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BACKGROUND: Automatic tube compensation (ATC) is a new option to compensate for the pressure drop across the endotracheal or tracheostomy tube (ETT), especially during ventilator-assisted spontaneous breathing. While several benefits of this mode have so far been documented, ATC has not yet been used to predict whether the ETT could be safely removed at the end of weaning, from mechanical ventilation. METHODS: We undertook a systematic trial using a randomized block design. During a 2-year period, all eligible patients of a medical intensive care unit were treated with ATC, conventional pressure support ventilation (PSV, 5 cmH2O), or T-tube for 2-h. Tolerance of the breathing trial served as a basis for the decision to remove the endotracheal tube. Extubation failure was considered if reintubation was necessary or if the patient required non-invasive ventilatory assistance (both within 48 h). RESULTS AND CONCLUSIONS: After the inclusion of 90 patients (30 per group) we did not observe significant differences between the modes. Twelve patients failed the initial weaning trial. However, half of the patients who appeared to fail the spontaneous breathing trial on the T-tube, PSV, or both, were successfully extubated after a succeeding trial with ATC. Extubation was thus withheld from four and three of these patients while breathing with PSV or the T-tube, respectively, but to any patient breathing with ATC. It seems that ATC can be used as an alternative mode during the final phase of weaning from mechanical ventilation. Furthermore, this study may promote a larger multicenter trial on weaning with ATC compared with standard modes.

Background: In tracheally intubated or tracheostomized spontaneously breathing patients, tube resistance can highly increase the patient's work of breathing. In this study we focused upon the relationship between total (WOB tot ) and tube-related additional inspiratory work of breathing (WOB add ) and compared different ventilatory modalities for proper tube compensation. Methods: In ten tracheostomized spontaneously breathing patients we measured WOB tot and WOB add in the continuous positive airway pressure (CPAP) mode, under inspiratory pressure support of 5, 10, and 15 cmH 2 O in the pressure support ventilation (PSV) mode, and under flow-adjusted pressure support in the automatic tube compensation (ATC) mode. WOB add and WOB tot were calculated on the basis of measured tracheal pressure and esophageal pressure, respectively. Inspiratory peak tracheal pressure above PEEP was taken as an estimate of pressure support beyond mere tube compensation (i.e., overcompensation). Results: The percentage of the tube-related WOB add on WOB tot in the CPAP mode was 52%. It decreased with increasing pressure support in the PSV mode from 32% (PSV 5 cmH 2 O) to 17% (PSV 15 cmH 2 O). WOB add was only 15% of WOB tot in the ATC mode. In contrast to the other ventilatory modes, reduction of WOB add in the ATC mode was achieved with the smallest amount of overcompensation, i.e. with minimal pressure assist beyond mere tube compensation. Conclusion: In tracheally intubated or tracheostomized spontaneously breathing patients, adequate compensation of tube resistance (i.e. with minimal overcompensation and minimal undercompensation) is best done by the ATC mode.

The association between long-term exposure to ambient air pollution and respiratory symptoms was investigated in a cross-sectional study in random population samples of adults (aged 18 to 60 yr, n = 9,651) at eight study sites in Switzerland. Information on respiratory symptoms was obtained with an extended version of the European Community Respiratory Health Survey questionnaire. The impact of annual mean concentrations of air pollutants was analyzed separately for never-, former, and current smokers. After controlling for age, body mass index, gender, parental asthma, parental atopy, low education, and foreign citizenship, we found positive associations between annual mean concentrations of NO2, total suspended particulates, and particulates of less than 10 micrometers in aerodynamic diameter (PM10) and reported prevalences of chronic phlegm production, chronic cough or phlegm production, breathlessness at rest during the day, breathlessness during the day or at night, and dyspnea on exertion. We found no associations with wheezing without cold, current asthma, chest tightness, or chronic cough. Among never-smokers, the odds ratio (95% confidence interval) for a 10 micrograms/ m3 increase in the annual mean concentration of PM10 was 1. 35 (1.11 to 1.65) for chronic phlegm production, 1.27 (1.08 to 1.50) for chronic cough or phlegm production, 1.48 (1.23 to 1.78) for breathlessness during the day, 1.33 (1.14 to 1.55) for breathlessness during the day or at night, and 1.32 (1.18 to 1.46) for dyspnea on exertion. No associations were found with annual mean concentrations of O3. Similar associations were also found for former and current smokers, except for chronic phlegm production. The observed associations remained stable when further control was applied for environmental tobacco smoke exposure, past and current occupational exposures, atopy, and early childhood respiratory infections when restricting the analysis to long-term residents and to non- alpine areas, and when excluding subjects with physician-diagnosed asthma. The high correlation between the pollutants makes it difficult to sort out the effect of one single pollutant. This study provides further evidence that long-term exposure to air pollution of rather low levels is associated with higher prevalences of respiratory symptoms in adults.

This article reviews the pharmacological treatment of severely hypoxaemic critically ill patients, notably those with acute respiratory distress syndrome (ARDS), acute lung injury or the sepsis syndrome. Haemodynamic support in hypotensive patients often initially requires aggressive fluid resuscitation with crystalloids or colloids, combined with vasopressors to maintain adequate end-organ perfusion. The catecholamine of choice in severe hypotension with low systemic resistance is norepinephrine (noradrenaline); dopamine is often used in mild hypotension. Once haemodynamic stabilisation is achieved, loop diuretics such as furosemide (frusemide) are used to obtain the lowest volaemia that guarantees adequate perfusion. If the fraction of inspired oxygen necessary to achieve the satisfactory haemoglobin oxygen saturation of 90% approaches 1, a trial of nitric oxide with or without almitrine is justified. Oxygen consumption can be lowered by treating fever with paracetamol (acetaminophen) and physical cooling. Occasionally, deep sedation using a combination of an opioid (most often morphine or fentanyl) and a benzodiazepine (lorazepam or midazolam) is necessary; in the presence of renal or hepatic insufficiency, propofol is a valid, although expensive, alternative. Paralysis with pancuronium or vecuronium has been associated with critical illness polyneuropathy and is used only as a last resort. Corticosteroids may be indicated in the subacute (fibroproliferative) phase of ARDS. Other anti-inflammatory treatments (such as cytokine antagonists, cyclo-oxygenase inhibitors, antioxidants or monoclonal anti-endotoxin antibodies), as well as surfactant supplementation, have failed to improve prognosis in randomised trials.

