巽 浩一郎

Arterial oxygenation during sleep in Sherpa highlanders has been relatively unexplored. This study was designed to investigate arterial oxygen saturation (Sa(O(2))) and pulse rate (PR) during sleep in 61 Sherpa (29 men, 32 women) who had lived at 3,450-3,850 m in Nepal, from adolescence through old age, and to estimate the relative effects of aging on arterial oxygenation during sleep. The mean Sa(O(2)) during sleep (mSa(O(2))) was found to decrease with age, and to negatively correlate with the mean PR during sleep. About one-third of subjects (n=19) exhibited a periodical fluctuation of Sa(O(2)) during sleep. The subjects who exhibited a periodical fluctuation of Sa(O(2)) during sleep were older and their mSa(O(2)) were lower compared with those who did not exhibit a periodical fluctuation of Sa(O(2)), and the cycle of periodical fluctuation got longer with advancing years. These findings indicated that sleep desaturation occurs in high altitude residents with advancing years.

Fas ligand (FasL)-expressing tumor cells are found to effectively mediate rejection of the coinoculated FasL negative parental cells while having no effect on the growth of histologically distinct tumor cells. These observations indicate that FasL induces a specific immune response against Ag derived from FasL-bearing tumors and suggest a possible role for FasL in tumor Ag presentation. Indeed, tumor cells expressing FasL can efficiently interact with dendritic cells (DCs) and this interaction requires the expression of membrane-bound FasL on tumors and Fas on DCs. Moreover, DCs cocultured with FasL-expressing tumors are able to elicit a tumor-specific immune response in vivo, suggesting that DCs acquire tumor Ag during the Fas/FasL-mediated DC-tumor contact. These results identify a novel role for FasL in augmenting tumor-DC interactions and subsequent tumor Ag acquisition by DCs, and suggest that FasL-expressing tumor cells could be used to generate tumor-specific DC vaccines.

Endobronchial ultrasonography (US) with 4.5-F small-caliber US probes, combined with bronchoalveolar lavage technique, was evaluated in autopsied lungs and 22 patients with various pulmonary interstitial or alveolar diseases. Several different echoic patterns were found that may reflect changes due to pathologic alteration of lung parenchyma. This technique may have potential for evaluation and diagnosis of peripheral lung diseases.

A case of lung adenocarcinoma and extensive deep vein thrombosis in a patient with Peutz-Jeghers syndrome (PJS) is presented. A 31-year-old Chinese man complained of shoulder pain and swelling of the right arm. A series of diagnostic procedures revealed a primary adenocarcinoma in the left upper lobe with cervical and supraclavicular lymph node metastases accompanied by deep vein thrombosis in the superior vena cava and right jugular vein. In addition, typical pigmentation of the lips and oral mucosa and multiple hamartomas in the stomach, duodenum and colon led to the diagnosis of PJS. PJS is known to be associated with increased risk of malignancies, especially in the gastrointestinal tract, breast, genitals and pancreas. As bronchoscopic examination showed no hamartomatous lesions in the bronchi, the development of primary lung cancer in this young patient might be independent of any hamartomatous lesion and might be associated with some genetic factors relating to PJS.

A novel gene transcript that is downregulated by HPV16 E6 protein was identified in mouse cells using differential hybridization and designated E6DG1. The cloned cDNA of E6DG1 was 1.3 kb in length and contained a small ORF potentially encoding a polypeptide of 45 amino acids. In vitro transcription and translation of E6DG1 cDNA resulted in a product of approximately 7 kDa and Western blot analysis using antibodies for E6DG1 peptide detected 7 and 14 kDa proteins. Downregulation of E6DG1 mRNA levels in cells expressing HPV16 E6 protein was observed at subconfluent cell densities, but not in confluent cells. Repression of E6DG1 protein enhanced the anchorage-independent growth and weakened the cell adhesion in Panc1 cells. Immunofluorescence analysis revealed the localization of E6DG1 within the nucleus. These results indicate that the E6DG1 protein may function in a signaling pathway related to anchorage-independent growth and adhesion control.

STUDY OBJECTIVES: Alveolar septal cell apoptosis may contribute to the pathogenesis of emphysema. Because tumor necrosis factor (TNF)-alpha is assumed to play an important role in the induction of apoptosis, and allele 2 of the polymorphism at position--308 in the promoter of the TNF-alpha gene has been associated with alteration of TNF-alpha secretion in vitro, we hypothesized that genotypes containing this allele would show more destructive emphysematous changes of the lung. DESIGN: The percentage ratio of the low attenuation area to the corresponding lung area was evaluated using a visual scoring system for CT findings in patients with COPD (n = 84), and these patients were classified into two groups: those with a visual score < 11 and those with a visual score > or = 11. A polymerase chain reaction-based assay was developed to determine the TNF-alpha genotype (TNF-alpha-308*1/2) between subjects with high and low visual scores on chest CT scans. RESULTS: The TNF-alpha-308*1/2 allele frequency tended to differ between patients with a visual score < 11 (0.90/0.10) and those with a visual score > or = 11 (0.81/0.19) [odds ratio, 2.15; 95% confidence interval, 0.87 to 5.30; p = 0.09]. CONCLUSION: These results indicate that the TNF-alpha-308 allele 2 may be partly associated with the extent of emphysematous changes in patients with COPD.

