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Medical e-Leamingシステム(YUMESUMA e-net:Yokohama City University,MedicalCenter,Medical e-Learning System founded by Sugiyama and Matsuse,e-net)を導入する機会を得たので,オフライン環境下での試行から本番系システムによる実施にいたる概要を報告し,Medical e-Leamingの意義,問題点,今後の方向性などを検討した.その結果,いわゆるe-LeamingシステムどしてのYUMESUMAは,単に学習のIT化という位置づけにおいてのみ有効性が高いのではなく,情報を迅速に伝える手段として,高い確実性を持ちうることが実証された.従って,毎年,多数の専門職が新規に採用され人事異動の頻繁な大学附属病院において,Medical e-Leamingは,情報の周知,安全管埋徹底に極めて有用なシステムと思われた., A medical e-learning system (YUMESUMA e-net) was introduced at our hospital. Here, the processes from its trial in an off-line environment to its application to a real working system are outlined, and the significance, problems, and direction of future development of medical e-learning are evaluated. YUMESUMA as an e-learning system was found to be effective not only as an information technology to assist medical learning but also as a highly reliable tool for rapid transmission of information. Therefore, at a university hospital, where many experts are newly employed every year and personnel changes are frequent, medical e-learning is considered to be a useful system for transmission of information and safety management.

Glutathione S-transferase P1 (GSTP1) is one of the important xenobiotic-metabolizing enzymes. It was reported that GSTP1 was overexpressed in malignant tissues, and its expression level was associated with resistance to chemotherapeutics. We carried out transfection of GSTP1 sense and antisense vectors to examine effects of GSTP1 on cell cycle arrest and apoptosis induced by camptothecin in HeLa cells. Transfection of GSTP1 antisense vector induced apoptosis. Camptothecin-induced S- or G2/M arrest was intensified by transfection of GSTP1 antisense vector, and subsequent apoptosis was attenuated by transfection of GSTP1 sense vector. These results suggest that GSTP1 has protective effects against camptothecin-induced cytotoxicity.

Objectives and background : Nocturnal apnea and hypoxia are implicated in the pathogenesis of pulmonary and systemic hypertension in obstructive sleep apnea syndrome (OSAS). We have hypothesized that vasodilating factors including nitric oxide (NO) are affected by nocturnal apnea and hypoxia in patients with OSAS. Method : We examined the serum level of NO production in 24 patients with OSAS (mean age 54.2±7.9 years) and 24 age-matched control subjects (53.4±8.1 years) and tested the effects of oxygen administration on the production of NO in the patients. Results : The serum level of nitrite/nitrates (NO x ), which are stable metabolites of NO, was lower in patients with OSAS than in control subjects. Administration of 1–2 l/min of oxygen during night increased the patients' NO x level from 35.6±7.3 to 57.8±11.6 μM. Compressed air administration did not affect the NO x level in the patients. Conclusion : These results indicate that systemic NO production is impaired in OSAS patients, possibly due to nocturnal hypoxia.

Because elderly patients with chronic obstructive pulmonary disease are often overlooked, screening efforts are at the moment directed at higher risk subjects such as heavy smokers with obstructive airways disease. Because only 10–20% of heavy smokers developed symptomatic airflow obstruction, a different genetic susceptibility to cigarette smoke-lung injury is implicated in the pathogenesis of chronic obstructive pulmonary disease. Several candidate gene polymorphisms are proposed as the genetic risk for the development of chronic obstructive pulmonary disease. The current candidates are the polymorphisms in the 3′ non-coding region of the α1-antitypsin gene, α1-antichymotrypsin gene, tumor necrosis factor-α gene, microsomal epoxide hydrolase gene, and glutathione S-transferase P1 gene, and microsatellite polymorphism in the heme oxygenase-1 gene promoter. However, the results are variously reported between Japanese and Caucasians. The association studies of the polymorphisms with chronic obstructive pulmonary disease require further confirmation in different ethnic groups by other researchers using a large population. The current strategy and pitfalls of the gene explorations of chronic obstructive pulmonary disease are discussed.

Objectives : The sensitivity and specificity of overnight monitoring of arterial oxygen saturation (SaO 2 ) using an oximeter were evaluated in elderly subjects who are being investigated for possible sleep apnea syndrome (SAS). Methods : Seventy-five consecutive elderly subjects with habitual snores (47 men, 28 women; mean (±SE) age 75.5±0.9 years (range 65–94 years)) were studied. The SaO 2 was measured with an oximeter and a chart recorder during the night immediately before detailed polysomnographic studies. The SaO 2 recordings were classified by two observers as positive or negative using a number of significant oxyhemoglobin desaturation (SDS) of more than 2, 4, and 6%. The sensitivity of the oximeter alone for the recognition of the SAS was calculated as the number of true positive SaO 2 records divided by the total number of positive definitive (polysomnographic) records. The specificity was defined as the number of true negative SaO 2 records divided by the total number of negative definitive records. Results : Of the 75 subjects, 24 had moderate SAS (apnea index (AI)>15) and 55 had mild to moderate SAS (AI>5). The sensitivity and specificity of the dosimeter as a screening test were determined with the two diagnostic thresholds of the AI. For AI exceeding 5 or 15, the respective sensitivity by using the criterion of SDS of more than 4% was 85.5 or 91.7%, with corresponding specificity of 85.0 or 92.2%. Conclusions : The nocturnal oximeter monitoring allows recognition of elderly subjects with a mild to moderate SAS, and 4% desaturation of SaO 2 is a candidate index to detect a significant number of apneas in elderly SAS patients with an oximeter.