The effect of long-term exposure to air pollutants was studied in a cross-sectional population-based sample of adults (aged 18 to 60 yr; n = 9,651) residing in eight different areas in Switzerland. Standardized medical examination included questionnaire data, lung function tests, skin-prick testing, and end-expiratory CO concentration. The impact of annual means of air pollutants on FVC and FEV1 was tested (controlling for age and age squared, sex, height, weight, educational level, nationality, and workplace exposure). Analyses were done separately for healthy never-smokers, ex-smokers (controlling for pack-yr), for current smokers (controlling for cigarettes per day and pack-yr smoked), and for the whole population. Significant and consistent effects on FVC and FEV1 were found for NO2, SO2, and particulate matter10 microm (PM10) in all subgroups and in the total population, with PM10 showing the most consistent effect of a 3.4% change in FVC per 10 microg/m3. Results for ozone were less consistent. Atopy did not influence this relationship. The limited number of study areas and high intercorrelation between the pollutants make it difficult to assess the effect of one single pollutant. Our conclusion is that air pollution from fossil fuel combustion, which is the main source of air pollution with SO2, NO2, and PM10 in Switzerland, is associated with decrements in lung function parameters in this study.

To clarify the influence of an elevated carboxyhemoglobin (COHb) blood level on the course of acute myocardial infarction and to evaluate the administration of supplemental oxygen on the COHb level and the incidence of complications.Prospective clinical study with randomized, unblinded intervention.Coronary Care Unit of a university hospital.78 consecutive patients with acute myocardial infarction. Excluded were patients with severe dyspnea, pulmonary edema or any other medical indication for supplemental oxygen therapy.Randomized therapy with 41/min oxygen in 35 patients.COHb was measured at admission and 4 h later. The incidence of serious arrhythmias and the maximal creatine kinase (CK) values were recorded. In patients with initial COHbor = 5%, there were significantly more arrhythmias and significantly higher maximal CK values than in those with normal COHb admission (89 vs 33%, p0.001; and 1897 +/- 1602 u/l vs 960 +/- 1097 u/l, p=0.05). This effect was seen only in patients with Q-wave infarction, not in those with non-Q-wave infarction. Supplemental oxygen had no effect on the incidence of arrhythmias.We conclude that myocardial infarction patients with acute Q-wave infarction and increased COHb levels at admission suffer a more severe course of the disease. This outcome was not influenced by oxygen therapy. Whether this finding indicates a casual relationship and whether higher oxygen concentrations would favorably alter the course of acute myocardial infarction remains to be determined.

Exercise testing with measurement of maximal oxygen uptake (VO2max) is increasingly used in the assessment of lung resection candidates, but its predictive value for postoperative complications remains controversial. We therefore sought to determine the prognostic value of VO2max compared with other pulmonary function tests. A consecutive group of 80 patients (mean age 61 yr; 57 males and 23 females) scheduled for lung resection (62 malignancies, 12 benign disorders, and 6 carcinoids) underwent pulmonary function tests and symptom-limited cycle ergometry. All patients underwent lung resections: 21 pneumonectomies, 45 lobectomies, and 14 segmental or wedge resections. Group A (64 patients, 80%) had an uneventful postoperative course, whereas Group B (16 patients, 20%) had complications; 3 of them died (4% overall mortality rate). In a stepwise logistic regression analysis used to determine independent risk factors for postoperative complications (within 30 d), VO2max expressed as a percentage of predicted (84 +/- 19 for Group A versus 61 +/- 11 for Group B) proved to be the best predictor (predictive value 85.5%). Although VO2max expressed in absolute values (ml/kg/min) was also highly predictive (79.5%), a ROC curve analysis proved the percentage predicted values to be significantly more sensitive. Of 9 patients with a VO2max60% of predicted, 8 had complications, including all 3 patients who died after resections of more than one lobe (sensitivity 50%, specificity 98%). The estimated probability (probit model SAS software package) of suffering no complication was 0.9 for VO2max75% of predicted and 0.1 for a VO2max43%.(ABSTRACT TRUNCATED AT 250 WORDS)

Salmeterol provides bronchoprotection against a number of constrictor stimuli for more than 12 h after a single dose. This effect could be due either to functional antagonism at the level of airway smooth muscle or to cell-stabilizing effects of the compound. In this study, we attempted to clarify this mechanism by comparing the effects of salmeterol (50 micrograms), salbutamol (200 micrograms) and placebo on the airway responsiveness to histamine (to assess functional antagonism), and to adenosine 5'-monophosphate (AMP) (to assess additional cell-stabilizing effects), 14 h after drug treatment. Thirteen patients with mild allergic asthma were studied in a double-blind, randomized protocol on 6 days, at least 48 h apart. Forced expiratory volume in one second (FEV1) was measured before and 15 min after inhalation of the study medication. Then, 14 h later (8 a.m. the following morning), a bronchoprovocation test with histamine or AMP was performed. We found that 14 h after inhalation, salmeterol still had a significant effect on FEV1 in comparison to placebo and salbutamol. The provocative dose producing a 20% fall in FEV1 (PD20histamine) was significantly increased after salmeterol, whilst the increase in PD20AMP did not reach significance. The shift in PD20 (in doubling dose steps) induced by salmeterol pretreatment was not different between histamine and AMP. We conclude that the prolonged protective effect of salmeterol occurs via an extended bronchodilating and functional antagonistic action and not via a cell-stabilizing effect.

