10 patients these tests were repeated after 3-6 months of nasal CPAP. All were also tested for spirometry and arterial blood gas analysis. Patients were middle-aged (48.9 +/- 9.9 years) and their mean apnea-hypopnea index was 58.3 +/- 20.4/hour. After 2 week of nasal CPAP, PaO2 significantly increased (77.7 +/- 11.8 vs. 84.6 +/- 9.8 mmHg) and PaCO2 significantly decreased (44.9 +/- 3.8 vs. 42.3 +/- 3.7 mmHg). The ventilatory response to hypoxia significantly decreased (0.80 +/- 0.51 vs. 0.61 +/- 0.51 liter/min/%) whereas the ventilatory response to hypercapnia significantly increased after 2 weeks (1.47 +/- 0.73 vs. 1.80 +/- 0.76 liter/min/mmHg). Similar findings were also observed after 3-6 months of nasal CPAP in 10 OSA patients. Nasal CPAP treatment can alter the ventilatory responses in patients with OSA.

The exact nature of asleep blood pressure in relation to awake blood pressure is still unclear in patients with obstructive sleep apnoea. This study aimed: 1) to investigate the asleep blood pressure in both apnoeic and ventilatory periods; 2) to determine the diurnal and nocturnal factors correlated with the changes in blood pressure from apnoea to ventilatory periods during sleep. Thirty-two patients, newly diagnosed as moderate to severe obstructive sleep apnoea with a standard nocturnal polysomnography, were enrolled. The blood pressure was monitored by using the noninvasive continuous monitoring method during polysomnographic study. The mean blood pressures in ventilatory periods during nonrapid eye movement (NREM) and rapid eye movement (REM) sleep were 117.5+/-17.9 mm Hg and 128.8+/-21.9 mm Hg, and those in apnoea periods were 94.5+/-15.4 mm Hg and 102.7+/-19.0 mm Hg. The average blood pressure during NREM sleep (103.0+/-16.1 mm Hg) was higher than the awake blood pressure (97.0+/-15.7 mm Hg). The blood pressure during REM sleep was greater than that during NREM sleep. The changes in the nocturnal blood pressure from apnoea to ventilatory periods were inversely correlated with the age and nocturnal mean nadir saturation. In conclusion, patients with obstructive sleep apnoea have higher asleep blood pressure than awake blood pressure.

We prospectively examined the survival rate of 67 chronic obstructive pulmonary disease (COPD) and 74 late sequelae of pulmonary tuberculosis (TB seq) patients to clarify whether nocturnal oxyhemoglobin desaturation (NOD)could be one of the independent factors determining their mortality. The sleep monitoring of arterial oxygen saturation (SpO2) and pulmonary function tests were assessed in all patients at the time of registration. Forty %of COPD and 24%of TB seq died as the direct result of deterioration of chronic respiratory failure during the 7-year observation period. Cox's proportional hazards analysis showed that NOD was an independent prognostic factor in both groups, and this was especially prominent when evaluated in terms of sleep lowest SpO2 in COPD and 85% desaturation time in TB seq. No significant prognostic factor was observed among age, vital capacity percent predicted (%VC), forced expiratory volume in one second (FEV1.0%)and partial pressure of carbon dioxide (PaCO2). We conclude that the degree of NOD can affect mortality in COPD and TB seq.(Internal Medicine 37: 354-359, 1998)

There is growing evidence that extracellular ATP causes a dramatic change in the membrane conductance of a variety of inflammatory cells. In the present study, using the nystatin perforated patch recording configuration, we found that ATP (0.3-30 microM) induced a transient outward current in a concentration-dependent manner and that the reversal potential of the ATP-induced outward current was close to the K+ equilibrium potential, indicating that the membrane behaves like a K+ electrode in the presence of ATP. The first application of ATP to alveolar macrophages perfused with Ca2+-free external solution could induce the outward current, but the response to ATP was diminished with successive applications. Intracellular perfusion with a Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N', N'-tetraacetic acid, also diminished the response. When cyclic ADP-ribose (cADPR) was applied to the macrophage cytoplasm, a transient outward current was elicited. Thereafter, the successive outward current was inhibited, suggesting the involvement of cADPR in the response. Intracellular perfusion with inositol 1,4, 5-trisphosphate also induced a transient outward current, but the successive current was not inhibited. The ATP-induced outward current was abolished when 8-amino-cADPR (as a blocker of cADPR, 10(-6)-10(-5) M) was introduced into the cytoplasm. Homogenates of alveolar macrophages showed both ADP-ribosyl cyclase and cADPR hydrolase activities, and CD38 (ADP-ribosyl cyclase/cADPR hydrolase) expression was confirmed by reverse transcriptase-polymerase chain reaction and Western blot analyses. These results indicate that ATP activates K+ currents by releasing Ca2+ from cADPR-sensitive internal Ca2+ stores.