Chronic obstructive pulmonary disease (COPD) and diffuse panbronchiolitis (DPB) are both characterized by chronic airflow limitation. Although the aetiology of these diseases is under investigation, it is commonly hypothesized that neutrophils have a major role in the disease pathogenesis. The variation of the genes related to chemotaxis of neutrophils may confer a risk for the development of both COPD and DPB. In the present report, the authors investigated the association between genetic variation that codes for the 416th and 420th amino acid of Gc-globulin, reported to be associated with chemotaxis of neutrophils, and susceptibility to COPD and DPB. Blood samples obtained from patients with COPD (n=63), DPB (n=82), and control subjects (n=82) were used for the genotyping assay. The proportion of GC*1F homozygotes was significantly higher in the COPD patients than the control subjects (COPD 36.5% versus control 20.7%), and the odds ratio for GC*1F homozygotes was 2.2 (95% confidence interval 1.1–4.6) for the COPD group. There was no difference on the distribution of the other genotypes (GC*1F-1S heterozygotes, GC*1S homozygotes, GC*2-1F heterozygotes, GC*2-1S heterozygotes and GC*2 homozygotes) or the allele frequencies among these groups. These findings suggest that the GC*1F gene polymorphism of Gc-globulin may be one of the risk factors for chronic obstructive pulmonary disease. However, no association between this polymorphism of Gc-globulin and susceptibility to diffuse panbronchiolitis was found.

Patients with obstructive sleep apnea syndrome (OSAS) are likely to exhibit an impaired swallowing reflex. However, mechanisms of disturbed swallowing reflex have not been determined. Because the upper-airway function is inhibited by hypoxia and hypercapnia, we examined the relationship between the swallowing function and gas exchange during day and night in patients with OSAS. Twenty-four patients with OSAS and 24 age-matched controls were studied. OSAS was diagnosed from overnight polysomnography. The swallowing reflex was judged by the latent time (LT) for swallowing following bolus injection of distilled water at the suprapharynx, the inspiratory suppression time (IST) from swallowing termination to the next onset of inspiration, and the threshold for evoking the swallowing response in terms of a volume of water (TV). Whereas the LT values are positively correlated with PaCO2 but not with PaO2 during the day, the values of IST and TV were not associated with daytime PaCO2 or PaO2. Nocturnal nadir SaO2 was correlated with LT, IST, and TV. These results indicate that oxyhemoglobin desaturation and hypercapnia may be associated with one of the mechanisms of the impaired swallowing function in patients with OSAS.

Cigarette smoking is thought to be a major risk factor in various lung diseases including lung cancer and emphysema. However, the direct effect of cigarette smoke on the viability of lung-derived cells has not been fully elucidated. In this study, we investigated the viability of human lung fibroblast-derived (HFL1) cells to different concentrations of cigarette smoke extract (CSE). CSE induced apoptosis at lower concentrations (10–25%) and necrosis at higher concentrations (50–100%). We also examined the effects of glutathione S-transferase P1 (GSTP1), one of the xenobiotic metabolizing and antioxidant enzymes in the lung, against the cytotoxicity of CSE. Our results indicated that the level of HFL1 cell death was decreased by transfection with a GSTP1 expression vector and was increased by GSTP1 antisense vector transfection. Therefore, transient overexpression and underexpression of GSTP1 appeared to inhibit and enhance the cytotoxic effects of CSE on HFL1 cells, suggesting that GSTP1 may have protective effects against cigarette smoke in the airway cells.

Gliomatosis cerebri is a rare form of glioma, which diffusely extends to both cerebral hemispheres. Because it sometimes fails to show severe neurological symptoms in spite of diffuse invasion, the antemortem diagnosis is difficult. We report a case of a 77-year-old woman, who was admitted with progressive left hemiparesis and dysarthralgia. Plain CT scan of the brain showed almost no abnormal findings. MRI T2-weighted image revealed widespread and nearly symmetrical extension of a high intensity area from the corpus callosum to the deep white matter of both cerebral hemispheres. Open biopsy of the brain showed glioblastoma multiforme, which finally confirmed the clinical diagnosis of gliomatosis cerebri. We also review the classic and recent literatures.

Human beta defensin 2 (HBD-2), the most recently discovered human defensin, has been considered to work as a host defense substance against microbial infection. Using Escherichia coli ATCC 25922, we investigated how some cations and anions influenced the antimicrobial activity of HBD-2. This activity, measured in 10 mM phosphate buffer at a concentration of 20 microg/ml, reduced significantly in the presence of 100 and 150 mM sodium or potassium chloride. The reduction was not significantly different when the total amounts of sodium and potassium ions were equal. The kind and the valence of anions (chlorine and sulfate ions) did not affect the bactericidal activity as long as the concentrations of sodium ions were equal. Divalent ions (calcium and magnesium ions) added to 10 mM of Tris buffer significantly inactivated HBD-2 at much lower concentrations (more than or equal to 0.01 mM and 0.05 mM, respectively) than the monovalent ions did. These findings suggest that HBD-2 kills the bacteria through at least two phases, which are affected independently by either monovalent or divalent ions and unaffected by anions.

Objective The goal of this article was to review the status of gene therapy involving cystic fibrosis (CF), particularly the progress that has been made over the past decade in adenovirus (Ad)-mediated CF lung disease. Background CF is theoretically an ideal disease to use in the study of gene therapy. Over the past decade, considerable progress has been made, with the path from CF gene discovery to clinical application being cleared. Clinical trials, mainly using Ad vectors, have been conducted, involving >200 patients with CF. Conclusions The results of the past decade of study have been both encouraging and frustrating. Good evidence exists that there are low levels of CF transmembrane conductance regulator (CFTR) gene transfer and limited evidence of small changes in ion transport. Although Ad vectors are the most advanced method for CF gene transfer to human airways, the current vectors are not yet suitable for in vivo application. The main problem involves the inefficiency of the Ad vectors when they are applied to the apical surface of the airway epithelia. Therefore, further applications of current Ad vectors in gene therapy in vivo will require improvements in efficiency and minimization of the toxicity/inflammatory responses in patients with CF. Although the efficiency of gene transfer is not sufficient to correct the functional defect of CF airways, many strategies to improve this gene transfer are being explored.

We examined the effects of angiotensin-converting enzyme (ACE) inhibitors on spontaneous or stimulated generation of reactive oxygen species (ROS) by bronchoalveolar lavage (BAL) cells prepared from 6 patients with chronic obstructive pulmonary disease (COPD) and from age-matched control subjects without COPD. The ROS produced by BAL cells were measured by the lucigenin-dependent chemiluminescence method. The application of ACE inhibitors into culture media containing BAL cells inhibited spontaneous and stimulated generation of ROS by BAL cells from COPD patients and control subjects in an ambroxol-concentration-dependent manner. Alacepril, an ACE inhibitor bearing SH-group, inhibited the oxygen radical production and generation by BAL cells from COPD patients in a dose-dependent fashion. Approximately 0.6–0.7 mM of alacepril inhibited 50% of the ROS production by BAL cells from COPD patients, whereas a slightly higher concentration (3 mM) of lisinopril, an ACE inhibitor not bearing an SH-group, was necessary to inhibit the production of ROS. These results suggest that an ACE inhibitor may act as an pulmonary antioxidant in patients with COPD.