We compared the value of exercise testing and measurement of pulmonary haemodynamics (PH) in the pre-operative assessment of 5 patients (mean age: 64 years, 3 men) with clinical stage I or II bronchog

In the larger airways, the blood circulation forms a subepithelial (mucosal) and outer (peribronchial) microvascular network. This raises the possibility that blood flow in these two networks is regulated independently. We used hypoxemia as a stimulus to induce changes in tracheal mucosal blood flow normalized for systemic arterial pressure (Qtr n) measured with an inert soluble gas technique and total bronchial blood flow (Qbr) and normalized Qbr (Qbrn) measured with an electromagnetic flow probe in anesthetized sheep. Fifteen minutes of hypoxemia [PO2 40 +/- 7 (SD) Torr] decreased mean Qtr n from 1.1 +/- 0.4 to 0.8 +/- 0.4 ml.min-1.mmHg-1.10(2) (-27%; P less than 0.05; n = 7) and increased mean Qbr n from 12.1 +/- 3.2 to 17.1 +/- 5.4 ml.min-1.mmHg-1.10(2) (+41%; P less than 0.05; n = 6). The rise in Qbr correlated with cardiac output (r = 0.68; P less than 0.05). Phentolamine pretreatment (0.1 mg/kg iv) blunted the hypoxemia-related decrease of mean Qtr n (-8%; P = NS). Tyramine (2.5 mg) applied locally to the trachea decreased mean Qtr n significantly after 30 and 45 min by 31 and 19%, respectively (P less than 0.05). 6-Hydroxydopamine (0.2 mg 4 times for 1 h locally applied) prevented the hypoxemia-induced as well as local tyramine-induced decrease in mean Qtr n (0 and 0%).(ABSTRACT TRUNCATED AT 250 WORDS)

In a double-blind placebo-controlled prospective clinical trial we studied the efficacy and safety of the benzodiazepine antagonist, flumazenil. In 23 patients admitted to the Intensive Care Unit with coma due to overdose with benzodiazepines or other sedatives, flumazenil i.v. (up to 2 mg or placebo) was given. In 13 patients given flumazenil the Glasgow Coma Scale (GCS) increased significantly from 4.9 to 7.8 (p less than 0.05). Six of these 13 patients, including mainly benzodiazepine mono-intoxications, needed only one series of injections (up to 1.0 mg flumazenil); the GCS increased thereby from 4.5 to 10.7 within a maximum of 5 min (p less than 0.01). In the remaining 7 patients, needing two series of injections of flumazenil (up to 2.0 mg), GCS did not rise significantly and coma was related to intoxications with nonbenzodiazepine sedatives, flunitrazepam and in one patient, encephalitis. In the 10 patients receiving placebo, the GCS did not change. A significant increase in the GCS from 5.5 to 10.8 (p less than 0.001) was, however, observed when flumazenil (up to 1.0 mg) was given after placebo. In patients with EEG monitoring the changes in waveform pattern paralleled the clinical response. Effects could be detected within 1-2 min after flumazenil injection and lasted up to 45 min. There were no adverse reactions or benzodiazepine withdrawal symptoms. We conclude that flumazenil is an effective and safe drug in the treatment of benzodiazepine overdose. The use of flumazenil is of diagnostic value in mixed-drug intoxications or coma of unknown origin and is of therapeutic importance for reversal of benzodiazepine intoxications.

Automatic tube compensation (ATC) is a new option to compensate for the pressure drop across the endotracheal or tracheostomy tube (ETT), especially during ventilator-assisted spontaneous breathing. While several benefits of this mode have so far been documented, ATC has not yet been used to predict whether the ETT could be safely removed at the end of weaning, from mechanical ventilation.We undertook a systematic trial using a randomized block design. During a 2-year period, all eligible patients of a medical intensive care unit were treated with ATC, conventional pressure support ventilation (PSV, 5 cmH2O), or T-tube for 2-h. Tolerance of the breathing trial served as a basis for the decision to remove the endotracheal tube. Extubation failure was considered if reintubation was necessary or if the patient required non-invasive ventilatory assistance (both within 48 h).After the inclusion of 90 patients (30 per group) we did not observe significant differences between the modes. Twelve patients failed the initial weaning trial. However, half of the patients who appeared to fail the spontaneous breathing trial on the T-tube, PSV, or both, were successfully extubated after a succeeding trial with ATC. Extubation was thus withheld from four and three of these patients while breathing with PSV or the T-tube, respectively, but to any patient breathing with ATC. It seems that ATC can be used as an alternative mode during the final phase of weaning from mechanical ventilation. Furthermore, this study may promote a larger multicenter trial on weaning with ATC compared with standard modes.

To examine incidence and outcome of intensive care unit (ICU) admission in patients with haematological malignancy and analyse prognostic factors associated with outcome.Retrospective cohort study in an intensive care unit of a tertiary referral center.78 patients with severe haematological malignancy were admitted 97 times between 1990-97 to the medical ICU for septic shock (18), respiratory failure (30), postoperative monitoring (19), cardiovascular (10) and central nervous complications (8) or for other reasons (12). Median age was 43 (4-73) years, average duration of ICU stay was 4 (1-43) days. Forty-two patients required mechanical ventilation, 46 vasopressors and 8 haemodialysis.Rates of ICU admission differed by treatment of the underlying disease. There were 18, 10 and 27 ICU admissions per 100 treatments in patients undergoing chemotherapy for acute leukaemia, autologous and allogeneic stem cell transplantation (p0.005) respectively. Thirty-two of 78 patients died within 60 days of ICU admission. Organ failure, i.e. cardiovascular failure requiring vasopressors, respiratory failure requiring mechanical ventilation and renal failure, requiring haemodialysis, was most significantly associated with outcome. Mortality by day 60 after admission was 16%, 36%, 64%, and 83% (p0.0002) for patients without organ failure, and for patients with 1, 2 or 3 failing organs. In a multivariate logistical regression model, only the organ failure score (p0.0005) and evidence of liver damage, defined as ASAT or ALAT100 IU/ L (p0.007), but not age, sex, primary disease and treatment of the underlying disease predicted outcome.Multi-organ failure and evidence of liver damage but no other patient, disease, or treatment related factor predict outcome in patients with haematological disease admitted to the ICU.