Chronic hypoxemia has been suggested as the cause of weight loss in malnourished patients with chronic obstructive pulmonary disease. Insulin-like growth factor I (IGF-I) is believed to improve nitrogen balance and have anabolic effects, and it has been proposed as one of the mediators of vascular smooth muscle proliferation. The aim of this study was to assess the effects of IGF-I administration on the nutritional status and pulmonary vasculature in normoxic and chronic hypoxic rats. Twenty rats were randomly assigned to the normoxic (n = 10) and chronic hypoxic groups (n = 10). They received daily subcutaneous injections of either 3.2 mg/kg of recombinant human IGF-I (rhIGF-I) or isotonic saline (control group) for 3 weeks. Body weight was greater in IGF-I-treated rats compared with vehicle-treated rats, especially during the early and late stages of chronic hypoxic exposure, whereas similar weight gain was observed between IGF-I- and vehicle-treated normoxic rats. In addition, IGF-I treatment increased serum total protein and albumin at the end of hypoxic exposure. However, IGF-I had no additive effects on the degree of pulmonary hypertension. These results indicated that IGF-I promoted anabolism under chronic exposure to hypoxia, whereas no adverse effect was observed in the development of pulmonary hypertension.

Ku70 protein, cooperating with Ku80 and DNA-dependent protein kinase (DNA-PK) catalytic subunit (DNA-PKcs), is involved in DNA double-strand break (DNA DSB) repair and V(D)J recombination. Recent studies have revealed increased ionizing radiosensitivity in Ku70-deficient cells. The presented study, using a human squamous cell lung carcinoma cell line, demonstrated that introduction of an antisense Ku70 nucleic acid made the cells more radio- and chemosensitive than the parental cells. Ku70 protein expression was suppressed in the cells with antisense Ku70 construct when compared to the wild-type cells. A relatively small but statistically significant increase in radiosensitivity of the cells was achieved by the introduction of the antisense Ku70. The increased radiosensitivity in vitro was accompanied by an approximately two-fold increase in alpha and alpha/beta values in a linear-quadratic model. The antisense Ku70 increased the chemosensitivity of the cells to some DNA-damaging agents such as bleomycin and methyl methanesulfonate, but not to cisplatin, mitomycin C, and paclitaxel. This system provides us with partial suppression of Ku70, and will be a useful experimental model for investigating the physiological roles of the DNA DSB repair gene.

Interaction between Fas and Fas ligand (FasL) induces apoptotic cell death of Fas-positive cells. Expression of FasL on tumors therefore possibly kills activated Fas-positive cytotoxic T cells that infiltrated into the tumors and consequently the tumors can evade from systemic immune responses. Previous studies however showed that forced expression of FasL in tumors induced neutrophil-mediated inflammatory reactions and accordingly produced T cell independent antitumor effects in the inoculated animals. We then analyzed the FasL-mediated antitumor responses with genetically mutated mice. Murine lung carcinoma (A11) cells transfected with the FasL gene (A11/FasL), which was able to kill Fas-positive B cells, did not form subcutaneous tumors and produced few lung spontaneous metastatic foci in immunocompetent mice. The mice that rejected A11/FasL cells developed tumor-specific protective immunity. A11/FasL cells were also rejected in T cell-defective nude mice and in CD18-deficient mice which showed impaired neutrophil functions, but not in Fas-defective (lpr/lpr) mutant mice. Antitumor activities on A11 cells were dependent on the number of co-injected A11/FasL cells but those on irrelevant B16 murine melanoma cells were not produced even with a large number of co-injected A11/FasL cells. In contrast to previous reports, the present study implies that T cells can also be effectors of FasL-mediated antitumor responses and neutrophils are not absolutely required for the responses.