A 88-year-old woman was admitted with appetite loss and dehydration in April 1999. She first noticed finger swelling in May 1996 and systemic sclerosis (SSc) was diagnosed in February 1997 on the basis of a clinical picture of low-grade fever, diffuse skin thickening, Raynaud's phenomenon, and pulmonary fibrosis. Retrospectively pulmonary fibrosis could have been identified on chest X ray film in September 1995. Although her appetite loss and dehydration were improved by hydration, pleural effusion continued. After detailed examinations, anti-topoisomerase 1 (Scl-70) antibody, anti-Sm antibody, and an anti-double-stranded DNA antibody (dsDNA) were found in her serum. However, the other antibodies to anti-SS-A, SS-B, Jo-1, and RNP were not detected. These results suggest that this elderly case was a very late onset overlap syndrome of systemic lupus erythematosus (SLE) and SSc. Thus, the pleural effusion in this case may have been caused by SLE-associated pleuritis. Although the late onset elderly cases with overlap syndrome are very rare, SLE, SSc, and their combination can be found in aged patients over 80 years old. SLE and SSc should be carefully considered for the differential diagnosis of pleural effusion and skin thickening even in elderly patients.

The effects of anaesthesia on upper airway reflexes in older animals have not been elucidated fully. We studied young (4-month-old) and old (28-month-old) guinea-pigs to examine the relationship between aspiration and altered upper airway reflexes during anaesthesia. We administered an adenovirus vector carrying Escherichia coli LacZ gene (Ad vector) intranasally to guinea-pigs with or without anaesthesia. LacZ gene expression was investigated in the nostrils and lungs of each animal under anaesthesia. No LacZ gene expression was found in the lungs of unanaesthetized animals given Ad vector. Thus intranasal administration of Ad vector was aspirated into the lower airways under anaesthesia. Next we examined the effect of age on anaesthesia-induced aspiration. At a lower concentration of halothane in 100% oxygen, greater LacZ gene expression in the lungs was measured in older than in younger animals, suggesting that older animals are liable to aspirate oropharyngeal contents into the lower airways during light anaesthesia. This novel animal model of aspiration using Ad vector may be useful to explore the mechanism of aspiration during and after anaesthesia in young and old animals.

Background The swallowing reflex is well coordinated with breathing patterns in normal humans. However, patients with obstructive sleep apnea syndrome (OSAS) may have a swallowing disorder that reflects the abnormal function of nerves and muscles in the suprapharynx. Objective To examine the relationship between the swallowing function and sleep-disordered breathing in patients with OSAS. Participants Twenty patients with OSAS with a mean (± SD) age of 53.4 ± 8.9 years old, and 20 age-matched control subjects with a mean age of 51.4 ± 9.1 years old. Methods OSAS was diagnosed using the recordings of overnight polysomnography. The swallowing function in the subject was tested using a swallowing provocation test. The swallowing reflex was determined according to the following criteria: latent time (LT), the time following a bolus injection of distilled water at the suprapharynx to the onset of swallowing; inspiratory suppression time (IST), the time from the termination of swallowing to the next onset of inspiration; and threshold volume, the minimum volume of water (range, 0.4 to 2 mL) that could evoke the swallowing response. Results Whereas the LT values in patients with OSAS were larger than the LT values in the control subjects, the IST values (which may reflect the switching mechanism from deglutition apnea to breathing) were actually shorter. In addition, a greater bolus volume was necessary to elicit swallowing in patients with OSAS than was necessary in the control subjects. Conclusion Patients with OSAS are likely to exhibit an impaired swallowing reflex, probably due to the perturbed neural and muscular function of the upper airways.

加齢とともに薬物有害作用出現頻度が上昇するが, これは多剤投与と密接な関係があり, 投与薬剤が増加するにつれ Medication Error も増える. 緊急入院症例の1/3は Medication Error による過量投与である. 高齢者の薬物有害作用は重篤な例が増加し, 発現臓器も多岐にわたり, 薬剤起因性老年症候群と呼ぶことも可能である. 多剤投与の原因は加齢により病名数が増加し, 症状所見が増加することによる. 高齢者の薬物有害作用を減少させるためには, 患者の総合的機能評価を行い, 患者からみた薬の優先順位を考え (Patient-Oriented Medication), 非薬物療法を常に念頭におく. こうした観点を踏まえた高齢者の薬物療法の教育体制の整備が重要である.

We evaluated variations in spirometric indices (i.e., forced vital capacity [FVC], peak expiratory flow [PEF], and forced expiratory volume in 1 sec [FEV1]) and static respiratory muscle pressures (i.e., maximum static inspiratory pressure [PImax] and maximum static expiratory pressure [PEmax]) within a span of 12 hr in 60 healthy elderly subjects, 60 young subjects, and 30 Chronic Obstructive Pulmonary disease (COPD) patients. There were no differences among data of FVC, PEF, FEV1, PImax, and PEmax on three separate occasions within a day in the elderly or the young. The mean coefficient of variation (CV) values of PEF and PImax on three occasions were 3.0 +/- 0.3% and 4.2 +/- 0.4% in the elderly, and 2.4 +/- 0.2% and 3.7 +/- 0.3% in the young, respectively. No subjects had more than 9% CV on each measurement in the study, suggesting that there is nosignificant daytime variation in measurement of expiratory flow and respiratory pressures in young and elderly people. However, FVC, PEF FEV1, and PImax values in the morning were smaller than those measured at the other two occasions in COPD patients. The results indicate that COPD affects diurnal variation in pulmonary function, but age alone has little impact on diurnal variation.