The Cdc6 protein (Cdc6p) has essential roles in regulating initiation of DNA replication. Cdc6p is recruited to origins of replication by the origin recognition complex (ORC) late in mitosis; Cdc6p in turn recruits minichromosome maintenance (Mcm) proteins to form the pre-replicative complex. Cdc6p is thought to interact with one or more Mcm proteins but this point has not yet been demonstrated. In the present study we observed that Cdc6p interacted significantly only with Mcm2p out of six Mcm proteins in yeast two-hybrid cells. Our results indicate that the interaction of Cdc6p with Mcm2p is specific, although we cannot exclude the possibility that the interaction might not be direct. In attempts to identify domains of Cdc6p important for interaction with Mcm2p, we tested interactions of various deleted versions of Cdc6p with Mcm2p and also with Cdc4p, which was previously known to interact with Cdc6p. The portion of Cdc6p from amino acid residues 51 to 394 was able to interact with Mcm2p. During the course of the studies we also discovered a previously undetected Cdc4p interaction domain between residues 51 and 394. Interestingly, when all six putative Cdc28 phosphorylation sites in Cdc6p were changed to alanine, a 6-7-fold increase in binding to Mcm2p was observed. This result suggests that unphosphorylated Cdc6p has higher affinity than phosphorylated Cdc6p for Mcm2p; this might partly explain the previous observation that Cdc6p failed to load Mcm proteins on replication origins during S phase when the cyclin-dependent protein kinase was active, thus helping to prevent the reinitiation of activated replicons.

The purpose of this article is to draw attention to the possible complications of foreign body ingestion or aspiration associated with dental treatment, especially oral implant treatment. A guide for the management of swallowed or inhaled objects is given. When the object cannot be coughed out, then it is mandatory to take frontal and lateral chest roentgenograms to identify the object's position in the intestinal system or in the tracheobronchial tree. In case of ingestion, attempts should be made to recover the foreign object by esophagoscopy. Aspirated foreign bodies should be removed within 24 hours. Acute obstruction can be life threatening and delaying the removal of foreign objects may make a bronchoscopy technically more difficult. The clinician must be aware of the complications involved in accidentally inhaling or ingesting foreign bodies during dental treatment. Patients at greater risk of swallowing or aspirating foreign objects need to be identified and extra preventive steps must be taken to avoid such complications.

In tracheally intubated or tracheostomized spontaneously breathing patients, tube resistance can highly increase the patient's work of breathing. In this study we focused upon the relationship between total (WOBtot) and tube-related additional inspiratory work of breathing (WOBadd) and compared different ventilatory modalities for proper tube compensation.In ten tracheostomized spontaneously breathing patients we measured WOBtot and WOBadd in the continuous positive airway pressure (CPAP) mode, under inspiratory pressure support of 5, 10, and 15 cmH2O in the pressure support ventilation (PSV) mode, and under flow-adjusted pressure support in the automatic tube compensation (ATC) mode. WOBadd and WOBtot were calculated on the basis of measured tracheal pressure and esophageal pressure, respectively. Inspiratory peak tracheal pressure above PEEP was taken as an estimate of pressure support beyond mere tube compensation (i.e., overcompensation).The percentage of the tube-related WOBadd on WOBtot in the CPAP mode was 52%. It decreased with increasing pressure support in the PSV mode from 32% (PSV 5 cmH2O) to 17% (PSV 15 cmH2O). WOBadd was only 15% of WOBtot in the ATC mode. In contrast to the other ventilatory modes, reduction of WOBadd in the ATC mode was achieved with the smallest amount of overcompensation, i.e. with minimal pressure assist beyond mere tube compensation.In tracheally intubated or tracheostomized spontaneously breathing patients, adequate compensation of tube resistance (i.e. with minimal overcompensation and minimal undercompensation) is best done by the ATC mode.

Objectives Occupational exposures to inhalative irritants have been associated with an increased reporting of respiratory symptoms in previous studies. Methacholine responsiveness represents a continuous measure of airway responsiveness. As such, it may be less subject to recall bias and more sensitive to detecting effects of occupational exposure on airways. Such effects may be stronger among atopic persons. The objective of the study was to examine the relationship between self-reports of occupational exposure to dusts, gases, vapors, aerosols, and fumes and methacholine responsiveness. Methods A sample was studied of never smokers (N=3044) chosen randomly from 8 areas in Switzerland. Atopy was defined as any positive skin test to 8 inhalative allergens. Nonspecific bronchial reactivity was tested using methacholine chloride and quantified by calculating the slope of the dose-response. Results The methacholine slopes were 19% [95% confidence interval (95% CI) 6-32] higher for never smokers with exposure to dusts, fumes, vapors, gases, or aerosols than for the unexposed group. When only atopic never smokers were examined, the increase was larger (37%, 95% CI 7-75), and for persons with ?2 positive skin prick tests the effect was still higher (42%, 95% CI -1.5-104). Exposure to vapors and aerosols was strongly associated with increased methacholine slopes among the atopic subjects. Conclusion Occupational exposure, particularly to dusts and fumes, was associated with increased bronchial reactivity in never smokers in this study. The magnitude of the effect was larger among atopic subjects.

We report a case of Takayasu’s arteritis with predominant pulmonary involvement, which led eventually to complete obliteration of the right pulmonary artery. Subsequently, cavitation and chronic inflammation developed in the nonperfused right lung. A right pneumonectomy was performed to control the infectious process, leading to functional improvement and better control of the underlying immunologic disorder.