A 31-year-old male with obstructive sleep apnea syndrome was treated with KTP/532 laser midline glossectomy. He had complained of severe snoring and hypersomnolence for 2 years and sleep apnea for 1 year. His apnea index (Al) was 65.0 events/h and the lowest arterial O2 saturation (SaO2) was 44%. Cephalometric analysis and flexible fiberoptic pharyngeal endoscopy during Muller's maneuver indicated that the space-occupying sites responsible for sleep apnea were at two different levels (oropharynx-soft palate and hypopharynx-base of the tongue). The application of KTP/532 laser to midline glossectomy with uvulopalatopharyngoplasty caused slight bleeding but no obvious complications. Postoperative respiratory parameters were greatly improved: Al 5.5 and lowest SaO2 85%. Cephalometric and fiberoptic findings showed an enlarged pharyngeal space at the level of the base of the tongue. Sleep-related complaints disappeared completely.

BACKGROUND--Cyclical changes in systemic blood pressure occur during apnoeic episodes in patients with obstructive sleep apnoea (OSA). Although several factors including arterial hypoxaemia, intrathoracic pressure changes, and disruption of sleep architecture have been reported to be responsible for these changes in blood pressure, the relative importance of each factor remains unclear. This study assessed the role of hypoxaemia on the increase in blood pressure during apnoeic episodes. METHODS--The blood pressure in apnoeic episodes during sleep and the blood pressure response to isocapnic intermittent hypoxia whilst awake were measured in 10 men with OSA. While asleep the blood pressure was measured non-invasively using a Finapres blood pressure monitor with polysomnography. The response of the blood pressure to hypoxia whilst awake was also measured while the subjects intermittently breathed a hypoxic (5% or 7% oxygen) gas mixture. Each hypoxic gas exposure was continued until a nadir arterial oxygen saturation (nSaO2) of less than 75% was reached, or for a period of 100 seconds. The exposure was repeated five times in succession with five interposed breaths of room air in each run. RESULTS--The mean (SD) increase in blood pressure (delta MBP) during apnoeic episodes was 42.1 (17.3) mm Hg during rapid eye movement (REM) sleep and 31.9 (12.5) mm Hg during non-REM sleep. The delta MBP during apnoeic episodes showed a correlation with the decrease of nSaO2 (delta SaO2) (r2 = 0.30). The change in blood pressure in response to intermittent hypoxia whilst awake was cyclical and qualitatively similar to that during apnoeic episodes. Averaged delta MBP at an SaO2 of 7% and 5% oxygen was 12.6 (5.7) and 13.4 (3.6) mm Hg, respectively, whereas the averaged delta MBP at the same delta SaO2 during apnoeic episodes was 38.4 (15.5) and 45.2 (20.5) mm Hg, respectively. CONCLUSIONS--The blood pressure response to desaturation whilst awake was about one third of that during apnoeic episodes. These results suggest that factors other than hypoxia may play an important part in raising the blood pressure during obstructive sleep apnoea.

1. An attempt has been made to test the hypothesis that, in the caudal part of nucleus tractus solitarii (NTS) where carotid sinus nerve (CSN) afferents project, L-glutamate (Glut) modulates the hypoxic ventilatory response. 2. Unanaesthetized, peripherally chemodenervated (carotid body denervated; CBD) and sham-operated, freely moving rats were used. During peripheral chemoreceptor stimulation by hypoxia (10% O2 for 30 min) or doxapram (Dox) infusion (2 mg kg-1 (30 min)-1), ventilation was recorded and successively, under the same conditions, the extracellular Glut concentration ([Glut]o) in the caudal NTS was measured by in vivo microdialysis. [Glut]o was also measured during hyperoxic hypercapnia (10% CO2-30% O2 for 30 min). 3. Furthermore, the effects on ventilation of exogenous Glut, the NMDA (N-methyl-D-aspartate) receptor antagonist MK-801 or the ionotropic receptor antagonist kynurenate microinjected into the caudal NTS were investigated in sham-operated rats. 4. In sham-operated rats, both ventilation and [Glut]o in NTS were increased during peripheral chemoreceptor stimulation. On the other hand, no increases in either ventilation or Glut release were observed in CBD rats. In spite of ventilatory augmentation during hypercapnia, no response of [Glut]o to hypercapnia was observed in either group. 5. Local Glut application into NTS increased ventilation. Pretreatment with MK-801 or kynurenate reduced the hypoxic ventilatory response. This reduction in ventilation was mainly due to the decrease in tidal volume. 6. These results suggest that hypoxia induced the release of Glut in NTS and that this effect was mediated by arterial chemosensory input.

