The forced expiratory volume-time curve estimation using the electrocardiogram.

The feasibility of estimating the forced expiratory volume-time curve from the amplitude modulation of the electrocardiogram was studied using a numerical torso model and ECG signal processing. A two dimensional numerical model of the torso was solved for the maximum expiration and inspiration to study the changes in the surface potential as a result of changes in the lung volume. The numerical model showed that significant changes in the surface potential amplitude occur between maximum inspiration and maximum expiration and that this amplitude change in the left-right axis of the torso might be three times as large as in the front-back axis. In the experimental setup, ECG waveforms from the surface of the chest and the mouth air flow were simultaneously recorded from four male subjects during several forced vital capacity (FVC) maneuvers. The amplitude of the QRS complex was measured for different expired lung volumes and an estimation of the forced expiratory volume-time curve was obtained. The FVC and the FEV1 (forced expiratory volume after 1 s) spirometry indices were calculated for the two volume-time curves obtained from the electrocardiogram and from the spirometry measurements. The results differ between 0.1 and 0.8 1. These preliminary results are encouraging and might indicate that a relationship between the volume-time curve during FVC test and the electrocardiogram signals does exist. Further validation in a larger number of subjects and patients is needed before the technique can be applicable for clinical use.

Telespirometry: novel system for home monitoring of asthmatic patients.

OBJECTIVES: To describe a newly developed telespirometry system consisting of a portable spirometer that transmits the lung ventilatory values by telephone from the patient's home to a remote monitoring center and to assess the ability of the telespirometry system to detect early signs of asthmatic deterioration. METHODS: Thirty-nine patients with moderate to severe asthma were monitored with the telespirometry system. The lung function testing and transmission of the spirometric data by telephone from the patient's home to a remote monitoring center were performed according to the patient's judgment. All previous transmissions of the spirometric data were analyzed retrospectively to detect early signs of asthmatic deterioration, which resulted in dispatch of the mobile intensive care unit (MICU) to the patient's home. RESULTS: In 19 patients (49%), analysis of the spirometric data detected early signs of asthmatic deterioration. Analysis of the spirometric data correlated with decisions to dispatch the MICU in 22 of 39 (56%) patients. In patients with severe asthma, the decision was made during oral communication between the patient and the operator and was based on clinical impression rather than functional results. CONCLUSION: Home monitoring of asthmatic patients with the telespirometry system may improve the management of the disease and the quality of life and reduce costly hospitalizations.

The prognostic application of cytokeratin typing of nonsmall cell lung carcinoma. A retrospective study.

BACKGROUND: In a previous study, the authors used a variety of anticytokeratin monoclonal antibodies to show that a large proportion of lung tumors cytologically diagnosed as squamous cell carcinoma contain cells expressing simple epithelial cytokeratins, suggesting that these tumors have their origin in adenocarcinoma. These findings raised the possibility that cytokeratin (CK) typing might have a diagnostic capacity not attainable by standard histopathology. The aim of the current study was to assess the value of CK typing for this purpose by determining the correlation between the diagnosis of lung tumors based on CK typing and the survival rate of the patients. METHODS: Paraffin embedded tissue sections of 66 nonsmall cell lung carcinoma (NSCLC) specimens were examined. These included 18 adenocarcinomas, 32 squamous cell carcinomas, and 16 undifferentiated carcinomas, all diagnosed surgically and histopathologically, and further classified as either Stage I or II. CK typing was performed using the streptavidin-biotin-peroxidase method, employing the following anti-CK monoclonal antibodies: Ks.B.17 (which reacts with CK 18), A3-3 (which reacts with CK 13), and E5-9 (which reacts with CK 10). RESULTS: Comparison between the 5-year survival rates (5 ysr) of patients with different NSCLC indicated that all types of Stage II tumors had a much poorer prognosis than Stage I tumors. Differences found in the 5 ysr among patients with different types of Stage I tumors were not statistically significant (adenocarcinomas, 33% 5 ysr; squamous cell carcinomas, 59% 5 ysr; undifferentiated carcinomas, 36% 5 ysr; all diagnosed by conventional histopathology). Similarly, no significant differences were noted in 5 ysr between patients with tumors stained positively or negatively with monoclonal antibodies A3-3 or E5-9 (anti-CK 13 and anti-CK 10, respectively). In contrast, highly significant differences (P = 0.002) were found in the 5 ysr between patients with Stage I tumors positively or negatively stained with monoclonal antibody Ks.B.17 (23% vs. 75% 5 ysr, respectively) regardless of the histologic types of tumors. Especially informative was a combination of immunohistochemical and histologic diagnoses, with best survival rates (87% 5 ysr) in Ks.B.17 negative tumors histologically diagnosed as Stage I squamous cell carcinomas and worst survival rates (14% 5 ysr) in Ks.B.17 positive tumors diagnosed as adenocarcinomas. CONCLUSIONS: The current study showed that CK 18 typing of lung tumors can provide a more accurate diagnosis and therefore facilitate the planning of more suitable therapeutic approaches.