We used a denaturing gradient gel electrophoresis (DGGE) procedure with 40-nucleotide guanine- and cytosine-rich sequences in the polymerase chain reaction (PCR) and sequencing analysis to analyze the T cell antigen receptor (TCR)-Vgamma gene repertoire of infiltrating T lymphocytes in pulmonary lymphoproliferative disorders. Six of 15 low-grade mucosa-associated lymphoid tissue (MALT) lymphomas and 8 of 15 cases of lymphocytic interstitial pneumonia (LIP) showed some oligoclonal bands for TCR-Vgamma genes on DGGE. Sequencing analysis demonstrated plural oligoclonal TCR-Vgamma clones among the oligoclonal PCR products on DGGE, leading to the conclusion that conventional antigen-specific oligoclonal expansions may play some role in the pathogenesis of pulmonary lymphoproliferative disorders. The frequency of oligoclonal infiltrating T cell expansions in human immunodeficiency virus (HIV)-related LIP (100%) was significantly higher than in low-grade pulmonary MALT lymphomas (40%) or in HIV-negative LIP (30%). Because recent evidence demonstrates that the V3 loop in the proviral amino acid sequences of mononuclear cells from bronchoalveolar lavage is more homogeneous than those from peripheral blood, this homogeneity might result in oligoclonal expansions of infiltrating T lymphocytes as a consequence of ongoing reactions against lung-specific viral strains.

The Medical Research Council (MRC) and Nocturnal Oxygen Therapy Trial (NOTT) studies performed in the late 1970s regarding effects of long-term oxygen therapy (LTOT) have revealed that LTOT improved the prognosis in patients with hypoxemic COPD and established the basis of prescription of LTOT. However, whether LTOT improved HRQoL as a secondary end point has not been clarified. Therefore we prospectively examined the effects of LTOT on HRQoL, evaluated by SF-36 and SGQR, in 43 patients with chronic lung diseases who were prescribed LTOT. HRQoL was assessed before LTOT and short- and long-term after prescription of LTOT. In this study it was demonstrated that LTOT ameliorated some physical and mental functions in patients with chronic lung diseases.

Interaction of Fas and Fas ligand (FasL) in immunocompetent cells plays a crucial role(s) in their effector functions and in the regulation of host immune responses. Expression of FasL in tumors possibly counteracts Fas-positive effector T cells that infiltrate into tumors and consequently the Fas/FasL interaction can contribute to the escape of tumor cells from systemic immune systems. However, forced expression of FasL in tumors unexpectedly induced migration of neutrophils into the tumors and the FasL-expressing tumors were rejected due to the inflammatory reaction. Since FasL is released from the cell surface, we examined whether soluble or membranebound FdsL molecules produced such antitumor effects. Faspositive B cells were effectively killed by membrane-bound but not soluble FasL in which the leader sequence of interleukin-4 was ligated with the extracytoplasmic portion of FasL. Mice inoculated with All murine lung cancer cells expressing membrane-bound FasL did not develop tumors and had few spontaneous lung metastatic foci. In contrast, mice injected with A11 cells secreting soluble FasL developed tumors the growth of the tumors and the number of lung metastatic foci from subcutaneous tumors were not different from those of parent tumors. The chemotactic activity of FasL, tested by intraperitoneal injection of parent and the FasL-expressing A11 cells, showed that the level of neutrophil migration by All cells secreting soluble FasL was greater than that by parent cells but was not as significant as that by All cells expressing membranebound FasL. The antitumor activity induced by expressed FasL seems to be correlated with the apoptosis-inducing activity through the Fas/FasL interaction but not directly with the chemotactic activity for neutrophils.

慢性閉塞性肺疾患(COPD)の初期には自覚症状は認めないため,その正確な疫学は不明であるが,非可逆釣な疾患であることより,今後の一つの方向性として,早期のCOPD・発症リスクのある症例の把握が必要になる.予後に影響を及ぼす因子としては,血液ガスの値,小児期・青年期の呼吸機能の発達の程度,喫煙状況,呼吸困難の程度,栄養状態,気道閉塞の可逆性,組織低酸素の程度,肺循環障害の程度などが挙げられる.さらには,発症年齢,性差,治療の影響(吸入ステロイド・非侵襲的人工呼吸)なども考えられる.

Tumor necrosis factor α (TNF-α), a potent proinflammatory cytokine, may be involved in the development of chronic obstructive pulmonary disease (COPD). The production of TNF-α is elevated in the airways of these patients. A polymorphism at position -308 of the TNF-α gene promoter (TNF-α-308*1/2) is known to be associated with alteration of TNF-α secretion in vitro. In this study we examined the differences in TNF-α-308*1/2 allele frequency to investigate the association of this polymorphism with the presence of smoking-related COPD. TNF-α-308*1/2 allele frequency in 106 patients (73 men and 33 women) was compared with 110 asymptomatic smoker/ex-smoker control subjects matched for sex and age and population control subjects consisting of 129 blood donors. Genotype was analyzed by the polymerase chain reaction-restriction fragment length polymorphism technique on genomic DNA isolated from peripheral blood lymphocytes. TNF-α-308*1/2 allele frequencies were significantly different among the groups: 0.835/0.165 in patients with COPD, 0.918/0.082 in smoker/ex-smoker control subjects, and 0.922/0.078 in population control subjects. These results indicate that TNF-α-308*1/2 alleles are significantly associated with the presence of smoking-related COPD.