To examine the role of disturbed upper airway reflexes in aspiration, we administered 20 microliters of the adenovirus (Ad) vector Ad-CMV-LacZ or 20 microliters of phosphate buffered saline (PBS) intranasally to C57 black mice. We investigated expression of the LacZ gene by this Ad vector in the nostrils of each mouse, with or without anesthesia. Under anesthesia, LacZ gene expression was detected in the lungs of every mouse given the Ad vector. However, no LacZ gene expression was found in the trachea or lungs of mice given the Ad vector without anesthesia. In mice given PBS or wild-type adenovirus transnasally during anesthesia, there was no LacZ gene expression in the nostrils, trachea, or lungs, suggesting that with 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal) staining, blue-stained cells indicated transferred LacZ gene expression. These results suggested that aspiration of intranasal solution into lower airways was caused by disturbed upper airway reflexes during anesthesia. This process can be analyzed by the distribution of LacZ gene expression in airways. We next examined the effect of age on anesthesia-induced aspiration. Twenty-six-mo-old mice exhibited more LacZ gene expression in their lungs than did 6-mo-old mice at a concentration of 0.5 to 4.0% halothane in 100% oxygen. This suggests that light anesthesia may depress upper airway reflexes and cause aspiration in older animals. This novel model of aspiration, generated with the Ad-CMV-LacZ vector, may be useful for elucidating the mechanism of development of aspiration pneumonia in relation to age-related impairment of upper airway reflexes.

To examine the relationship between disturbed upper airway reflexes and aspiration pneumonia, we administered a total volume of 20 microliters of Ad-CMV-lacZ (Ad vector) or 20 microliters of phosphate buffer solution (PBS) intranasal to C57 black mice. In nostrils, the lacZ gene expression was investigated in each mouse with or without anesthesia. Under anesthesia, the lacZ gene expression was detected by Xgal staining in the lungs of every mouse given the Ad vector. However, no gene expression was measured in the lungs of those given the Ad vector without anesthesia. In mice treated with PBS, there was no lacZ gene expression in the nostrils, trachea, or lungs, irrespective of anesthesia. These results suggest that unconsciousness or disturbed upper airway reflexes caused by anesthesia caused aspiration, resulting in an intranasal bolus that can reached the lower airways. This process can be analyzed in mice tracted with adenovirus vectors carrying the E. coli LacZ gene. Mice given Ad-CMV-lacZ transnasally can be used to study aspiration pneumonia in relation to unconsciousness.

A 73-year-old woman was admitted to the geriatric ward of the University of Tokyo Hospital with anemia, osteepeina, and renal dysfunction. Although symptoms typical of multiple myeloma such as punched-out lesions and hyperproteinemia were not found, protein electrophoresis revealed that lambda type Bence-Jones protein was excreted in urine. Multiple myeloma was diagnosed. Furthermore, renal dysfunction was accompanied renal tubular acidosis type II (proximal type). Renal dysfunction in patient with multiple myeloma in usually caused by so-called myeloma casts in the distal tubules, but renal tubular acidosis type II is rarely observed. It is possible that injury of the proximal renal tubular eithelium by Bence-Jones protein resulted in renal tubular acidosis type II in this patient.

Endothelin (ET) 1, a 21 amino acid constrictor peptide, is one of the most potent agonists of airway smooth muscle and acts on two different receptors, i.e., ETA and ETB receptors. Recently, it has been shown that there are species and organ differences in physiological roles of each ET receptor. In rats, however, the physiological roles of ET receptors remain to be clarified. We questioned whether ET-1 might affect airway and lung tissue via different ET receptor subtypes in rats. To answer this question, we investigated the effects of ET-1 on lung behaviour in anesthetized, open-chested, mechanically ventilated (f = 1 Hz, VT = 9 mL/kg, PEEP = 3 cmH2O (1 cmH2O = 98.1 Pa)) rats in the absence or the presence of ETA and ETB selective antagonists, i.e., BQ-123 and BQ-788, respectively. Using alveolar capsules, we calculated lung elastance (EL), resistance of lung (RL), tissue (Rti), and airway (Raw), and hysteresivity (eta = 2 pifRti/EL) under control conditions and after intravenous administration of ET-1 (10(-8) mol/kg). ET-1 induced significant increases in RL, Rti, Raw, EL, and eta. BQ-123 did not affect ET-1 induced constriction, while BQ-788 significantly reduced delta RL, delta Rti, delta Raw, delta EL during ET-1 induced constriction. The effects of the combination of BQ-123 and BQ-788 were not different compared with BQ-788. Eta was not affected by BQ-123 and BQ-788. These data suggest that ETB, but not ETA, receptors may have significant physiological roles in rat lungs in response to ET-1.

Although acute responses to anticholinergic drugs in chronic obstructive pulmonary disease (COPD) have been extensively reported, it is not clear whether the response to these drugs is affected by their long-term use. We assessed the bronchodilator response at rest and the ventilatory response during exercise to the anticholinergic inhalational drug oxitropium bromide (OTB) in patients with COPD. We performed both spirometry and symptom-limited testing repeatedly on 14 men with COPD (age from 60 to 79 years; mean ± SE, 70.3 ± 2.0 years) before and after inhalation of OTB and repeated these tests after 1 year. The postinhalational forced expiratory volume in 1 second (FEV 1 ) was statistically significantly greater than the preinhalational value both before (baseline measures) and after 1 year of OTB use (baseline, 1.35 ± 0.07 to 1.49 ± 0.08 L [mean ± SE]; 1 year after, 1.29 ± 0.07 to 1.43 ± 0.08 L [mean ± SE]). Bronchodilator response as indicated by the absolute change in FEV 1 (ΔFEV 1 ) and the percent change of FEV 1 in the study after 1 year was virtually unchanged from values of baseline. The exercise capacity as measured by the maximal oxygen uptake was increased by the inhalation of OTB both before and after 1-year use of the drug (baseline, 1034 ± 31 to 1146 ± 48 mL/min [mean ± SE]; 1 year after, 1006 ± 36 to 1088 ± 51 mL/min [mean ± SE]). These results suggest that the duration of treatment with the anticholinergic drug OTB may have little effect on the resulting improvement in bronchodilation and exercise performance.