Assessment of a new transtelephonic portable spirometer.

BACKGROUND: A new portable spirometer, the Spirophone, has been developed that records a subject's blow and can then transmit all the data by telephone to a receiving centre for analysis and comment. Tests of this device were undertaken to determine its accuracy and reliability. METHODS: The performance of the Spirophone was tested using computer generated wave forms, by delivering blows from calibrated syringes at different flows, and by comparing subjects' blows with those recorded with a commercial spirometer. RESULTS: Using computer generated wave forms all lung function indices were accurate to within 1% and blows delivered from calibrating syringes were accurate to within 5%. When subjects performed repeated forced vital capacity (FVC) manoeuvres there were no significant differences between lung function indices recorded with the Spirophone and with a commercial spirometer. With the Spirophone and commercial spirometer in series the FVC and forced expiratory volume in one second (FEV1) were within 5% of each other in nine out of 10 healthy subjects. CONCLUSION: The Spirophone recorded maximal forced expiratory manoeuvres with acceptable accuracy, reliability, and reproducibility, and this system offers the ability to monitor a patient's lung function at a centre remote from the patient.

New model-based indices for maximum expiratory flow-volume curve in patients with chronic obstructive pulmonary disease.

New lung function indices based on a lumped parameter model of the maximal expiratory flow-volume (MEFV) curve are presented. The waveforms obtained by the model were compared to the flow-volume curves recorded from normal subjects and from patients with small airways disease, asthma and emphysema. We were able to reproduce the flow-volume curves using the model and calculate new parameters that indicate the degree of lung function impairment and may be applicable to identify mild chronic obstructive pulmonary diseases. Further studies in larger groups of patients are required to better define the true predictive value of the new indices described for the diagnosis of COPD.

The protective role of the immunomodulator AS101 against chemotherapy-induced alopecia studies on human and animal models.

The immunomodulator AS101 has been demonstrated to exhibit radioprotective and chemoprotective effects in mice. Following phase-I studies, preliminary results from phase-II clinical trials on non-small-cell-lung-cancer patients showed a reduction in the severity of alopecia in patients treated with AS101 in combination with chemotherapy. To further substantiate these findings, the present study was extended to include 58 patients treated either with the optimal dose of 3 mg/m2 AS101 combined with carboplatin and VP-16, or with chemotherapy alone. As compared with patients treated with chemotherapy alone, there was a significant decrease in the level of alopecia in patients receiving the combined therapy. The newly developed rat model was used to elucidate the protective mechanism involved in this effect. We show that significant prevention of chemotherapy-induced alopecia is obtained in rats treated with Ara-C combined with AS101, administered i.p. or s.c. or applied topically to the dorsal skin. We show that this protection by AS101 is mediated by macrophage-derived factors induced by AS101. Protection by AS101 can be ascribed, at least in part, to IL-1, since treatment of rats with IL-1 RA largely abrogated the protective effect of AS101. Moreover, we demonstrate that in humans there is an inverse correlation between the grade of alopecia and the increase in IL-1 alpha. In addition, protection by AS101 could be related to PGE2 secretion, since injection of indomethacin before treatment with AS101 and Ara-C partly abrogated the protective effect of AS101. To assess the ability of AS101 to protect against chemotherapy-induced alopecia, phase-II clinical trials have been initiated with cancer patients suffering from various malignancies.