Inhaled PGI2 has been reported to elicit pulmonary vasodilation, but whether it is also effective in treating chronic hypoxic pulmonary hypertension is still uncertain. We designed this study to address the in vivo effectiveness of inhaled Beraprost, a stable PGI2 analogue, on pulmonary vascular tone during hypoxic exposure in normoxic (N) and chronically hypoxic (CH) rats. Pulmonary vasodilation was observed by low-dose inhaled Beraprost in N rats, but not in CH rats. It was not until higher doses of Beraprost were given that pulmonary vasodilation was obtained in CH rats. When the agent was continuously administered by an intravascular route at the inhaled dose, it elicited no vasodilation in N rats. On the contrary, it elicited profound vasodilation in CH rats, although a concomitant systemic hypotension was observed. The PGI2 receptor mRNA expression was unchanged in the lungs of CH rats compared with that of N rats. We conclude that low doses of aerosolized Beraprost may reduce pulmonary vascular tone in rats without preexisting lung diseases. In contrast, when hypoxic pulmonary hypertension is present, the threshold of Beraprost inhalation was elevated to provoke pulmonary vasodilation.

Objective. To define the clinico-epidemiological features of pulmonary histiocytosis X in Japan. Methods. A nationwide survey was carried out in 1997 using two questionnaires. Results. The first questionnaire, which attempted to determine the number of patients during 1996, revealed that the number of patients treated at hospitals with 200 or more beds during the one-year period was estimated to be 160 (95% confidence interval: 140-180). The estimated crude prevalence among those aged 16 to 70 years was calculated as 0.27 and 0.07 per 100,000 population in males and females, respectively. The second questionnaire was concerned with the clinico-epidemiological features of the disease. Seventy-three histologically diagnosed patients were evaluated. It primarily afflicted younger adults, between the ages of 20 and 50, and showed a male predominance. Over 90% of the patients were smokers or ex-smokers and over 50% started smoking before 20 years of age, suggesting a strong association with cigarette smoking. Steroid therapy was applicable to 34% of the patients. In the patients who received steroid therapy, regression and stabilization were observed in 28% and deterioration in 36%. As for the patients for whom steroids were not required, remission occurred in 63% and progression in 10%. The ratio of remissions plus stabilization was higher in the patients who were not treated with steroids compared with those who required steroid therapy (p&lt 0.05). Conclusion. In patients with pulmonary histiocytosis X therapeutic results obtained with steroids seemed not to be encouraging, although steroids are thought to be the most plausible treatment.

In order to evaluate the applicability of volume acceleration (A1) at the onset of inspiration as an index of neuromuscular output, CO2 rebreathing in six healthy subjects and incremental-load exercise in eight healthy subjects was performed while measuring A1 and mouth occlusion pressure (P0.1). During CO2 rebreathing, A1 increased linearly with end-tidal CO2 partial pressure and P0.1. During incremental-load exercise, P0.1 and A1 increased exponentially with minute ventilation and mean inspiratory flow, and A1 increased linearly with P0.1. Dyspnoea sensation at rest and exercise with or without the circuit system in eight healthy subjects was examined. Dyspnoea sensation increased markedly with the circuit system in some subjects. Incremental-load exercise was carried out by 13 healthy subjects and 21 patients with chronic obstructive pulmonary disease (COPD) to evaluate the difference in A1 as respiratory drive between the two groups in the absence of a respiratory circuit. In patients with COPD, A1 responses to minute ventilation, mean inspiratory flow and carbon dioxide output (VCO2) were greater than those in healthy subjects. In patients with COPD, the A1 response to VCO2 was greater in those with a lower FEV1.0 (forced expiratory volume in 1.0 s), but the ventilatory response to VCO2 was lower in those with a lower FEV1.0. These data suggest that A1 reflects neuromuscular output during CO2 rebreathing and incremental-load exercise under conditions where mechanical properties of the respiratory system are expected to be involved. During exercise, flow increased markedly, and the influence of the resistance of the respiratory circuit also increased. Therefore the use of A1 has the advantage of less resistance (no respiratory circuit) and less additional respiratory effort, in comparison with the use of P0.1, especially in patients with COPD.

Background: The increase in viscosity caused by secondary polycythemia is thought to be one of the major causes of pulmonary hypertension secondary to chronic emphysema. However, very few clinical studies considered the relation between pulmonary hypertension and polycythemia in the case of chronic obstructive pulmonary disease. Objective: The purpose of this study is to elucidate the relative contribution of an increase in hemoglobin level (Hb) to mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR). Methods: We retrospectively investigated 41 patients with chronic emphysema who had undergone a right heart catheterization. Multiple-regression analysis and F test were performed to investigate both direct effects of Hb and PaO2 as independent variables on mPAP and PVR as dependent variables. Results: Significant correlations were found between PaO2 and mPAP (or PVR), or Hb and mPAP (or PVR), indicating that both Hb and PaO2 are contributory to mPAP and PVR. The F test demonstrated that Hb and PaO2 could directly affect the level of either mPAP or PVR. Conclusions: It was concluded that Hb had a direct effect on mPAP and PVR, independently of hypoxia in patients with chronic emphysema. Copyright (C) 2000 S. Karger AG, Basel.