Rhabdomyolysis is not common in the elderly. Two elderly patients with rhabdomyolysis and respiratory infection with Streptococcus pneumoniae. The first patient was a 71-year-old woman with bronchiectasis who admitted to our hospital due to pneumonia. The second patient was an 84-year-old man who was admitted because of appetite loss, fever, and a cough producing of yellowish sputum. In both patients, sputum cultures were positive for S. pneumoniae, but blood cultures were not. The serum creatine kinase levels peaked on the day of admission at levels ten to thirty times higher than fold above the upper limit of normal; the serum lactate dehydrogenase levels were 1.5 times higher than the upper limit of normal. The creatine kinase levels returned to normal 5 to 7 days after admission, treated with antibiotics and recovered from pneumonia. The cases of these two patients, along with those described in previous reports of rhabdomyolysis associated with pneumococcal pneumonia indicate that measuring the serum creatine kinase level is important in detecting rhabdomyolysis, especially in elderly patients with respiratory infection caused by S. pneumoniae, and detection may help to prevent renal failure.

Acid-aspiration-induced injury is one of the leading causes of adult respiratory distress syndrome. Intercellular adhesion molecule-1 (ICAM-1) is a ligand for lymphocyte-function-associated antigen-1 alpha (LFA-1 alpha), and it has been shown to be required for leukocyte migration into inflamed areas. The purpose of this report was to investigate the role of the ICAM-1/LFA-1 alpha pathway in a rat model of acid-aspiration-induced injury. Animals received 3.0 ml/kg HCI (0.1N; pH, 1.0) intratracheally pretreated with control monoclonal antibodies (mAbs) (HCI group) or anti-ICAM-1 and LFA-1 alpha mAbs (Test group). In the HCI group, increases in lung resistance (RL) (229 +/- 23% baseline), lung wet-to-dry weight ratio (W/D) (11.9 +/- 0.4), protein concentration (TP) (0.447 +/- 0.054 mg/ml), and the number of neutrophils (PMN) (159.0 +/- 19.4 x 10(4)) of bronchoalveolar lavage fluid were observed. In the Test group, HCI-induced injury was significantly reduced (RL, 122 +/- 7% baseline; W/D, 7.2 +/- 0.1; TP, 0.277 +/- 0.016 mg/ml; PMN, 8.8 +/- 0.8 x 10(4)). The administration of mAbs to ICAM-1 and LFA-1 alpha after HCI instillation partially attenuated HCI-induced responses. These observations suggest that the ICAM-1/LFA-1 alpha pathway might be involved in the pathogenesis of adult respiratory distress syndrome caused by acid aspiration.

In Japan a number of reported cases of diffuse panbronchiolitis (DPB) have been associated with human T lymphotropic virus type I (HTLV-I) infection. In this study the hypothesis that HTLV-I proviral DNA may be prevalent in DPB was examined using polymerase chain reaction (PCR) for the region of env or the two-step PCR for the pX region of this virus. The presence of HTLV-I proviral DNA was studied in the peripheral blood mononuclear cells (PBMC) obtained from 10 patients with DPB. The presence of proviral DNA in PBMC in 12 patients with chronic obstructive pulmonary disease (COPD), eight patients with idiopathic interstitial pneumonia (IIP), four patients disease were also studied as relevant controls. The lung tissue obtained from 11 patients with DPB, 12 patients with diffuse aspiration bronchiolitis (DAB) at autopsy, and the surgical lung samples obtained from 12 patients with bronchogenic cancer were also studied. Peripheral blood mononuclear cells obtained from one DPB patient and one bronchogenic carcinoma patient were positive for the HTLV-I pX region. The presence of the pX region was also found in the lung tissue of three DPB patients (27.3%) and one DAB patient (8.3%). None of other subjects were positive for HTLV-I proviral DNA, In conclusion, HTLV-I is not the causative virus in the pathogenesis of COPD, IIP, bronchiectasis and bronchogenic carcinoma. There is a likelihood that HTLV-I infection is associated with some cases of DPB; however this association needs further verification.

To investigate the long-term effects of the inhaled anticholinergic bronchodilator, oxitropium bromide (OTB), on lung function, exercise capacity, and dyspnea in patients with chronic obstructive pulmonary disease (COPD), spirometry and symptom-limited exercise testing before and 1, 6, and 12 months after the regular use of OTB (600 micrograms/day) were performed in 12 patients with the use of OTB (mean age 69.9 +/- 3.1 years; FEV1/FVC 53.3 +/- 1.6%) as well as in 12 control patients who were not treated with OTB (Mean age 68.8 +/- 2.8 years; FEV1/FVC 52.6 +/- 1.9%). The dyspnea was evaluated by the slope of the regression line between Borg scale and oxygen uptake (Vo2) during exercise (Borg scale slope: BSS). At 1, 6, and 12 months after the start of OTB, the forced expiratory volume in one second (FEV1) and the exercise capacity (maximal Vo2) were greater than the pretreatment values and the dyspnea index (BSS) was significantly improved compared with the pretreatment value, while these parameters slightly worsened in the control patients over one year. In conclusion, the chronic use of an inhaled anticholinergic bronchodilator may provide beneficial improvements in expiratory flow rate, exercise performance, and dyspnea in mild to moderate COPD patients over one year.

With the aging of Japan's population, physicians need to be aware of advances in geriatric medicine. To assess the status of geriatric medicine in undergraduate education, we surveyed of medical student's opinions on gerontology and geriatric medicine. A questionnaire was sent to six-year medical students at a total of 20 schools that did not include geriatric medicine in their curriculum. Responses were obtained from 950 students (47.6%) at 16 schools (80%). Almost half of the students (42%) had experiences in health care facilities for the elderly. Ten percent were content with their education in geriatric medicine education and 59% were not. A total of 41.4% felt that geriatric medicine is difficult because it involves many different subjects. Some students had experience as volunteers working with elderly people; they were aware of the aging of Japan's population, and felt that their training in basic geriatrics and in geriatric diseases was insufficient. A total of 56% agreed that all medical schools should have classes in geriatric medicine and 14% did not. Medical students in the schools without classes in geriatric medicine identified dementia (73%), cerebral vascular accidents (51%), cancer (24%) and osteoporosis (19%) as common in elderly people, with no differences between schools. The corresponding data for medical students in schools with classes in geriatric medicine were dementia (77%), cerebral vascular accidents (44%), osteoporosis (29%), and cancer (16%). Undergraduate medical students seem to be exposed to widely differing curricula with regard to geriatric medicine. We found a lack of uniformity in the teaching of gerontology and geriatric medicine to undergraduate medical students in Japan.