Bone marrow-sparing and prevention of alopecia by AS101 in non-small-cell lung cancer patients treated with carboplatin and etoposide.

PURPOSE: The aim of this study was to evaluate the ability of the immunomodulator AS101 to prevent chemotherapy-induced neutropenia and thrombocytopenia and thus allow patients to receive full-dose antineoplastic agents according to protocol design. We also aimed to determine the production level of various hematopoietic growth factors in treated patients. PATIENTS AND METHODS: This study of 44 unresectable or metastatic non-small-cell lung cancer (NSCLC) patients was an open-label prospective randomized study of standard chemotherapy alone versus chemotherapy plus AS101. Each patient received carboplatin (300 mg/m2 intravenously [IV] on day 1 of a 28-day cycle, and etoposide (VP-16) (200 mg/m2 orally) on days 3, 5, and 7 of each cycle. AS101 was administered at 3 mg/m2 three times per week starting 2 weeks before chemotherapy. RESULTS: AS101, which manifested no major toxicity, significantly reduced neutropenia and thrombocytopenia and thus allowed all treated patients to receive full-dose antineoplastic agents, in contrast to only 28.5% of the control group. Continuous treatment with AS101 significantly reduced the number of days per patient of thrombocytopenia and neutropenia and did not provide protection to tumor cells as reflected by the higher overall response rate compared with the chemotherapy-alone arm. Interestingly, AS101 treatment also significantly prevented chemotherapy-induced alopecia. These effects correlate with the ability of AS101-treated patients to increase significantly the production of colony-stimulating factors (CSFs) interleukin-1 alpha (IL-1 alpha) and IL-6. CONCLUSION: AS101 has significant bone marrow (BM)-sparing effects and prevents hair loss in chemotherapy-treated patients, with minimal overall toxicity. These effects are probably due to increased production of IL-1 alpha, IL-6, and granulocyte-macrophage (GM)-CSF.

Maximum expiratory flow-volume curve: mathematical model and experimental results.

A mathematical simulation of the maximum expiratory flow-volume (MEFV) curve was developed using a lumped parameter model. The model uses a theoretical approximation of an activation function representing the lung's pressure-volume relationship during maximally forced expiration. The waveforms obtained by the model were compared to the flow-volume curves recorded from normal subjects and for patients with small airways disease, asthma, and emphysema. We were able to reproduce the flow-volume curves using the model and calculate new parameters that reflect the dependency of airways resistance on expired volume during FVS manoeuvre. These new parameters are based on the entire information presented in the flow-volume curve and on the reduction in flow at all lung volumes. We also calculated the mean slope of the resistance-expired volume curves obtained from the model by fitting a straight line to the curve. Using representative data for normal and COPD patients different mean slopes of 0.095, 0.13, 0.49 and 1.44 litre-1 were obtained for normal subject, small airways disease, asthma and emphysema patients, respectively. The model-based parameters may be applicable to human studies. However, further studies in large groups of patients are required to better define the true predictive value of the new indices described for the diagnosis of COPD.

Flow cytometric analysis and cytokeratin typing of human lung tumors. A preliminary study.