SHINDOH, C., HIDA, W., KUROSAWA, H., EBIHARA, S., KIKUCHI, Y., TAKISHIMA, T. and SHIRATO, K. Effects of Unilateral Phrenic Nerve Denervation on Diaphragm Contractility in Rat. Tohoku J. Exp. Med., 1994, 173 (3), 291-302- We examined the early effects of phrenic nerve denervation on the diaphragm muscle 1, 3, 7 and 14 days after unilateral denervation in rats. In the denervated hemidiaphragms, force frequency curves at 3, 7 and 14 days decreased significantly by 51%, 50% and 38% respectively of the peak tension of the force frequency curves of the diaphragms of rats with sham operation. Twitch tensions increased significantly at 14 days, and contraction times and half relaxation times slowed significantly at 3, 7 and 14 days. The tensions of denervated diaphragms at 5min during the fatigue runs was significantly increased at 14 days. As determined by histological staining, the mean cross sectional area of fast-twitch fibers (type II) decreased significantly from 2, 742 (sham) to 1, 599μm2 (14 days), but that of the slow-twitch fibers (type I) did not change significantly during the same period. These findings suggest that, during the first two weeks of denervation, fast twitch fibers (type II) atrophy more rapidly than slow twitch fatigue resistant fibers (type I), as confirmed by the contractile properties and histological findings.

Since the prevalence and clinical characteristics of young-onset hypertension are still to be elucidated, we performed targeted-screening at an annual university health check-up for two consecutive years. Out of 16,464 subjects in 2003 and 17,032 in 2004 that were aged less than 30 years, 22 and 26 students (all males) exhibited high blood pressure (BP), respectively, on three occasions during casual BP measurements at the Tohoku University Health Center (systolic and diastolic BP of 140 and/or 90 mmHg or greater, respectively). These students were asked to measure their BP at home, and 9 subjects in total were diagnosed as having essential hypertension (EH). The remaining students were diagnosed as having white coat hypertension (WCH). In 8 out of 9 EH students, their father and/or mother had also been treated with antihypertensive medication. Adjustment by attendance ratio for each BP measurement suggested that the incidence of EH was around 0.1% and that of hypertension (EH and WCH) was around 0.5% in university students aged less than 25 years, since most of the subjects and hypertensive students were between 18 and 24 years old. Body mass index of the EH, which was more than 25 kg/m2 (overweight), was significantly higher than that with WCH. In conclusion, the combination of repeated casual BP measurements and home BP effectively identified young-onset EH. The clinical parameters indicated that male gender, genetic background, and excessive weight were risk factors for young-onset hypertension.

Hypoxia causes a life-threatening situation, and the ventilatory response to hypoxia plays an important role in preventing death. We have hypothesized that persons with a blunted hypoxic ventilatory response may have a weak defense response to hypoxic episodes and be susceptible to fatal respiratory disturbances. However, precise correlations between the hypoxic ventilatory response and respiratory disturbances are not well understood. In the present study we examined the hypoxic and hypercapnic ventilatory responses in nine inbred mouse strains (A/J, AKR/N, BALB/c, C3H/He, C57BL/6, DBA/2, NZW, SWR/J, and 129Sv). Breathing frequency, tidal volume and minute ventilation of unanesthetized and unrestrained mice were assessed by whole body plethysmography. Age-matched mice were exposed for 3 min to 10% O(2) in N(2) gas or 10% CO(2) in hyperoxic gas to determine the acute ventilatory response to chemical stimuli. Basal respiratory variables and hypoxic ventilatory responses differed among the strains, but the hypercapnic ventilatory response did not differ. The hypoxic ventilatory response was the highest in AKR/N mice and the lowest in SWR/J mice. These findings suggest that genetic factors may have influenced the hypoxic ventilatory response but not the hypercapnic ventilatory response. To examine the effects of severe hypoxic stress on the respiratory cycle, we exposed the strain with the highest or lowest hypoxic ventilatory response to 6% O(2) in N(2) until the onset of apnea. The "appearance time of apnea", which is defined as the time from the hypoxic loading to the onset of apnea, was shorter in the SWR/J strain than in the AKR/N strain. We suggest that a lower hypoxic ventilatory response may be a risk factor for apnea under hypoxia.

In Japan, spirometry has not been included as an item in medical check-ups for all persons. The purpose of this study was to show evidence to recommend spirometry routinely on medical check-up for the early detection of chronic obstructive pulmonary disease (COPD). There were 12,760 enrolled persons who underwent medical check-up. COPD was defined as a ratio of forced expiratory volume in one second to slow vital capacity of 70% or less. We investigated the prevalence and its characteristics of COPD in people on medical check-up. The prevalence of COPD was 3.6% in all subjects, 4.5% in males, and 1.8% in females. In the comparison between males and females, the prevalence of COPD in males of most age groups was higher than that of females, and this difference was greater with aging. Males in their 50s and over 60 years old and females over 60 years old showed remarkably high prevalences. Occupations associated with a high smoking rate such as transportation-related occupations showed a higher prevalence of COPD. These results suggest that spirometry for all persons in medical check-ups can identify many COPD patients not aware of this disease. Spirometry should be carried out routinely on medical check-up.