The association between long-term exposure to ambient air pollution and respiratory symptoms was investigated in a cross-sectional study in random population samples of adults (aged 18 to 60 yr, n = 9,651) at eight study sites in Switzerland. Information on respiratory symptoms was obtained with an extended version of the European Community Respiratory Health Survey questionnaire. The impact of annual mean concentrations of air pollutants was analyzed separately for never-, former, and current smokers. After controlling for age, body mass index, gender, parental asthma, parental atopy, low education, and foreign citizenship, we found positive associations between annual mean concentrations of NO2, total suspended particulates, and particulates of less than 10 micrometers in aerodynamic diameter (PM10) and reported prevalences of chronic phlegm production, chronic cough or phlegm production, breathlessness at rest during the day, breathlessness during the day or at night, and dyspnea on exertion. We found no associations with wheezing without cold, current asthma, chest tightness, or chronic cough. Among never-smokers, the odds ratio (95% confidence interval) for a 10 micrograms/ m3 increase in the annual mean concentration of PM10 was 1. 35 (1.11 to 1.65) for chronic phlegm production, 1.27 (1.08 to 1.50) for chronic cough or phlegm production, 1.48 (1.23 to 1.78) for breathlessness during the day, 1.33 (1.14 to 1.55) for breathlessness during the day or at night, and 1.32 (1.18 to 1.46) for dyspnea on exertion. No associations were found with annual mean concentrations of O3. Similar associations were also found for former and current smokers, except for chronic phlegm production. The observed associations remained stable when further control was applied for environmental tobacco smoke exposure, past and current occupational exposures, atopy, and early childhood respiratory infections when restricting the analysis to long-term residents and to non- alpine areas, and when excluding subjects with physician-diagnosed asthma. The high correlation between the pollutants makes it difficult to sort out the effect of one single pollutant. This study provides further evidence that long-term exposure to air pollution of rather low levels is associated with higher prevalences of respiratory symptoms in adults.

A 54-year-old patient with polycystic kidney disease developed relapsing urinary-tract infections after renal transplantation. In the post-transplantation period he underwent two rejection episodes. The general condition worsened without obvious reason. Six months after transplantation the patient was hospitalized due to gram-negative sepsis. Despite adequate antimicrobial treatment he continued to lose weight and complained of dysphagia. Chest X-ray and computer tomogram of the thorax showed multiple cavitating infiltrations of the lung. A few days later the patient died from an extended subarachnoidal hemorrhage.

Regulation of glucocorticoid receptor (GR) expression by its cognate ligand was examined in the glucocorticoid-sensitive human leukemic T-cell line 6TG1.1 and in the human B-cell line IM-9. In contrast to the decrease in GR mRNA seen in IM-9 cells after treatment with 1 microM dexamethasone for 16-18 h, treatment of 6TG1.1 cells resulted in an 8-fold increase in GR mRNA, as determined by Northern blot and RNase protection analysis, with a corresponding 3- to 4-fold increase in GR protein. Half-maximal induction of GR mRNA and protein in 6TG1.1 cells was observed between 10-100 nM dexamethasone, and inclusion of 1 microM RU 38486 completely blocked the effects of 100 nM dexamethasone, demonstrating that positive autoregulation of GR expression in 6TG1.1 cells is a receptor-mediated response. Positive autoregulation of GR expression was also observed in glucocorticoid-resistant CEM-C1 cells, which contain functional GR, but whose growth is unaffected by glucocorticoids. Thus, positive autoregulation is neither a consequence nor the sole cause of growth arrest. The degree of negative autoregulation in IM-9 cells and positive autoregulation in 6TG1.1 cells was unaffected by inhibition of protein synthesis with cycloheximide. Measurement of GR mRNA turnover in 6TG1.1 cells treated with actinomycin-D revealed a half-life of 2.5 h, which was unaffected by dexamethasone treatment. A similar half-life was determined in IM-9 cells and was also unaffected by steroid treatment. These results are consistent with the interpretation that glucocorticoid-mediated autoregulation of GR expression is a tissue-specific primary transcriptional response.

A 27-year-old man, in good health but a moderate smoker, suddenly had two episodes of haemoptysis. Routine clinical examination was unremarkable. Erythrocyte sedimentation rate was increased to 34 mm/h. The chest radiography showed ill-defined, contrast-poor infiltrations bilaterally, as well as left hilar enlargement. Lung scintigraphy and pulmonary arteriogram suggested pulmonary embolism, possible from a "pelvic vein spur", i.e. an intimal proliferation due to crossing of the common iliac artery over the pelvic vein. He was placed on oral anticoagulants. Three months later he had another severe haemoptysis, providing the indication for an exploratory thoracotomy. This revealed the left pulmonary artery wall to have inflammatory changes with aneurysmal dilatation. The aneurysm was plicated. Histological examination demonstrated chronic vasculitis as seen in Behçet's syndrome, a diagnosis confirmed by the findings of ulcers of the oral mucosa and the presence of HLA B5 allo-antigens. Immunosuppressive treatment was given with prednisone (1 mg/kg), azathioprine (2.5 mg/kg) and ciclosporin (5 mg/kg). Over the next 12 months there has been only one further haemoptysis.

Chronic cor pulmonale is defined as right-heart hypertrophy or right-ventricular dilatation and/or chronic right-heart failure, secondary to disorders of the respiratory system. Most cases of cor pulmonale are secondary to chronic obstructive pulmonary disease. Other etiologies include restrictive lung diseases (e.g. idiopathic pulmonary fibrosis) and multiple pulmonary emboli, with the important, although small group of patients with chronic major vessel thromboembolism. In some instances abnormal ventilatory drive, disorders of the thoracic cage or neuromuscular diseases will eventually lead to cor pulmonale. Pathogenetic mechanisms involve hypoxic pulmonary vasoconstriction, mechanical narrowing of vessels and obstruction of the pulmonary vascular bed, which are discussed in further detail.