In the current study a comparative analysis of keratin typing and DNA content was carried out in human lung tumors from transthoracic fine needle aspiration biopsies (TFNAB) (18 patients) or from surgically resected tumor tissues (14 patients). According to the cytologic and histologic features, 2 of the 32 tumors were diagnosed as benign tumors, 11 as squamous cell carcinomas, 12 as adenocarcinomas, and 7 as undifferentiated large cell carcinomas. Two cases in the adenocarcinoma and one in the undifferentiated large cell carcinoma groups were pulmonary metastasis or second primary tumors. Malignant cells of tumors which reacted positively with KK8.60 anticytokeratin polypeptides No. 10 and 11 (and hence contain keratinizing cells) displayed diploid DNA content in a flow cytometric assay regardless of their cytologic or histologic appearance. In contrast, all tumors which lacked such positive cells (most of which were defined as adenocarcinomas and undifferentiated tumors) were hyperdiploid. The close correlation between high DNA content and both malignancy and the absence of advanced squamous differentiation (keratinization) suggests that such combined analysis may provide new tools for the cytologic diagnosis and prognosis of lung cancers.

[Pulmonary siderosis caused by inhalation of iron dust or fumes].

Pulmonary Siderosis results from inhalation of iron dust or fumes. It falls into the group of pneumoconioses in which the pulmonary reaction is minimal despite a heavy dust load. Since fibrosis is not caused by inhalation of iron dust, the clinical course is benign and pulmonary function tests and blood gases are within normal limits. We report the first case of sideropneumoconiosis from Israel, in a 39-year-old iron welder. Since this condition is still not recognized as an occupational disease in Israel, the aim of this presentation is to bring it to appropriate medical attention.

Endogenous digoxin-like immunoreactive factor is elevated in advanced chronic respiratory failure.

Digoxin-like immunoreactive factor (DLIF) is an endogenous substance with natriuretic and diuretic activity. Elevated plasma levels of DLIF are found in various clinical states characterized by water and sodium retention. Chronic respiratory failure, particularly of an advanced stage, also is frequently associated with water and sodium retention. In order to determine whether elevated plasma levels of DLIF are present in chronic respiratory failure, we measured plasma DLIF levels in seven patients (four with COPD [two of whom had associated sleep apnea disturbance] and three with kyphoscoliosis) suffering from advanced chronic respiratory failure with severe hypoxemia and hypercapnia. We found that in these patients plasma levels of DLIF were significantly higher than in healthy control subjects. We conclude that patients with advanced chronic respiratory failure respond with increased levels of DLIF. This may represent an attempt at homeostasis of water and sodium metabolism which is frequently deranged in this clinical condition.

Immunocytochemical characterization of lung tumors in fine-needle aspiration. The use of cytokeratin monoclonal antibodies for the differential diagnosis of squamous cell carcinoma and adenocarcinoma.

In the current study, immunocytochemical typing of intermediate filaments was used for a differential diagnosis of human lung tumors from transthoracic fine-needle aspiration biopsies (TFNAB). The authors have compared the cytologic diagnosis of 53 lung cancer cases with the immunofluorescence patterns obtained using a panel of monoclonal antibodies, five of which (KG 8.13, KM 4.62, Ks B.17, KS 8.12, KK 8.60) react with specific cytokeratin polypeptides and one with vimentin (VIM 13.2). Only in six of 23 samples cytologically diagnosed as squamous cell carcinoma did the immunocytochemical typing of cytokeratins (ICTC) confirm the cytologic diagnosis. In seven cases some of the tumor cells stained positively with antibody Ks B.17 specific for simple epithelial keratin (No: 18), suggesting the presence of some cells of glandular origin. In ten additional cases the ICTC was in conflict with the cytologic diagnosis of squamous cell carcinoma (i.e., antibodies Ks 8.12 and KK 8.60 were negative, and antibody Ks B.17, positive) supporting a diagnosis of adenocarcinoma. In 14 of 18 cases cytologically diagnosed as adenocarcinoma, the ICTC confirmed the diagnosis whereas in four cases additional presence of some squamous cells was noticed. The ICTC labeling of cases cytologically diagnosed as undifferentiated and large cell carcinomas was similar to that of the group of adenocarcinomas. Thus, the application of cytokeratin typing for TFNAB samples seems to provide a vital complementation to routine cytologic study, especially for cases cytologically diagnosed as squamous carcinoma.