Obstructive sleep apnea (OSA) is commonly associated with systemic hypertension and now recognized as an independent risk factor for daytime hypertension. We aimed to study the short- and long-term effect of nasal continuous positive airway pressure (CPAP) in hypertensive and normotensive patients with OSA. Forty-six patients with moderated to severe OSA were treated with nasal CPAP and followed after one year of treatment. Clinic blood pressure, heart rate, and body weight were taken before and followed up for one year after beginning nasal CPAP. In this study 25 patients with OSA were found to have hypertension (54.3%). The hypertensive group showed a significant reduction in clinic blood pressure after nasal CPAP, whereas the normotensive group showed no changes. The subgroup of hypertensive patients with OSA who had no anti-hypertensive medication revealed a decrease in clinic blood pressure comparable to those with anti-hypertensive drugs. The heart rate was not significantly changed in any patients. There was no significant correlation between the decrease in body weight and the reduction in blood pressure. These results suggest that nasal CPAP alone might have a substantial blood pressure lowering effect in hypertensive patients with OSA. This effect could decrease the morbidity and mortality related to cardiovascular complications in patients with OSA.

In patients with chronic obstructive pulmonary disease (COPD), pulmonary hypertension (PH) is associated with a worse prognosis. Recently, information has been increasing concerning the cellular and molecular aspects of the pathophysiology of PH in COPD. The most striking finding is the role of vascular endothelial cells and endogenous mediators released by these cells. Endothelial cell-dependent relaxation is impaired in COPD patients with PH. Moreover, vascular remodelling in these patients is mainly responsible for irreversible PH in advanced COPD. Smoking cessation will slow down the progression of the disease process and may prevent the development of PH in COPD. The timing of initiation of long-term oxygen therapy is important for the effective management of PH in COPD. Research on therapeutic agents for the effective treatment of PH is still needed in the management aspect of patients with COPD. This review focuses on the recent advances in our understanding of the pathophysiology and treatment of PH in COPD.

The purpose of this study was to examine our hypothesis that γ-aminobutyric acid (GABA) in the nucleus tractus solitarii (NTS) may be related to the hypoxic ventilatory decline (HVD) and that chemoreceptor stimulation was essential to activate this mechanism. We used unanesthetized, freely moving rats in this study. An in vivo microdialysis technique was used to measure the extracellular GABA concentration ([GABA]o), and an in vivo microinjection technique was used to examine the effects of the GABA agonists and antagonists on the ventilation during hypoxia. The GABA agonists injected into the NTS attenuated the ventilation during hypoxia. By hypoxic exposure, [GABA]o was increased during the HVD. However, by carotid body denervation (CBD), this GABA increase was abolished. Although GABA antagonists microinjected into the NTS during the HVD phase significantly increased the depressed ventilation, this effect on the ventilation was abolished by CBD. These results suggest that the GABA in the NTS has a pivotal role in the HVD and that this mechanism is not activated without chemoreceptor stimulation.

The prevalence of sleep apnea syndrome (SAS) is approximately 7.5% in Japanese adults aged 18-68 years old. SAS is characterized by repeated episodes of apnea, especially obstructive apnea, during sleep. Severe SAS has life-threatening complications such as pulmonary hypertension, arrhythmias, right heart failure or brain damage, which could be caused by hypoxemia and/or hypercapnia. Upper airway relaxation is responsible for the obstruction during apnea, and an increase in the activities of the upper airway muscles dilates and stiffens the upper airway wall. Maintaining the activities of the upper airway muscles may contribute to keeping the airway patent. Submental electrical stimulation of the upper airway muscles would be a novel treatment method for obstructive apnea.

We assessed the effect of sustained isocapnic hypoxia (PCO2 = 40 Torr, SaO2 = 80%) on the sensation of dyspnea in 16 normal healthy males. Subjects rated the sensation of dyspnea (c) on 15 cm visual analog scales during 20 min of sustained hypoxia. Following this hypoxic period, 8 subjects undertook mild exercise (10-50 W on a bicycle ergometer for 3 min) under the continuation of hypoxia. During sustained hypoxia, psi increased initially with ventilation from 0.6 +/- 0.2 (n = 16, mean +/- SE) to 2.9 +/- 0.6 at peak ventilation, but it decreased with ventilatory depression to 1.6 +/- 0.4. Dyspnea intensity during hypoxic exercise was significantly smaller than that at peak ventilation in the resting hypoxic period (2.3 +/- 0.7 vs. 3.9 +/- 1.0), although the ventilation was greater during exercise (24.0 +/- 3.0 vs. 19.7 +/- 1.4 l/min). These results indicate that sustained hypoxia has a biphasic, i.e., initial stimulatory and delayed depressant, effect on dyspnea and on ventilation. It is suggested that the dyspnea sensing mechanism is suppressed during mild exercise under sustained hypoxia.