A double-blind, randomized cross-over trial was carried out in 24 patients with chronic airflow obstruction. The patients were required to demonstrate a minimum 15% absolute increase in forced expiratory volume (FEV1) after a standard dose (0.4 mg) of fenoterol (F). On a separate occasion the effect of ipratropium bromide (IB; 0.04 mg) on FEV1 was tested also; according to the increase in FEV1 the patients were grouped into IB responders (delta FEV115%) and IB nonresponders (delta FEV115%). Two puffs of F/IB (0.1 mg/0.04 mg), salbutamol (S; 0.2 mg) and placebo (P) were given by metered-dose inhaler at the same time of the day on three different occasions. FEV1 and specific airway resistance (sRaw) were assessed before and at specific intervals following inhalation. The results showed that F/IB and S produced similar maximal increases in FEV1 (delta FEV1 32% for F/IB and 31% for S) and decreases in sRaw (delta sRaw 24% for F/IB and 21% for S). These effects were significantly different both from baseline values and from P. FEV1 was still significantly different 8 h after inhalation from P in the F/IB group, but not in the group that received S. The effect of IB on FEV1 in the pretest was compared with the subsequent response to F/IB. In IB responders F/IB seemed to produce slightly more effective bronchodilation. Side effects were minimal and clinically insignificant. In conclusion, F/IB, with its ability to effect sustained bronchodilation without adverse side effects, is a viable alternative to a monotherapy in chronic obstructive pulmonary disease.

Until recently asthma was considered to be caused mainly by bronchospasm of the smooth airway musculature. Accordingly beta-adrenergic agonists were the drugs of choice. During the last decade, however it has become increasingly clear that ongoing chronic inflammation of the bronchial wall plays a prominent role in the disease process. During the early bronchoconstriction after allergen challenge, histamine is probably the most important mediator. The late reaction is characterized by an inflammatory infiltration of the bronchial wall, notably by eosinophils and lymphocytes. A complex interplay of mediators as leukotrienes, prostaglandins and PAF may lead to a chronic inflammation. Inflammatory changes are seen in bronchial biopsies and broncho-alveolar lavage fluid even of mild and asymptomatic asthmatic patients. Based on this new disease concept, antiinflammatory drugs have become the mainstay of therapy even in mild to moderate asthmatics. Beta-adrenergic agonists remain the most important drug for the relief of acute bronchospasm.

Dyspnea can be defined as an unusual perception of respiration and/or urge to breath more than usual. Up to 70% of all tumour patients suffer at one time from this complaint, and often only an incomplete palliation is achieved. Dyspnea in the tumour patient is often associated with anxiety, which leads itself to a further exacerbation of dyspnea (through increased respiratory work and dead-space ventilation). A thorough evaluation should exclude treatable causes of dyspnea such as atelectasis, pleural effusions, pneumonias, congestive heart failure, pulmonary emboli, reversible exacerbations of coexisting obstructive lung disease, central tumour obstruction and pericardial effusion. Therapeutic measures include bronchoscopic suction of retained secretions and physical measures to reduce secretions. Supplemental oxygen is indicated in hypoxemic patients and in those who derive benefit of it. The nonspecific drug therapy with benzodiazepines and/or opiates remains clinically useful, although its efficacy is questioned by some controlled studies.

The effects of angiotensin converting enzyme inhibition on systemic and coronary hemodynamics and on myocardial lactate metabolism were investigated before and 2 and 6 hours after cilazapril at rest and during supine submaximal exercise in 10 patients with New York Heart Association class II or III chronic congestive heart failure. Angiotensin converting enzyme inhibition, indicated by a significant increase in plasma renin activity, resulted in significant reductions in blood pressure and systemic vascular resistance. Myocardial oxygen demand decreased (resting double product 10.9 +/- 3.7 vs 12.2 +/- 3.8 mm Hg beats/min 10(-3); p less than 0.05), but coronary sinus blood flow remained unchanged and calculated coronary resistance decreased (0.45 vs 0.5 units, rest 6 hours; p less than 0.05) suggesting coronary vasodilatation. Changes in coronary vascular resistance were directly related to changes in systemic vascular resistance (r = 0.75, p less than 0.5). Myocardial lactate extraction increased at rest (47 +/- 60 vs 134 +/- 132 mumol/min; p less than 0.5) and during exercise (27 +/- 54 vs 491 +/- 317 mumol/min; p less than 0.05) both in patients with coronary artery disease (n = 5) and idiopathic dilated cardiomyopathy (n = 5). Resting lactate production was converted to lactate extraction in two patients with coronary artery disease. Neither plasma catecholamine nor atrial natriuretic peptide concentrations changed significantly. The results suggest coronary vasodilation and improved aerobic myocardial metabolism by angiotensin converting enzyme inhibition in patients with congestive heart failure.

The symptoms of adult respiratory distress syndrome (ARDS) include dyspnea, tachypnea, hypoxemia refractory to supplemental oxygen and bilateral infiltrations in the chest X-ray. Neutrophils are implicated in the pathogenesis as important effector cells acting by release of mediators. Activation of the complement system has been shown in several studies and can induce lung damage directly in animal models. Proteases and collagenase have been found in elevated concentration in bronchoalveolar lavage fluid, while the amount of protease-inhibitors has been found to be reduced. Arachidonic acid metabolites of the cyclooxygenase and lipoxygenase pathway, such as prostaglandins and leukotrienes, may play a role in the pathogenesis or perpetuation of the disease process. The same holds true for cytokines such as interleukin-1 or tumor necrosis factor. All of them have been found to be elevated either in plasma or bronchoalveolar lavage fluid of ARDS patients. Several lines of evidence implicate oxygen radicals as important mediators of lung damage in ARDS. The therapeutic implications of these new insights into the pathogenesis of ARDS are briefly discussed.

Inoperable tracheobronchial stenoses are most often due to malignant disease. Apart from systemic therapy, various local treatment modalities such as laser resection, cryotherapy and endobronchial radiation therapy have been designed to maintain airway patency. Recently, various models of tracheobronchial stents (or endoprostheses) have been designed to maintain airway patency. They prevent recurring endobronchial tumor growth or progressive extrinsic compression of dilated airways. Silicone stents are highly suitable for this purpose. We treated 12 patients (11 males, 1 female, median age 68,5 years) suffering from bronchial carcinoma (6), esophageal carcinoma (4), metastatic colon carcinoma (1) and metastatic osteosarcoma (1). One stent per patient was inserted at the following sites: 6 in the right main bronchus, 4 in the trachea, 1 in the left main bronchus and 1 tracheobronchial left. We observed 2 complications: one obstruction of a bronchial stent by secretions which could be managed by fiberbronchoscopy and one short fire to a bronchial stent on repeat laser therapy. Rapid and lasting relief of dyspnea was observed in all patients. Our initial experience with a median follow-up of 2 months confirmed the easy insertion technique, the excellent effect and tolerance as well as the simple postoperative care of these silicone stents. Their use immediately after relief of a tracheobronchial obstruction by local means can be recommended.