A medullary-spinal cord preparation without the pons isolated from the neonatal rat was used to investigate the role of inhibitory neurotransmitters in the respiratory depression induced by hypoxia (hypoxic respiratory depression HRD). The burst frequency (C4-f) and peak amplitudes of the integrated activity of the C4 roots (∫C4) and of the hypoglossal nerve (∫XII) were recorded. A marked decrease in C4-f (to 36 ± 6% of control, P &lt 0.05) with no change in the peak amplitudes of ∫C4 or ∫XII was observed 17-21 min after superfusion with hypoxic CSF bubbled with 5% CO2 in N2. Antagonists of GABA(A) (bicuculline 10 μM), GABA(B) (phaclofen 0.2-0.5 mM), glycine (strychnine 10 mM), adenosine (aminophylline 100 mM) or opioid (naloxone 1 mM) receptors were added to the bathing solution to block inhibitory synaptic transmission. Among these antagonists, only strychnine and naloxone alleviated HRD reducing the decline in C4-f to 57 ± 11 and 53 ± 6%, respectively (P &lt 0.05). Posthypoxic neural arrest (PHNA) following resumption of oxygenation was shortened by the application of aminophylline, strychnine or naloxone (by 91 ± 17, 96 ± 25 and 40 ± 6 s, respectively, P &lt 0.05). These findings indicate that the reduction in the frequency component of HRD depends on glycinergic and opioid-mediated neuronal inhibition in an in vitro medullary spinal cord preparation. It was also observed that the duration of PHNA was positively correlated with the severity of the fall in C4-f (r = 0.60, P &lt 0.01). (C) 2000 Elsevier Science Ireland Ltd.

呼吸不全は多臓器の細胞機能不全につながりうる.臨床的な呼吸不全の診断は,病歴の聴取と身体所見の把握により呼吸不全を疑い,動脈血液ガス分析を施行することで可能である.しかし,動脈血液酸素分圧60Torr以下というだけでは,呼吸不全の診断としては充分とはいえない.組織(生体)の低酸素症には,酸素運搬に関与する心拍出量・ヘモグロビン値も関与してくるので,診断には混合静脈血酸素分圧の値を考慮することが重要である.

The effect of sleep stage change on pulmonary circulation has not been well documented in patients with obstructive sleep apnea syndrome (OSAS). We investigated whether or not stage-specific change can affect pulmonary artery pressure (Ppa) in patients with OSAS. Thirty-one patients with OSAS underwent right cardiac catheterization in the daytime and the following night, including 19 patients in whom Ppa could be measured throughout non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Ten of the 19 patients had daytime pulmonary hypertension (PH) defined by a mean Ppa (P̄p̄ā) ≥ 20 mm Hg. Then we analyzed Ppa response to hypoxia spontaneously occurring during the period of sleep apnea. The slopes of the regression lines between arterial oxygen saturation measured by pulse oximeter (SpO2) and P̄p̄ā curves were almost the same in both NREM and REM patient groups with or without daytime PH, whereas the response curve was significantly shifted upward in REM compared with NREM patients with daytime PH. Furthermore, Ppa was elevated more markedly in association with REM burst, phasic REM, compared with tonic REM. We conclude that vascular tone of pulmonary artery could be elevated in association with REM sleep which is independent of the degree of hypoxia, and that this state-specific change is manifested in patients with daytime PH.

Uptake of 18F-fluorodeoxyglucose (FDG) and 11C-methionine (Met) in mediastinum and hilar lymph nodes was studied using PET in 31 patients with sarcoidosis. The aim of our study was to examine whether these different tracers play a differential role in clinical assessment of pulmonary involvement. Methods: Fluorine-18-fluorodeoxyglucose and 11C-Met PET were administered on different days. The differential absorption ratio of these tracers was calculated for the region of interest with the highest level of activity. Clinical reassessment of sarcoidosis was made at least 1 yr after the first PET examination. In seven patients whose lymph nodes still remained visible by other imagings at the time of reevaluation, the same PET study was performed again. Results: Both FDG and Met were accumulated in the lymph nodes in all but one patient. The FDG and Met uptake ratios in all patients were not correlated, but they could be divided into the FDG-dominant group (FDG/Met uptake ratio ≤ 2) and the Met-dominant group (FDG/Met uptake ratio &lt 2). Within each group, the FDG and Met uptake values were correlated. The rate of improvement assessed by clinical status and chest radiographs was considerably higher in the FDG- (78%) than in the Met-dominant group (33%). In the seven patients of the repeated PET examination, their FDG/Met uptake ratios were generally unchanged after 1 yr. Conclusion: The results suggest that the FDG/Met uptake ratio using PET may reflect the differential granulomatous status in sarcoidosis and be a useful tool for pretreatment evaluation.