We examined the effects of nasal continuous positive airway pressure (CPAP) on exercise performance in patients with obstructive sleep apnea (OSA). Six patients were treated with nasal CPAP on seven successive days and underwent overnight sleep studies and multiple sleep latency test (MSLT) at the beginning and after the last day of the treatment. The subjects also performed incremental exercise testing using a bicycle ergometer followed by 0-w, 25-w, 50-w,--(3 minutes each) until maximum level. Arterial oxygen pressure, arterial carbon dioxide pressure at rest while awake, apnea/ hypopnea index, longest apnea duration, the lowest percutaneous oxygen saturation measured by a pulse oximeter and the value of MSLT were significantly improved after nasal CPAP. Moreover, maximal oxygen consumption was significantly increased from 1841 ml/min +/- 350 to 2125 ml/min +/- 351 (p < 0.05); however, other cardiorespiratory parameters did not change significantly. The improvement of exercise performance by short-term nasal CPAP treatment in OSA patients may correlate with the improvement of sleepiness.

1. The parabrachial nucleus (PBN) is thought to play an important role in cardiorespiratory control. However, the circumstances under which it affects ventilation are still not known. The purpose of the present study was to investigate how the PBN modulates the ventilatory responses to hypercapnia, hypoxia or a resistive load in awake rats with chemical lesions of the PBN. 2. In three groups of rats (with lateral PBN lesion, with Kolliker-Fuse nucleus lesion and control), ventilation was measured under various conditions. 3. There was no difference in the breathing of normal room air in any of the groups. However, the lesioned groups showed a reduced ventilatory response to hyperoxic hypercapnia (inspired CO2 fractions (FI,CO2) of 3, 5, 8 and 10%) and to graded hypoxia (inspired O2 fractions (FI,O2) of 16, 12, 10 and 8%) compared with the control group. The control group showed a biphasic response to sustained hypoxia (FI,O2 at 10% for 30 min), known as 'hypoxic depression', while the lesioned groups showed moderate ventilatory exaggeration throughout hypoxia. In response to a resistive load, the lateral PBN lesion group showed no change in ventilatory compensation. 4. The PBN appeared to have a considerable influence on ventilation stimulated in various ways during wakefulness.

1. We examined the role of nitric oxide (NO) in respiratory regulation in the nucleus tractus solitarii (NTS), where L-glutamate release associated with peripheral chemoreceptor activation modulates the hypoxic ventilatory response. 2. Experiments were performed in unanaesthetized freely moving rats. First, the effects on the hypoxic ventilatory response of sodium nitroprusside (SNP, a NO donor) or NG-monomethyl-L-arginine (L-NMMA, a NO synthase inhibitor), microinjected into the NTS, were investigated. Second, using in vivo microdialysis, changes in extracellular L-glutamate during hypoxia were examined in the presence of L-NMMA. Third, the effect of L-NMMA on ventilatory augmentation by exogenous L-glutamate was examined. Furthermore, we measured extracellular L-citrulline concentration changes during hypoxia in the NTS to assess NO formation indirectly and also examined the effect of MK-801 (an NMDA receptor antagonist) on L-citrulline levels during hypoxia. 3. SNP increased ventilation during both normoxia and hypoxia. L-NMMA did not alter ventilation or L-glutamate levels during normoxia but significantly attenuated the hypoxic ventilatory response and the increase in L-glutamate during hypoxia. The inhibition by L-NMMA was blocked by L-arginine. The ventilatory augmentation by exogenous L-glutamate was attenuated by L-NMMA. L-Citrulline increased during hypoxia, and this increase was inhibited by MK-801. 4. We provide the first in vivo evidence that, in the NTS, NO works as a retrograde messenger in an L-glutamate-releasing positive feedback system contributing to the augmentation of ventilation during hypoxia.

BACKGROUND--It has previously been reported that short term submental stimulation can reduce the frequency of apnoea and improve sleep architecture in patients with obstructive sleep apnoea. The effects of submental stimulation during consecutive nights on apnoea or on daytime sleepiness have not, however, been studied. METHODS--Patients with obstructive sleep apnoea were studied by polysomnography on a control night, for five consecutive nights of submental stimulation, and on three following nights (n = 8). A multiple sleep latency test (MSLT) (n = 8) and measurement of the upper airway resistance (n = 5) were performed during the day after the polysomnographic study, on the control night, and on the fifth stimulation night. In an additional five patients with obstructive sleep apnoea, matched for age, sex, and weight, the effects of two nights of stimulation were examined for comparison. Submental stimulation began when an apnoea lasted for five seconds and stopped with the resumption of breathing as detected by oronasal flow. RESULTS--The apnoea index, the number of times per hour that SaO2 dropped below 85% (SaO2 < 85%/hour), and the total apnoea duration expressed as a percentage of total sleep time during stimulation nights decreased to approximately 50% of the corresponding values on the control night. This improvement persisted for at least two nights after the five consecutive stimulation nights, but not after the two consecutive stimulation nights. Sleep architecture and MSLT following the stimulation nights improved but upper airway resistance did not change. CONCLUSIONS--Submental stimulation for five consecutive nights in patients with obstructive sleep apnoea improved the breathing disturbance, sleep quality, and daytime sleepiness. The effect lasted for the following two nights, but did not completely abolish the sleep disordered breathing.