Activin A is a homodimeric protein structurally and functionally related to transforming growth factor beta (TGF-beta), and the expression of activin A is modulated by TGF-beta. Here, we demonstrate the expression of activin A in normal and bleomycin (BLM)-treated murine lungs. ICR mice were treated with BLM intraperitoneally for 10 days, whereas saline vehicle was injected into control mice. Intra-alveolar fibrotic changes were observed in the lung tissue obtained from the mice at day 14 after the final BLM administration. Immunohistochemical studies using a polyclonal antibody to activin A revealed the presence of activin A in the bronchiolar epithelium and smooth muscle cells of veins in both control and BLM-treated mice. In the BLM-treated mice at days 7 and 14, the marked infiltration of immunoreactive alveolar macrophages was observed in the area of fibrotic changes. Bioactivity of activin A measured by erythroid differentiation factor assay in the conditioned medium of alveolar macrophages obtained from BLM-treated mice at day 14 was significantly increased. These findings indicate that alveolar macrophages are a potent source of activin A after BLM treatment. The present study demonstrates for the first time the abundant expression of activin A in murine lung tissues after BLM administration, suggesting that activin A may play a role in the pathogenesis of BLM-induced pulmonary fibrosis.

Human α -1-protease inhibitor ( α -1-Pi) has been known to be a highly polymorphic protein. We hypothesized that antiprotease activity of each phenotype M of α l-protease inhibitor (PiM) might be different among smokers and that a variation of decrease in pulmonary function for a given amount of cigarette smoking might be associated with PiM phenotypes. To test this, we investigated the effect of cigarette smoking on pulmonary function in each PiM phenotype. The serum level of α l-Pi was measured by the turbidimetric immunoassay and the distribution of PiM phenotypes was determined using isoelectric focusing technique in 247 healthy subjects and 20 COPD patients. Serum levels of α -1-antitrypsin of healthy and COPD subjects were 205.1±31.1 and 179.2±44.4 (±SD) mg/dL, respectively (p>0.01). The frequency of each PiM phenotype in healthy subjects was shown as follows: M 1 , 0.555; M 1 M 2 , 0.328; M 2 , 0.041; M 1 M 3 , 0.057; M 2 M 3 , 0.016; M 3 , 0.004. The difference in the distribution of PiM phenotypes between healthy and COPD subjects was not significant. Single- and multiple-regression analyses showed that the ratio of FEV 1 to forced vital capacity (FVC), in which FEV 1 is expressed as percentage of FVC, the maximum flow rate at 50% of FVC divided by measured body height ( V ˙ 50 /Ht), and the maximum flow rate at 25% of FVC divided by body height ( V ˙ 25 /Ht) were closely related to age and that V ˙ 25 /Ht also was related to smoking index. However, PiM phenotype was unrelated to those pulmonary function variables. We conclude that PiM phenotype is not a major determinant of difference in magnitude of pulmonary impairments caused by cigarette smoking in each individual.

Tobacco smoke is associated with pulmonary emphysema via elastase-antielastase and oxidant-antioxidant imbalance. This study addressed the tobacco smoke-induced changes in the lungs of weanling rats with vitamin E depletion. Three-week-old Wistar rats fed on vitamin E-depleted or normal diet were intermittently exposed to tobacco smoke by Hamburg II machines for 4 weeks. Tobacco smoke significantly suppressed body weight increases, particularly in the vitamin E-depleted group. In the normal diet group, tobacco smoke induced emphysematous changes with significant increases in the mean linear intercept (Lm) and the destructive index (DI), which was supported by an increase in elastase-like activity and a decrease in elastase inhibitory capacity (EIC) in bronchoalveolar lavage (BAL) fluid. Vitamin E depletion alone altered neither Lm nor DI. In tobacco-exposed animals in addition to vitamin E depletion, elastase-like activity, EIC in BAL fluid and DI were comparable to that in tobacco-exposed animals on a normal diet. However, Lm was markedly decreased with thickened epithelium and shrunk alveolar space. These results suggest that vitamin E depletion, when linked to tobacco exposure, might induce impaired lung development in the weanling rats, which is different from the emphysematous changes.

To elucidate the influence of age on ventilation components during exercise, we investigated the change in fractional contribution of abdomen or thorax during exercise in 12 elderly (71.9 +/- 5.3, mean +/- SD years) and 12 young (25.0 +/- 4.9 years) normal male subjects using respiratory-inductive plethysmography. At rest, abdominal/thoracic contribution was not different between elderly and young. During exercise, abdominal contribution to total ventilation was decreased in the young compared to that at rest (rest: 53.6 +/- 2.9% vs exercise: 50.4 +/- 1.9-48.9 +/- 1.8%; p < .01), but significantly increased in the elderly (rest: 53.9 +/- 1.8% vs exercise: 57.3 +/- 1.7-59.8 +/- 2.0%; p < .01). Only in the elderly, respiratory frequency was increased during exercise compared to that at rest (rest: 20.1 +/- 0.8 [/min] vs exercise; 25.6 +/- 1.5-27.8 +/- 1.6 [/min]; p < .05). The breathing pattern in the elderly during exercise was partly simulated in the young by reducing thoracic compliance using chest strapping. This study demonstrates the greater participation of diaphragmatic motion together with rapid shallow breathing during lower graded exercise in the elderly as compared with the young. This ventilatory pattern during exercise may result from a stiffening of the thorax with advancing age.

The purpose of this study is to evaluate chemical and pathological changes of the lung and to elucidate the role of TNF alpha and elastase in acute lung injury induced by HCl or lipopolysaccharide (LPS). Anesthetized rats were injected with pH 1.4 0.7 ml/kg body weight of HCl and 0.5 mg/kg body weight (BW) of LPS (E. coli) into the lung. Acute tracheal injury model (Mendelson Syndrome) were made. Control animals received only saline. Animals were sacrificed 1, 6, or 12 hours after the HCl or LPS or HCl and LPS injection, bronchoalveolar-lavage (BAL) was performed in the same way in control and experimental groups. The other animals which were treated as well were excised by histology. There was neither increase in TNF alpha-production nor increase in neutrophils resulting from HCl injection only. Elastase-like activity was not detected in animals treated only with HCl. However, 1 hour after LPS injection, the production of TNF alpha (37.0 +/- 8.0 Units/ml) was significantly greater than that of the control group (12.1 +/- 4.2 Units/ml) in BALF. Six hours after HCl and LPS injection, the concentration of elastase-like activity (0.023 +/- 0.002 nM) was significantly greater than that of the LPS group (0.011 +/- 0.001 nM). Only patches of intraalveolar hemorrhage and elevation of fibrin was observed in the HCl injected rats at 1 hour after injection. Six hours after LPS injection, the alveolar spaces were filled with large amounts of neutrophils. These findings suggest that TNF alpha and elastase play a significant role in HCl and LPS-induced acute lung injury.