To determine if activation of the glucocorticoid receptor involves covalent charge modification of the steroid-binding protein, unactivated and activated IM-9 cell glucocorticoid receptors were examined by high resolution two-dimensional gel electrophoresis. As previously reported (Smith, A. C., and Harmon, J. M. (1985) Biochemistry 24, 4946-4951), two-dimensional electrophoresis of immunopurified, [3H]dexamethasone mesylate-labeled, steroid-binding protein from unactivated receptors resolves two 92-kDa isoforms (pI congruent to 5.7 and 6.0-6.5). After activation, the apparent pI of neither isoform was altered, indicating that there had been no covalent charge modification of the steroid-binding protein. Thus, the physicochemical changes observed after activation of the steroid receptor cannot be explained by dephosphorylation or other models which involve covalent charge modification of the steroid-binding protein. This conclusion was consistent with the observation that treatment of immunopurified, affinity-labeled receptors with calf intestine alkaline phosphatase did not alter the apparent pI values or distribution of the steroid-binding protein isoforms. However, chromatography of activated steroid-receptor complexes on DNA-cellulose revealed that only the more basic of the two steroid-binding protein isoforms bound to DNA. Therefore, the charge heterogeneity of the steroid-binding protein may be important in regulating the ability of the steroid-binding protein to interact with DNA.

The relationship between glucocorticoid receptor subunit dissociation and activation was investigated by DEAE-cellulose and DNA-cellulose chromatography of monomeric and multimeric [3H]triamcinolone acetonide ([3H]TA)-labeled IM-9 cell glucocorticoid receptors. Multimeric (7–8 nm) and monomeric (5–6 nm) complexes were isolated by Sephacryl S-300 chromatography. Multimeric complexes did not bind to DNA-cellulose and eluted from DEAE-cellulose at a salt concentration (0.2 M KCl) characteristic of unactivated steroid-receptor complexes. Monomeric [3H]TA-receptor complexes eluted from DEAE-cellulose at a salt concentration (20 mM KCl) characteristic of activated steroid-receptor complexes. However, only half of these complexes bound to DNA-cellulose. This proportion could not be increased by heat treatment, addition of bovine serum albumin, or incubation with RNase A. Incubation of monomeric complexes with heat inactivated cytosol resulted in a 2-fold increase in DNA-cellulose binding. Unlike receptor dissociation, this increase was not inhibited by the presence of sodium molybdate. Fractionation of heat inactivated cytosol by Sephadex G-25 chromatography demonstrated that the activity responsible for the increased DNA binding of monomeric [3H]TA-receptor complexes was macromolecular. These results are consistent with a two-step model for glucocorticoid receptor activation, in which subunit dissociation is a necessary but insufficient condition for complete activation. They also indicate that conversion of the steroid-receptor complex to the low-salt eluting form is a reflection of receptor dissociation but not necessarily acquisition of DNA-binding activity.

Regulation of glucocorticoid receptor (GR) protein and mRNA were examined in the human leukemic T-cell line CEM-C7. Unlike other cells in which GR regulation has been examined, the growth of these cells is inhibited by glucocorticoids, leading to cell death. Treatment of glucocorticoid-sensitive CEM-C7 cells with 1 microM dexamethasone for 18 h resulted in an increase in both cytoplasmic and nuclear GR protein, as determined by immunoblotting with anti-human GR antisera. Analysis of GR mRNA levels by Northern blotting revealed a corresponding increase in mRNA in steroid-treated cells. An increase in GR mRNA was detectable after as little as 3 h of treatment with dexamethasone, and GR mRNA concentration continued to increase for at least 18 h, well before the onset of growth arrest or cell death. GR mRNA concentration was not altered after dexamethasone treatment of the glucocorticoid-resistant mutant cell line ICR27TK.3, which lacks functional GR. Thus, the increase in GR seen in glucocorticoid-sensitive cells is a GR-mediated response. These results are in sharp contrast to the down-regulation of GR reported in other cells and tissues, and suggest that regulation of the GR by its cognate ligand may be tissue-specific.

A 71-year-old man with a long-standing history of rheumatoid arthritis required methotrexate treatment since 1986, with a total dose of 210 mg. In April 1987, before arthroplastic surgery, methotrexate was discontinued. Four weeks later a syndrome of fever, dry cough, shortness of breath, and diffuse air-space consolidations on the chest radiograph evolved. An antibiotic therapy had no beneficial effect, and a bronchoscopy yielded no pathogens. An open lung biopsy led to the diagnosis of methotrexate-induced pneumonitis. This is the first report of a case where methotrexate-induced pneumonitis developed several weeks after cessation of the treatment. Methotrexate can cause four types of pulmonary adverse reactions: pneumonitis, pulmonary edema, pulmonary fibrosis, and pleuritis. Possible pathogenetic mechanisms, symptoms, treatment, and prognosis are discussed.

In addition to the benzodiazepine antagonism we report, as a first observation, the effect of flumazenil on carbamazepine intoxication, where a mechanism other than benzodiazepine receptor antagonism must be supposed.