Background The impulse oscillometry is increasingly used for assessing the oscillatory mechanics of the respiratory system. The within-breath behaviour of the oscillatory mechanics in chronic obstructive pulmonary disease (COPD) is a well-known physiological feature. The purpose of this study was to develop a new approach for assessing this feature using impulse oscillometry. Methods The oscillatory mechanics were assessed by a commercially available impulse oscillometry device. The respiratory system resistance (Rrs) and reactance (Xrs) were measured during tidal breathing in patients with COPD (n=39) and healthy subjects (n=5). Selected data, the Rrs at 5 Hz (R5), Rrs at 20 Hz (R20), Xrs at 5 Hz (X5), and resonant frequency of Xrs (Fres) every 0.2 s, were extracted from the device. These data were divided into eight time fractions during the respiratory cycle to form averaged respiratory phases. Results The time courses of the R5 and X5 were notably dependent on the respiratory cycles in patients with COPD, while there was little such dependency in healthy subjects. Irrespective of respiratory phase, R5 and Fres increased, and X5 fell to a more negative level in patients with COPD in a severity-dependent fashion. The increase in the R5 and negative level in the X5 were more prominent in the middle of the expiratory phase. The severity dependence in the R20 was relatively small compared with that in the R5. Conclusions The results of this study suggest that impulse oscillometry can assess the within-breath behaviour of the oscillatory mechanics with high temporal resolution, which may be helpful for evaluating the severity of COPD. Further studies are needed to reveal which biomarkers obtained with this approach would be suitable for evaluating the airway obstruction., Article summary Article focus To develop a new approach for assessing the within-breath behaviour of the oscillatory mechanics in patients with chronic obstructive pulmonary disease (COPD) using impulse oscillometry. Key messages Impulse oscillometry provides a means of evaluating within-breath behaviour of oscillatory mechanics at high temporal resolution. Since it is possible that the oscillatory flow resistance varies markedly within a breathing cycle in patients with COPD, differences between the inspiratory and expiratory phases must be taken into account. Strengths and limitations of this study The within-breath behaviour of the oscillatory mechanics can be assessed by a commercially available impulse oscillometry device. Owing to the small number of subjects, the findings related to the pathophysiology of COPD were very limited.

IZUMIYAMA, T., HIDA, W., ICHINOSE, M., INOUE, H., TAKISHIMA, T., OKAZAKI, T. and SHIRATO, K. Small Airway Involvement in Mixed Connective Tissue Disease. Tohoku J. Exp. Med., 1993, 170 (4), 273-283-We studied pulmonary functions in 17 female patients with mixed connective tissue disease (MCTD) to detect early pulmonary involvement in this disease; in 8 of the 17 patients follow-up studies were also performed at 1.2- to 5.9-year intervals. In the first pulmonary function tests, decreases in vital capacity (VC) and diffusing capacity (DLCO) were observed in 6 (35%) and 8 (47%) patients, respectively. The ratio of forced expiratory volume in one second to VC was normal in all the patients, but pulmonary resistance and static compliance were abnormal in 6 (35%) and 10 (59%) patients, respectively. However, frequency dependence of dynamic compliance was found in all 16 patients tested. Moreover, 4 (24%) of the 17 patients had normal DLCO and DLCO-to-alveolar volume ratio (DLCO/VA). Reductions in DLCO and DLCO/VA were significantly correlated with the disease duration. These results suggest that small airway obstruction is an early and frequent indication of functional pulmonary impairment, and that impairment of alveolar gas exchange is progressive in patients with MCTD.

BACKGROUND--It is well known that upper airway resistance increases with postural change from a sitting to supine position in patients with obstructive sleep apnoea (OSA). It is not known, however, how the postural change affects the ventilatory and occlusion pressure response to hypercapnia in patients with OSA when awake. METHODS--The responses of minute ventilation (VE) and mouth pressure 0.1 seconds after the onset of occluded inspiration (P0.1) to progressive hypercapnia (delta VE/delta PCO2, delta P0.1/delta PCO2) both in sitting and supine positions were measured in 20 patients with OSA. The ratio of the two (delta VE/delta P0.1) was obtained as an index of breathing efficiency. The postural changes in response to carbon dioxide (CO2) after uvulopalatopharyngoplasty (UPPP) were also compared in seven patients with OSA. RESULTS--There were no significant changes in the resting values of end tidal PCO2, P0.1, or VE between the two positions. During CO2 rebreathing, delta VE/delta PCO2 did not differ between the two positions, but delta P0.1/delta PCO2 was significantly higher in the supine than in the sitting position (supine, mean 0.67 (SE 0.09) cm H2O/mm Hg; sitting, mean 0.57 (SE 0.08) cm H2O/mm Hg), and delta VE/delta P0.1 decreased significantly from the sitting to the supine position (sitting, 4.6 (0.4) l/min/cm H2O; supine, 3.9 (0.4) l/min/cm H2O). In seven patients with OSA who underwent UPPP, delta VE/delta P0.1 improved significantly in the supine position and postural change in delta VE/delta P0.1 was eliminated. CONCLUSIONS--These results suggest that in patients with OSA the inspiratory drive in the supine position increases to maintain the same level of ventilation as in the sitting position, and that the postural change from sitting to supine reduces breathing efficiency. Load compensation mechanisms of patients with OSA appear to be intact while awake in response to the rise in upper airway resistance.