The effects of high frequency oscillatory ventilation (HFOV) and conventional mechanical ventilation (CMV) on tracheal secretion were compared in 6 anesthetized dogs. Using a double-balloon endotracheal catheter, 5 ml of saline was instilled into an isolated tracheal segment during HFOV and CMV for 10 min respectively. Two eicosanoids, 15-hydroxyeicosatetraenoic acid (15-HETE) and 11-dehydrothromboxane B2 (11-dehydro-TXB2) were measured by radioimmunoassay in each sample. HFOV (stroke volume: 6 ml/kg, f: 10 Hz, bias flow: 5 l/min) and CMV (stroke volume: 12 ml/kg, f: 15/min) were performed in random sequence and achieved comparable gas exchange. The concentration of 15-HETE in tracheal fluid during HFOV (87 +/- 67 pg/ml) was decreased to less than half of that during CMV (286 +/- 184 pg/ml, P less than 0.05), while there was no significant change of 11-dehydro-TXB2 either in tracheal fluid or in plasma. This reduction of 15-HETE was tended to be enhanced by vagotomy (HFOV: 42 +/- 14, CMV: 120 +/- 103 pg/ml) with the concentration ratio of CMV/HFOV remaining unchanged. HFOV may provide hitherto unrecognized advantage over CMV by reducing airway secretion of 15-HETE, a potent inflammatory mediator.

To elucidate the effects of aging on ventilation in nocturnal disturbed breathing (NDB), we investigated 16 subjects aged 65 years or over with system developed by the authors using a respiratory inductive plethysmography connected to a personal computer. The subjects underwent 10 hours of continuous monitoring of lung volume and SaO2. Significant desaturation (SDS, greater than 4% drop in SaO2 from baseline value) and desaturation index [DI, sigma SDS(%) X duration (hr)] were calculated using the same program. The subjects with SDS below 50 were assigned to group A (n = 9, mean age = 79.7, male:female = 8:1) and the remaining subjects with SDS over 50 (n = 7, mean age = 74.7, male:female = 3:4) to group B. There was no significant difference in ventilatory parameters between group A and B. We then compared the male group (n = 11, mean age = 77.8) with the female group (n = 5, mean age = 76.8). The number of SDS in the female group (101.4 +/- 34.7) was significantly greater than that of the male group (33.4 +/- 8.3*, p less than 0.02), while minute ventilation of the female group (5.25 +/- 0.31 l/min) was significantly smaller than that of the male group (8.86 +/- 1.36* l/min, p less than 0.05). DI was found to significantly correlate with the SaO2 nadir and the number of apnea and SDS. There was no significant relationship between SDS and ventilatory parameters in this study. NDB among elderly female may be of more importance than has been reported.

S-phase kinase–associated protein 2 (SKP2), a member of the F-box family of ubiquitin–protein ligase complexes, controls the stability of cell cycle–related proteins including p27Kip1. The authors examined how the expression level of SKP2 affects the expression level of cell cycle–related proteins, cell cycle status, viability, and chemoresistance in A549 lung adenocarcinoma cells. Overexpression of SKP2 reduced the expression of p27Kip1, cyclin E, and p21Cip1, increased S-phase cells, rescued A549 cells from apoptosis due to adenoviral infection, and also increased chemoresistance against camptothecin, cisplatin, and AG1478. Down-regulation of SKP2 did not affect cell cycle status, and reduced cell viability.

We encountered a very rare case of cT0N2M0 small cell lung cancer (SCLC) with Lambert-Eaton myasthenic syndrome (LEMS). A 69-year-old man with a complaint of muscle weakness was admitted to our hospital. Although his chest radiograph on admission showed no abnormal findings, CT scanning detected a mediastinal lymphadenopathy. Also, 2-[18F]-2-fluorodeoxy-D-glucose position emission tomography (FDG-PET) revealed increased accumulation in the same portion in the mediastinum. A diagnosis of LEMS was made from the distinctive electromyogram (EMG) findings (waning and waxing phenomenon in response to low-and high-frequency repetitive stimulation, respectively) in combination with the increased serum level of a P/Q-type anti-voltage-gated calcium channel (VGCC) antibody. Subsequent histopathological diagnosis by mediastinoscopic resection of a paraaortic lymph node was small cell carcinoma. No distant metastasis was detected by MRI of the brain, abdominal CT scan or an FDG-PET. Eight courses of chemotherapy (carboplatin + etoposide) with radiotherapy of the mediastinum (for a total dose of 45 Gy) was performed. A decreased serum level of P/Q-type anti-VGCC antibody titers followed by marked improvement of neurological dysfunction (muscle weakness, gait disturbance and scanning speech) and of an EMG finding (a loss of waning phenomenon) was observed. A close relationship between reduction of the antibody titers and improvement of neurological symptoms after the therapy was noticed. It was suggested that monitoring the level of a P/Q-type anti-VGCC antibody titer in the serum is important for evaluating the efficacy of chemotherapy for LEMS associated with SCLC.