We investigated how signals arising from peripheral chemoreceptors could affect pulmonary vasculature in rats. Effects of the hypoxic exposure (10%) on mean pulmonary arterial pressure (mPAP), abdominal aortic flow (Q) and the estimated total pulmonary vascular resistance (mPAP/Q) were determined in anesthetized, artificially ventilated, carotid sinus nerve intact or chemodenervated rats. The pressor response of PAP to hypoxia seen in intact rats changed to the depressor response after chemodenervation. Hypoxia elicited a decrease in Q and an increase in mPAP/Q in both intact and chemodenervated rats. Selective carotid body stimulation by the intra-carotid injection of sodium cyanide (NaCN) in normoxia elicited an immediate but transient increase in PAP and Q before and after bilateral vagotomy. The peak change in PAP slightly preceded that in Q. These responses to NaCN were completely abolished by chemodenervation. These results indicate that the immediate chemoreflex contributes to the short-term regulation of pulmonary vasculature in rats. Copyright (C) 1998 Elsevier Science B.V.

The pulmonary artery pressure (PAP) response to hypoxia is characterized by an initial vasoconstriction followed by vasodilation. Pulmonary vessels can release endothelium-derived relaxing factor (EDRF), which is considered to be nitric oxide (NO), but the role of EDRF in the regulation of normal and hypoxic pulmonary vascular tone is still uncertain. We designed this study to address the in vivo role of EDRF in vasodilation during sustained hypoxia. We studied the effects of an EDRF-synthesis inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), on the pulmonary vascular response to sustained hypoxia (10% O2, 20 min) in normoxic (N) and chronically hypoxic (CH) rats. Biphasic PAP response was observed in N rats, whereas PAP was unchanged in CH rats during sustained hypoxic exposure. The L-NAME-induced PAP increase during normoxia was greater in CH than in N rats, suggesting that basal EDRF plays an important role in attenuating the severity of pulmonary hypertension in CH rats. Administration of L-NAME increased the initial increment in PAP by acute hypoxia and shifted the PAP response upward throughout sustained hypoxia, while still showing the biphasic pattern, in N rats. In contrast, PAP increased acutely and remained elevated with little recovery in the late phase in CH rats. The inducible NO synthase messenger RNA (mRNA) expression and protein showed greater increases in the lungs of CH than in N rats. These results suggest that EDRF release during sustained hypoxia may partly contribute to the roll-off in PAP response during sustained hypoxia in N rats, and that augmented EDRF may prevent a further increase in PAP during chronic hypoxia.

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 oxy hemoglobin 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.

Effective alveolar ventilation and hypoxic ventilatory response (HVR) are higher in females than in males and after endogenous or exogenous elevation of progesterone and estrogen. The contribution of normal physiological levels of ovarian hormones to resting ventilation and ventilatory control and whether their site(s) of action is central and/or peripheral are unclear. Accordingly, we examined resting ventilation, HVR, and hypercapnic ventilatory responses (HCVR) before and 3 wk after ovariectomy in five female cats. We also compared carotid sinus nerve (CSN) and central nervous system translation responses to hypoxia in 6 ovariectomized and 24 intact female animals. Ovariectomy decreased serum progesterone but did not change resting ventilation, end-tidal PCO2, or HCVR (all P = NS). Ovariectomy reduced the HVR shape parameter A in the awake (38.9 ± 5.5 and 21.2 ± 3.0 before and after ovariectomy, respectively, P &lt 0.05) and anesthetized conditions. The CSN response to hypoxia was lower in ovariectomized than in intact animals (shape parameter A = 22.6 ± 2.5 and 54.3 ± 3.5 in ovariectomized and intact animals, respectively, P &lt 0.05), but central nervous system translation of CSN activity into ventilation was similar in ovariectomized and intact animals. We concluded that ovariectomy decreased ventilatory and CSN responsiveness to hypoxia, suggesting that the presence of physiological levels of ovarian hormones influences hypoxic chemosensitivity by acting primarily at peripheral sites.