BACKGROUND: A high ratio of forced expiratory to forced inspiratory maximal flow at 50% of vital capacity (FEF50/FIF50) may identify upper airway dysfunction. Since hypercapnia increases the motor activity of airway dilating muscles its effects on the maximum expiratory and inspiratory flow-volume curves (MEIFV) in patients with obstructive sleep apnoea and in normal subjects in different postures was studied. METHODS: The effects of posture on the maximum expiratory and inspiratory flow-volume curves during the breathing of air and 7% carbon dioxide in 11 patients with obstructive sleep apnoea were compared with those in nine normal subjects. Measurements were made in the sitting, supine, and right lateral recumbent positions. Forced expiratory flow at 50% vital capacity (FEF50), forced inspiratory flow at 50% vital capacity (FIF50) and FEF50/FIF50 were determined. RESULTS: In the normal subjects FEF50, FIF50, and FEF50/FIF50 were not affected by change in posture or by breathing carbon dioxide. In the patients there was a fall in FIF50 and an increase in FEF50/FIF50 when breathing air in the supine position compared with values in the seated and lateral position. While they were breathing carbon dioxide there was a slight increase in FEF50 when patients were seated or in the lateral position compared with values during air breathing. Hypercapnia abolished the effects of posture on FEF50/FIF50. Values for FEF50/FIF50 in the supine position while they were breathing air correlated with the apnoeic index but not with other polysomnographic data. CONCLUSION: In patients with obstructive sleep apnoea the upper airway is prone to collapse during inspiration when the patient is supine, even when awake; this tendency can be reversed by breathing carbon dioxide.

We assessed the effects of negative intrathoracic pressure induced by inspiratory elastic loading on pulmonary, gas exchange with and without electrically induced hindlimb exercise in 8 normal, anesthetized dogs. Two elastic loads (EL) were used; one of 81 and one of 140 cmH2O/liter. These are equivalent to doubling and tripling the normal elastance of the dog's respiratory system, respectively. Elastic loading decreased ventilation and caused hypoxemia and hypercapnia, but it did not affect systemic arterial pressure or heart rate. During exercise, increase in ventilation was limited, whereas increase in cardiac output was not affected by elastic loading. Alveolar-arterial O2 tension difference (A-aDO2) was not changed significantly by exercise alone. However, elastic loading accompanied by exercise increased A-aDO2. Although comparable end-inspiratory pleural pressure was achieved with large EL (-29 +/- 2 cmH2O, mean +/- SE) and small EL with exercise (-30 +/- 2 cmH2O), the latter increased A-aDO2 whereas the former did not. Large negative intrapleural pressure combined with increased cardiac output may have caused transient interstitial edema.

In order to elucidate the mechanism of the bronchial response of monkeys to constrictive stimuli, the effects of pretreatment with aerosolized lidocaine, atropine, and isoproterenol were studied. Treatment with aerosolized lidocaine and atropine not only extinguished the cough reflex, but also decreased bronchial susceptibility to aerosolized methacholine. Moreover, the pretreatment with lidocaine blocked the histamine challenge, but atropine did not. The aerosolized lidocaine decreased the bronchoconstriction induced with methacholine, but not with histamine. Pretreatment with over 1% of isoproterenol did not extinguish the cough reflex. However, this dose of isoproterenol did suppress an increase in Rrs due to the challenge of both methacholine and histamine. Isoproterenol also decreased the bronchoconstriction due to the previous challenge by both methacholine and histamine. The antagonistic effects of lidocaine, atropine, and isoproterenol on the broncho-constriction of monkeys are discussed in relation to the subepithelial receptor.

For diagnosis of sleep apnea syndrome (SAS), there are three important steps wihch we have to consider. As the first step, we have to derive the following clinical symptoms from repeated questioning of patients and their families, for example, snoring, morning headache, daytime sleepiness, general fatigue, dyspnea, abnormal behavior during sleep or nocturnal enuresis, etc. Furthermore, we have to consider background diseases and complications. As the second step, it is necessary to take a screening test for patients, who are thought to have breathing disorders of sleep. We have developed a home sleep monitoring system which is very useful for a screening test. Home sleep monitor is consisted of two thermisters for mouth and nasal flow, a microphone for tracheal sound, three electrodes for electrocardiogram, amplifiers and microcomputer. The weight of this device is 280g. This device is equipped just before patient goes to bed, and brought back to hospital on the following day. Data such as trend display of apnea episodes, histogram of apnea episodes or trend display of heart rate are analyzed by a personal computer. As the third step, patient who is suspected of SAS by a screening test needs polysomnography to get correct diagnosis for SAS after admission to hospital. By polysomnography, we can obtain the informations of sleep stage, apnea type, degree of desaturation or hemodynamics during sleep.