Bronchial response to methacholine in "healthy" children of asthmatic parents. Effect of treatment with cromolyn sodium.

Cumulative dose response curves to inhaled methacholine were established in 24 "healthy" children of asthmatic parents and 7 healthy children of healthy parents. Atopic children of asthmatic parents demonstrated higher bronchial hyperreactivity (BHR) than nonatopic children. The BHR was about ten times less than in the atopic parents of asthmatic children, indicating marked increase in BHR with age in atopic members of asthmatic families. Six weeks of treatment with cromolyn sodium (disodium cromoglycate) decreased BHR significantly (p less than 0.05) in eight atopic children, while no change occurred in BHR in five nonatopic children.

Long-term survival of patients with chronic obstructive pulmonary disease following mechanical ventilation.

Fifty patients with chronic obstructive pulmonary disease (COPD) who survived their first artificial ventilation were followed for 15 years. Five-year survival was 30%, median survival 23.5 months, and average survival 44.9 months. Sudden death occurred in 47% of the patients (40% at home and 7% in the hospital). Using multivariate analysis, survival correlated positively and significantly with partial pressure of arterial oxygen (PaO2) on discharge (P less than 0.02), presence of wheezes or rhonchi (P less than 0.02), absence of right heart failure on admission (P less than 0.02), and male sex (P less than 0.05), and negatively with age (P less than 0.03). Sixty percent of the patients were artificially ventilated at least twice. Prognosis was better as the number of ventilations increased after the first ventilation. Our finding that discharge PaO2 was the factor that correlated best with survival suggests that treatment for these patients consist of continuous long-term use of domiciliary oxygen.

Nedocromil sodium and placebo in the treatment of bronchial asthma. A multicenter, double-blind, parallel-group comparison.

The efficacy of nedocromil sodium (4 mg twice daily by inhalation) in treating bronchial asthma was assessed by double-blind, placebo-controlled group comparison in 69 adults from three centers. The patients (34 active, 35 placebo) had a history of bronchial asthma with at least 15 percent reversibility. Inhaled corticosteroids, used by 22 and 24 subjects in the active and placebo groups respectively, were discontinued before the study, in which a two-week baseline was followed by six weeks of treatment. Two-weekly clinic assessments of lung function, symptoms and final opinions of treatment were significantly (p less than 0.05 p less than 0.001) in favor of nedocromil sodium. Daily diary cards showed a similar trend with significant drug effects seen after the third week. Blood and urine samples showed no abnormalities and the majority of patient withdrawals (five from nedocromil sodium and six from placebo treatment) were due to worsening asthma. Overall, we found nedocromil sodium to be well tolerated and effective in the management of bronchial asthma.

Effects of occupational exposure and smoking on respiratory symptomatology and PFT in healthy panelists and COPD patients.

A panel of 377 healthy adults and 920 COPD patients aged 30-65 years, is annually interviewed (ATS-NHLI health questionnaire) and performs pulmonary function test (PFT), which includes: FVC, FEV1, FEV1/FVC, PEF, FEF50 and FEF75. Baseline data analysis showed a more significant excess in respiratory symptoms (8.8% to 21.4%) and lower PFT (2.4% to 8.0%) among patients occupationally exposed to dust, than among healthy exposed panelists (-0.7% to 7.7% excess symptomatology and -0.3 to 5.8% lower PFT). Among patients a significant correlation between PFT and degree of occupational dust exposure was found. Significantly lower FEV1/FVC and excess in respiratory symptoms (with relative risks of 2.47-16.38) was present in healthy smokers vs. non smokers as compared with COPD patients.

Increased incidence of pulmonary tuberculosis in chronic interstitial lung disease.

Of 162 patients with chronic interstitial lung disease, eight (seven of them male) had active tuberculosis. This was 4.5 times higher than the incidence in the general population. The frequency of tuberculosis was similar in patients treated with and without corticosteroids.