Monocrotaline (MCT) is bioactivated in liver cytochrome P-450s to MCT pyrrole (MCTP), which primarily injures the lung endothelium to result in the development of pulmonary hypertension (PH) in rats. However, whether there is a relation between the degree of PH and the activity of liver cytochrome P- 450 to convent MCT to MCTP remains unclear. To examine the relation between these physiological and biochemical changes, we first measured the severity of MCT-induced (20 mg/kg) PH in male, female, castrated male, and phenobarbital (PB, liver P-450s inducer)-pretreated male rats. The degree of right ventricular hypertrophy was more severe in PB-pretreated male than in control male rats. It was also more severe in male than in either female or castrated male rats, suggesting that sex-specific P-450s could be involved in the metabolic pathways of MCT in the liver. Further to explore which of the isozymes (2A2, 2C11, and 3A) of P-450s in the liver is responsible for the bioactivation of MCT, we measured the rate of MCTP production in hepatic microsomes by a modified Mattock's method. Treatment of male rats with PB and pregnenolone 16α-carbonitrile (PCN), which is the specific inducer of P-450 3A, increased the rate of MCTP production, suggesting that P-450 3A may contribute to the conversion to pyrrole. Therefore we measured the amount of P-450 3A protein by immunoblotting and attempted to inhibit MCT metabolism by using antibodies to P-450 3A. P-450 3A was significantly induced by PCN (6.5- fold) and PB (4.6-fold) treatment and reduced by castration (0.38-fold). The amount of P-450 3A was closely correlated with the production of MCTP, and the conversion of MCT to MCTP was strongly inhibited by antibodies against P- 450 3A. These results indicated that P-450 3A was predominantly responsible for the metabolism of MCT to MCTP in rat liver and suggested a tight linkage between the degree of PH and the activity of liver P-450 3A.

Thirty-eight patients with late sequelae of pulmonary tuberculosis (TB seq.) were studied to clarify the characteristics of sleep desaturation in comparison with 40 patients with chronic obstructive pulmonary disease (COPD). While awake, the TB seq. group had a lower % VC and a higher PaCO2. In both groups, the sleep lowest SaO2 was positively correlated with the awake SaO2. The regression line between the sleep lowest SaO2 and the awake baseline SaO2 in the TB seq. group was located below that in the COPD group. Awake PaCO2 was negatively related to the sleep lowest SaO2 only in the TB seq. group. These results indicate that the sleep lowest SaO2 values were lower in TB seq. than in COPD patients with the same levels of SaO2 while awake. Sleep studies are necessary to reveal the indication for nocturnal oxygen therapy in TB seq. patients, especially when they are hypercapnic in spite of their good awake oxygenation.

Previously we showed that prolonged exposure to severe hypoxia produces decreased peripheral chemoreceptor responsiveness to hypoxia and attenuates central nervous system (CNS) chemosensory translation, which together may contribute to the decreased hypoxic ventilatory response (HVR) in chronic hypoxia. In this study, we sought to determine whether the central or peripheral activity of endogenous dopamine modulates this decreased HVR. We examined the effects of peripheral and central dopamine receptor blockade on HVR and carotid sinus nerve (CSN) response to hypoxia in controls and in cats exposed to a simulated altitude of 5500 m for 3 weeks. Domperidone increased CSN response to hypoxia in hypoxic cats to levels similar to those observed in controls. HVR was also augmented by domperidone in hypoxic cats, but remained below that of controls. As a result, the CNS chemosensory translation remained reduced in hypoxic animals. We further treated animals with haloperidol. However, this combined treatment with domperidone and haloperidol led to no further increase in CSN or ventilatory responses to hypoxia, or in CNS chemosensory translation in hypoxic cats. Thus, decreased HVR in hypoxic cats is mediated both by depression of hypoxic sensitivity of the carotid body, which is largely dopaminergic, and by decreased CNS chemosensory translation which must involve non-dopaminergic mechanisms. © 1995.

A 38-year-old woman was referred to our hospital for severe pulmonary hypertension (pulmonary arterial pressure 63/36 mmHg). Digital subtraction angiography showed complete obstruction of the right main pulmonary artery and severe stenosis of the left main pulmonary artery. Although there were no symptoms or signs of systemic arterial lesions, the initial diagnosis was aortitis syndrome with pulmonary arterial involvement, and prednisolone therapy was started (60 mg/day). Pulmonary arterial pressure decreased to 53/12 mmHg. At a dosage of 20 mg/day, however, multiple nodular shadows were present on the X-ray film of the chest, but they disappeared after the dosage was increased. The level of anti-myeloperoxidase antibodies in her serum changed at almost the same time as multiple nodular shadows appeared on the chest X-ray film. Because anti-MPO antibodies have been never detected in patients with aortitis syndrome, polyangitis overlap syndrome was suspected. However, we found no evidence of systemic vasculitis that is, vasculitis in other organs, including the kidney and the skin. Therefore, we made a diagnosis of idiopathic pulmonary arteritis with positive anti-MPO antibodies.