Regulation of glucocorticoid receptor (GR) protein and mRNA were examined in the human leukemic T-cell line CEM-C7. Unlike other cells in which GR regulation has been examined, the growth of these cells is inhibited by glucocorticoids, leading to cell death. Treatment of glucocorticoid-sensitive CEM-C7 cells with 1 microM dexamethasone for 18 h resulted in an increase in both cytoplasmic and nuclear GR protein, as determined by immunoblotting with anti-human GR antisera. Analysis of GR mRNA levels by Northern blotting revealed a corresponding increase in mRNA in steroid-treated cells. An increase in GR mRNA was detectable after as little as 3 h of treatment with dexamethasone, and GR mRNA concentration continued to increase for at least 18 h, well before the onset of growth arrest or cell death. GR mRNA concentration was not altered after dexamethasone treatment of the glucocorticoid-resistant mutant cell line ICR27TK.3, which lacks functional GR. Thus, the increase in GR seen in glucocorticoid-sensitive cells is a GR-mediated response. These results are in sharp contrast to the down-regulation of GR reported in other cells and tissues, and suggest that regulation of the GR by its cognate ligand may be tissue-specific.

Modern radiologic methods for assessment of parenchymal lung diseases are reviewed, with special reference to computed tomography (CT). In bronchogenic carcinoma and lung metastases CT is part of the initial workup, while in parenchymal lung diseases, emphysema and pulmonary infections CT should be used only for special indications. At present magnetic resonance imaging is inferior to CT in evaluating parenchymal lung diseases.

About half of patients with acquired immune deficiency syndrome (AIDS) have an associated pulmonary disease which is more often due to infections than to tumors. Rapid diagnosis is important, especially in Pneumocystis carinii pneumonia, since the prognosis depends on early treatment. A patient in good condition may be managed on an ambulatory basis. The manifestations of tuberculosis are often atypical, i.e. noncavitating with a diffuse infiltrate, hilar adenopathy and extrapulmonary foci. Treatment of atypical mycobacteria is not clearly effective and empirical treatment has little point since the resistance pattern is unpredictable.

Most solitary pulmonary nodules are detected by chance on routine chest radiography in asymptomatic individuals. Diagnostic evaluation is necessary unless the nodule's size and shape has remained unchanged for at least 2 years, as documented on earlier x-rays. Radiographic techniques alone are insufficient in evaluating the nodule's malignity. For this purpose invasive diagnostic procedures (transthoracic biopsy, bronchoscopy) are mandatory. If these fail to establish a definite diagnosis, thoracotomy may be performed.

The possible role of posttranslational modification in glucocorticoid receptor regulation was investigated. Glucocorticoid receptor (GR), prepared from the human B-cell line IM-9 and affinity labeled with [3H]-dexamethasone 21-mesylate, was examined by a combination of one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high-resolution two-dimensional gel electrophoresis. Two-dimensional electrophoresis of immunopurified [3H]dexamethasone 21-mesylate-labeled GR revealed the presence of two isoelectric species (apparent pI approximately to 5.7, and 6.0-6.5). Both forms were present in preparations of unactivated receptor. After GR activation, the pI of neither isoform was altered, indicating that activation does not involve covalent charge modification of the steroid-binding protein. However, only the pI 6.0-6.5 isoform bound to DNA, suggesting that covalent charge modification of the GR can alter its ability to bind to DNA. Two-dimensional electrophoresis of tryptic and chymotryptic fragments showed that the charge heterogeneity responsible for the two GR isoforms is located in a Mr 26,500 tryptic fragment derived from the steroid-binding domain of the protein. In addition, analysis of [3H]dexamethasone 21-mesylate-labeled tryptic fragments suggests that the Mr 26,500 fragment corresponds to residues 499-743 of the human GR. These results demonstrate that posttranslational modification of the steroid-binding domain may regulate the ability of the protein to bind to DNA.

The etiology of radiologic signs of circumscript parenchymatous lesions is multivarious. In some instances infarction of the lung has to be distinguished from pneumonia. The differential diagnosis has important therapeutic consequences for the patient. An important criterion for primary pneumonic infiltration is Xe-trapping within the area lacking perfusion, which can only be demonstrated by perfusion scintigraphy with Xe-133-NaCl. However, infarction of the lung lacks this pathologic feature. Pathophysiologically the various changes may occur as the result of obstruction of the vessel i.e. due to alveolar hypoxia and embolism. In order to improve the diagnostic methods a combination of perfusion scintigraphy using Xe-133-NaCl and Tc-99-macroaggregate and ventilation scintigraphy with Xe-127 was employed. We retrospectively evaluated 20 patients with the nuclear medical diagnosis of either pneumonia (n = 10) or infarction of the lung (n = 10). The following criteria were adopted: history, risk factors, X-ray of the chest, blood chemistry, ECG, phlebography, pulmonary angiography and histopathological diagnosis, as well as the course of the disease. According to our results the specificity of the scintigraphic diagnosis of pneumonia and infarction of the lung was 90%. However these results will have to be verified in a prospective study using pulmonary angiography as the reference method.

The molecular basis for the loss of steroid binding activity in receptorless (r-) glucocorticoid-resistant (dexr) mutants isolated from the glucocorticoid-sensitive (dexs) cell line CEM-C7 was investigated. Although there was little binding of the reversibly associating ligand [3H]dexamethasone in r- mutants, labeling with the covalent affinity ligand [3H] dexamethasone 21-mesylate revealed significant amounts of a 92 kilodalton human glucocorticoid receptor (hGR) protein. Immunoblots of hGR protein in r- and normal cells showed that r- mutants expressed approximately half the amount of immunoreactive hGR protein seen in dexs cells. Comparison of the genomic organization of the hGR genes in normal and mutant cells revealed no discernable differences in the structure, or dosage, indicating that the r- phenotype was not the result of gross deletion or rearrangement of the hGR genes. In addition, r- cells expressed the same 7 kilobase mRNA as normal cells. More importantly, the amount of hGR mRNA expressed in r- cells was never significantly less, and in some cases was greater than, that seen in normal cells, indicating that the decrease in immunoreactive hGR protein seen in r- cells is not the result of loss of hGR mRNA expression. Taken together with the known mutation rate of the hGR gene(s) in these cells, these results suggest that the hGR genes in dexs CEM-C7 cells are allelic and that dexs cells express both a normal hGR protein and one with an altered steroid binding site. Furthermore, they suggest that the r- phenotype is acquired as the result of mutation within the coding region of the originally functional allele, leading to loss of ligand binding and expression of immunoreactive product.