We studied bronchial responsiveness to methacholine in 10 normal subjects, in 60 patients with bronchial asthma and in 30 patients with bronchitis using a new device, with which we were able to obtain the dose-response curve of respiratory resistance (Rrs) continuously and graphically by the 3 Hz oscillation method during inhalation of methacholine. All normal subjects were non-responders, while all of the bronchial asthma cases, 63% of the chronic bronchitis cases and 50% of the acute bronchitis cases were responders. Among responders we found a very poor correlation between the initial respiratory conductance (Grs.cont) and the bronchial sensitivity (defined as the reverse of the cumulative dose until Rrs starts to increase); yet we found a good correlation between Grs.cont and the bronchial reactivity (defined as the slope of the decreasing rate of Grs). Metaproterenol and atropine decreased the bronchial sensitivity and reactivity in 28 asthmatic patients. We concluded that for clinical purposes the new method was very useful for assessing bronchial responsiveness to inhalation challenge because of its simplicity of operation as well as the quantitative differentiation between bronchial sensitivity and reactivity. Our results suggest that the bronchial response system to methacholine is explainable by a model of multiple dose-response curves without any parallel shift.

In 8 healthy subjects (group A) and 4 subjects with respiratory symptoms (group B), the lung pressure-volume curve (P-V curve), maximum expiratory flow-volume curve (MEFVC) and respiratory resistance (Rrs) at all vital capacities were measured. To avoid laryngeal artifact on a mouth pressure, an intratracheal catheter was used for measurement of Rrs which was obtained with 3 cycles/sec oscillatory forced pressure. Group B did not show a different elastic recoil from group A. In comparison of the maximum expiratory flow (Vmax) at 80, 70, 60 and 50% of the total lung capacity (TLC). Vmax of group B showed lower values than that of group A. Rrs was almost the same in both groups from 70% TLC upwards, but Rrs of group B was higher than that of group A from 65%TLC downwards. Since the lung elastic recoil pressures (Pst (1)) in the two groups were not different and Rrs's were different significantly only at low lung volumes, the decrease in Vmax of group B was supposed to be due to the increased Rrs which might reflect small airway obstruction.

MIKI, H., HIDA, W., SHINDOH, C., TAGUCHI, O., INOUE, H. and TAKISHIMA, T. Effect of Electrical Stimulation of Genioglossus Muscle on Upper Airway Resistance in Anesthetized Dogs. Tohoku J. exp. Med., 1987, 153 (4), 397-398 - The isolated upper airway pressure and flow changes during electrical stimulation of the genioglossus muscle in spontaneously breathing anesthetized dogs were measured at given pressures in the inspiratory direction. Upper airway resistance was maximal during no stimulation and decreased rapidly with stimulation at frequencies up to about 40Hz.

In order to examine the effect of sleep position on sleep apnea episodes, seven male patients diagnosed as having obstructive sleep apnea syndrome without any organic complication of the upper airway were studied while lying in a supine or lateral position during an all-night polysomnographic study. Apnea index, apnea time/total sleep time (%) and the number of episodes per hour in which oxyhemoglobin saturation dropped below 85% decreased significantly from 51.0 +/- 8.6 (mean +/- S.D.) events/hr, 40.4 +/- 5.8% and 36.2 +/- 9.8 episodes/hr during sleep in supine position to 27.6 +/- 9.1 events/hr, 19.4 +/- 6.0% and 12.9 +/- 5.3 episodes/hr during sleep in lateral position, respectively. Lowest oxyhemoglobin saturation increased significantly from 70.7 +/- 2.6% to 78.0 +/- 2.4%. Thus, sleep in the lateral position may be a simple treatment before essential treatment for patients with obstructive sleep apnea syndrome.

The effect of the inspiratory flow rate during deep inspiration on the regulation of bronchomotor tone was studied in nine normal and 22 asthmatic subjects. Changes in bronchial tone were assessed by respiratory resistance measured by an oscillation method. In normal subjects with bronchoconstriction induced by methacholine a rapid deep inspiration reduced respiratory resistance more than a slow deep inspiration. Asthmatic subjects with spontaneous airway narrowing showed an increase in respiratory resistance after deep inspiration that was greater after rapid than after slow deep inspiration. On the other hand, in asthmatics with methacholine induced bronchoconstriction, bronchodilatation occurred after deep inspiration and this was also greater after rapid than after slow deep inspiration. Lignocaine inhalation attenuated both bronchoconstriction and bronchodilatation induced by both slow and rapid deep inspiration. These results suggest that the effects of deep inspiration are mediated at least in part via receptors in the airways. It is suggested that in asthmatic patients with spontaneous bronchoconstriction irritant receptor activity will be increased in proportion to the speed of inspiration. After methacholine induced bronchoconstriction stretch receptor activity is likely to behave in a similar fashion, leading to an opposite effect.