We made a national questionnaire survey of conditions and results of lung volume reduction surgery (LVRS) performed for pulmonary emphysema in 273 hospitals. The survey covered: number of hospitals, number of patients, indications, operative procedures, improvement of FEV1% and dyspnea score, mortality, cause of death, 5-year survival rate, characteristics of patients who died, and current conditions of LVRS. The response rate was 63%. A total of 619 patients at 41 hospitals underwent LVRS. The most common types of surgical procedure were bilateral LVRS through median sternotomy and unilateral LVRS with video-assisted thoracoscopic surgery (VATS), followed by bilateral LVRS with VATS. Postoperative improvement in FEV1% averaged 39%. Dyspnea improved in 80% of patients. Mortality rate was 1.9% (8 of 432 cases). Postoperative infectious diseases, namely pneumonia and sepsis, were common causes of death. The 5-year survival was 65 +/- 8%. The causes of death over 5 years were respiratory failure in 60%, malignant neoplasms in 17%, cardiovascular accidents in 13% and others in 10%. The number of operations and hospitals decreased in 2002, compared to 2001.

p27Kip1 is a cyclin-dependent kinase inhibitor, it negatively regulates G1 progression and is reported to modulate apoptosis. Phosphorylation of this protein is thought to regulate its intracellular localisation and affect its stability. The aim of this study was to regulate p27Kip1 expression levels, and to examine how this protein affects cell cycle status and modulates viability in A549 lung adenocarcinoma cells. In addition, the association between phosphorylation status of p27Kip1 and its intracellular localisation was investigated, using expression vectors with cDNA of p27Kip1 or mutants in which the phosphorylation sites had been mutated. Although overexpression of p27Kip1 reduced cell cycle progression, its removal did not change cell cycle status. Modest induction of p27Kip1 rescued adenovector-induced apoptosis and its removal with short interfering RNA increased spontaneous cell death. It was also observed that p27Kip1 localised mainly in the cytoplasm, and forced expression of p27Kip1 cDNA with the substitution of serine (S) 10, threonine (T) 157 and T198 to glutamate (phosphor-mimetic) induced its cytoplasmic localisation. In conclusion, p27Kip1, when expressed physiologically, exists mainly in the cytoplasm, has little effect on cell cycle status and contributes viability in A549 lung adenocarcinoma cells. It was also surmised that intracellular localisation of p27Kip1 dominates its function and that its localisation was partly determined by its phosphorylation.

Glutathione S-transferase P1 (GSTP1) is known as a xenobiotic enzyme through conjugation of glutathione and also as an inhibitor of Jun N-terminal kinase (JNK). We intended to investigate whether GSTP1 affects chemoresistance against camptothecin in human lung adenocarcinoma cells. Camptothecin induced GSTP1 expression. Downregulation of GSTP1 increased necrosis induced by camptothecin in A549 cells but not in PC-14 and RERF-LC-KJ cells. This phenomenon in A549 cells was hardly changed by JNK inhibitor SP600125 but was almost diminished by l-buthionine-sulfoximine. These results suggest that GSTP1 has protective effects against camptothecin-induced necrosis in subset of human lung adenocarcinoma through glutathione conjugation.

Glutathione S-transferase P1 (GSTP1) belongs to xenobiotic enzymes, and is supposed to contribute to chemoresistance. Though it was reported that GSTP1 gene is suppressed by cytosine-guanine (CpG) island methylation of its promoter, this promoter is not strongly methylated and GSTP1 protein is highly expressed in lung cancer. We intended to induce methylation of GSTP1 CpG island by using a methylated sense oligonucleotide complementary to this region. When we transduced the methylated oligonucleotides to A549 lung adenocarcinoma cells, methylation of the GSTP1 promoter and reduction of GSTP1 expression was induced, cell viability was reduced; however, chemoresistance against cisplatin has not clearly changed.

We investigated how nutritional deficiency affects cell cycle and cell viability in A549 lung adenocarcinoma cells. Deprivation of various amino acids or glucose induced cell cycle arrest and cell death in a different manner. Cell death on deprivation of these nutrients was increased by downregulating of p27Kip1 with RNA interference. It was also observed that intrinsic p27Kip1 was segregated in cytoplasm in a glucose-deprived situation. In conclusion, amino acid or glucose deprivation induced cell cycle arrest and cell death, part of which is thought to be rescued by the existence of cytoplasmic p27Kip1.

Glutathione S-transferase P1 (GSTP1) is one of the xenobiotic-metabolizing and antioxidant enzymes, identified in the peripheral lungs. Recently, the authors reported the association between GSTP1 gene polymorphism and susceptibility to chronic obstructive pulmonary disease (COPD), and protective effect of GSTP1 against cigarette smoke in human lung fibroblasts in vitro. In this study, the authors investigated that depletion of GSTP1 by itself could induce cell death, including apoptosis, in human lung fibroblast-derived HFL-1 cells. The level of apoptosis and necrosis was increased significantly with GSTP1 antisense vector transfection. It was also observed that the transfection efficiency and the expression level of the vector were weaker in the transfectant of the antisense vector than in those of the sense and control vectors, which is also thought to indicate that inhibition of GSTP1 expression by the antisense vector alone affects cellular viability. However, there was no difference among these transfectants neither on glutathione (GSH) level nor on c-Jun NH2-terminal kinase (JNK) activation. Therefore, the authors report here that underexpression of GSTP1 appeared to induce apoptosis on lung fibroblasts, which suggests that GSTP1 may have protective effects against apoptosis in the airway cells, though the mechanism of this apoptotic pathway is still to be elucidated.

Objective Repeated nocturnal hypoxia is implicated in the pathogenesis of cardiovascular complications in obstructive sleep apnea syndrome (OSAS). We hypothesized that circulating vascular endothelial growth factor (VEGF) levels are affected by nocturnal hypoxemia in patients with OSAS. Methods We examined the serum VEGF levels in patients with OSAS and in control subjects. We also tested the effects of oxygen or air administration on the subjects' VEGF levels. Patients and Materials Twenty-four OSAS patients (mean age 54.2±3.6 years) and 24 age-matched control subjects (53.2±3.6 years). Their serum samples were tested. Results Serum VEGF levels at 8 : 00 AM were significantly higher in OSAS patients than in controls (p

A 65-year-old woman complained of dyspnea and a productive cough after surgical treatment and irradiation therapy for thymoma. Chest radiography and high-resolution computed tomography showed small nodules in centrilobular lesions in all of both lung fields, but predominantly in the lower fields. In addition, blood tests showed hypogammaglobulinemia. Chronic sinusitis, mild hypoxemia, severe obstructive impairment and the pathological findings of bronchiolitis led to a diagnosis of sinobronchial syndrome caused by Good syndrome. Treatment with oral erythromycin 600 mg/day was started. After 6 months, the patient improved both clinically and radiologically. Low-dose, long-term treatment with erythromycin was effective against sinobronchial syndrome caused by Good syndrome.