Thirty-eight patients with late sequelae of pulmonary tuberculosis (TB seq.) were studied to clarify whether or not nocturnal oxyhemoglobin desaturation (NOD) could relate to acute exacerbation of chronic respiratory failure (AE). All patients had been untreated with home oxygen therapy, because they were not severely hypoxic. We performed sleep studies, pulmonary function tests and arterial blood gas analysis and investigated past history about AE in each patient. Twelve patients had experienced AE with right heart failure and they were classified as CHF (congestive heart failure) group. The rest was classified as Non-CHF group. These two groups were compared as for each variable examined. There was no difference between the two groups in age, body weight, %VC, FEV(1.0%), and awake Pa(O2). Awake Pa(CO2) was significantly higher in CHF group. Although no difference was observed in baseline Sa(O2), the degree of NOD was significantly greater in CHF group when evaluated by lowest Sa(O2) during sleep and 85% desaturation time (total time spent with Sa(O2) less than 85%). Moreover, 21 of Non-CHF and 6 of CHF were studied for cardiac parameters using right side cardiac catheterization. While the differences of mean pulmonary arterial pressure and cardiac output between the two groups were not significant, pulmonary arteriolar resistance was higher in CHF group. We concluded that NOD in TB seq. had a major role in AE with right heart failure. We speculated that AE might be caused, at least partly, by pulmonary vasopressor response to recurrent NOD.

18歳から59歳までの男性約7,000名を対象とした疫学調査により, いびきの程度と, 年齢, 肥満, いびきの家族歴, 日中の傾眠, 高血圧, 喫煙, アルコール摂取, 交通事故との関連を検討した. 毎晩往復の大いびきをかく人, ないし毎晩大いびきで時に息が止まる人を重度のいびき群とした. 加齢, 肥満, 喫煙, アルコール摂取はすべていびきの増悪因子であることが認められた. また重度のいびき群では, いびきの家族歴があり, 日中の傾眠および高血圧の既往歴, もしくは治療中の人の割合が有意に多かった. 交通事故との関連は認められなかった. アンケートにて重度のいびき群の中で, 40歳以上で肥満を伴い, かつ日中の傾眠および起床時の頭痛があるというすべてに解答した被検者は全体の0.25%であった.

In an open, prospective, multicenter trial the clinical efficacy of imipenem/cilastatin sodium (IPM/CS) for the treatment of 14 cases with aspiration pneumonia was investigated. The mean age was 75.4 years old. Diseases of central nervous system were present in 11 cases, cardiovascular diseases, pulmonary diseases and diabetes mellitus in 2 cases each respectively. Seven cases were community-acquired and another seven were hospital-acquired. Six cases were moderate and 8 cases were severe. Causative organisms were determined in 9 cases (64.3%),multiple causative organisms were isolated in 3 cases. Isolated organisms were Staphylococcus aureus (4),Pseudomonas aeruginosa (3), Klebsiella pneumoniae (3), Escherichia coli (1), Acinetobacter calcoaceticus (1). Detection of anaerobes was not attempted. Clinical effects of IPM/CS were excellent in 3, good in 8, fair in 2, poor in 1, the efficacy rate was thus 78.6%. P. aeruginosa was isolated from 2 out of 3 cases in which therapy with IPM/CS failed. Monotherapy with IPM/CS appears to be highly effective for cases of aspiration pneumonia, but the disease due to IPM-resistant P. aeruginosa is an exception. © 1990, Japan Antibiotics Research Association. All rights reserved.

In an open, prospective, multicenter trial we investigated the clinical efficacy of Imipenem/cilastatin sodium (IPM/CS) for the treatment of pulmonary infection. Out of 129 cases collected, 103 could be evaluated for utility of IPM/CS: 83 with pneumonia (49 moderate and 34 severe cases), 6 with lung abscess, 5 with empyema, 9 with chronic bronchial infection caused by Pseudomonas aeruginosa. In 83 cases of pneumonia, the mean age was 67.6 years old, significant underlying diseases were present in 87.9%, and 21 cases (25.3%) were hospital-acquired. Causative organisms were determined in 36 cases (43.4%), and multiple causative organisms were isolated in 5 cases. The principal pathogens were Streptococcus pneumoniae (8), Staphylococcus aureus (8), P. aeruginosa (8), Haemophilus influenzae (6), Klebsiella pneumonia (6). The efficacy rate of the cases of pneumonia in monotherapy with IPM/CS was 84.6%: moderate 87.2%, severe 80.6%, community-acquired 91.7%, and hospital-acquired 61.1%. Monotherapy with IPM/CS was highly effective in cases of aspiration pneumonia. The efficacy rate in cases in which the causative organism was P. aeruginosa was low (50.0%). The efficacy rate of the cases of lung abscess was 100% and of empyema was 50.0%. Of 9 cases of chronic bronchial infection due to P. aeruginosa, in 5 cases treated with IPM/CS combined with tobramycin and I case treated combined with amikacin, the efficacy rate was 66.6% and the eradication rate 33.3%. We consider monotherapy with IPM/CS to be highly effective in cases of moderate and severe pneumonia, with the exception of disease due to imipenem-resistant P. aeruginosa. © 1990, Japanese Society of Chemotherapy. All rights reserved.