Abstract: A 65 year old male, presented with ophthalmoplegia and reduced vision in his left eye. The magnetic resonance imaging (MRI) of the brain revealed three hyperintensity areas located in the left parasellar area, left lacrimal gland and right frontal bone. Chest CT revealed bilateral pulmonary masses. The pathological diagnosis was necrotizing granuloma and vasculitis. Nine months after the diagnosis, the right eye was involved. This case report presents a rare manifestation of blinding necrotizing sarcoid granulomatosis that had responded to steroid therapy, but had a relapsing clinical course.
Abstract: ABSTRACT: background: Lung cancer is the commonest cause of cancer death in developed countries. Adenocarcinoma is becoming the most common form of lung cancer. Cigarette smoking is the main risk factor for lung cancer. Long-term cigarettes smoking may be characterized by genetic alteration and diffuse injury of the airways surface, named field cancerization, while cancer in non-smokers is usually clonally derived. Detecting specific genes expression changes in non-cancerous lung in smokers with adenocarcinoma may give us instrument for predicting smokers who are going to develop this malignancy. Objectives: We described the gene expression in non-cancerous lungs from 21 smoker patients with lung adenocarcinoma and compare it to gene expression in non-cancerous lung tissue from 10 non-smokers with primary lung adenocarcinoma. METHODS: Total RNA was isolated from peripheral non-cancerous lung tissue. The cDNA was hybridized to the U133A GeneChip array. Hierarchical clustering analysis on genes obtained from smokers and non-smokers, after subtracting were exported to the Ingenuity Pathway Analysis software for further analysis. RESULTS: The genes subtraction resulted in disclosure of 36 genes with high score. They were subsequently mapped and sorted based on location, cellular components, and biochemical activity. The gene functional analysis disclosed 20 genes, which are involved in cancer process (P = 7.05E-5 to 2.92E-2). CONCLUSIONS: Detected genes may serve as a predictor for smokers who may be at high risk of developing lung cancer. In addition, since these genes originating from non-cancerous lung, which is the major area of the lungs, a sample from an induced sputum may represent it.
Abstract: BACKGROUND: A large solitary fibrous tumour of the pleura (SFTP) is a very rare occurrence. The aim of this study was to retrospectively review the clinical characteristics, surgical treatment and outcome of patients with a large SFTP operated on in our General Thoracic Surgery Unit. METHODS: We conducted a retrospective analysis of the clinical records of six patients who underwent surgery for a huge SFTP between 1998 and 2004. RESULTS: Six patients (four men and two women, mean age 73.3 years) with a large SFTP (mean diameter 20.3 and mean weight 1265 g) underwent surgery during this period with full excision of the tumour. Five tumours were excised together with the implantation basis, and in one case extended resection with pneumonectomy was performed. The presentation symptoms resolved in all cases after surgery. CONCLUSIONS: Despite the huge size of these tumours (giant SFTP), surgical resection is an acceptable method of treatment in elderly patients with low morbidity and mortality rates.
Abstract: BACKGROUND: Chronic obstructive pulmonary disease is an increasing cause of chronic morbidity and mortality around the world. The major cause of the disease is smoking. Despite the gravity of the problem there is no knowledge of its rate in the Israeli smoking population. OBJECTIVES: To assess the prevalence of COPD and early lung cancer among smokers. METHODS: People aged 45 up to 75 with a history of at least 20 pack-years cigarette smoking, including quitters, were screened for COPD. They were interviewed and a spirometry was performed. RESULTS: Of the 1150 people recruited 92% underwent and performed acceptable spirometry; 22% of these subjects had airflow limitation and were diagnosed with COPD according to the GOLD classification. Only 4% had been diagnosed as COPD prior to this screening. The majority of those tested were unaware of or unconcerned about developing the disease. There was no correlation between pack-years smoking and development of COPD, but there was a relative correlation of pack-years smoking and severity of COPD, particularly in the older group (r = 0.42). CONCLUSIONS: About one-fifth of the smokers aged 45 and up developed COPD. There is a significant gap between the disease distribution and its awareness in the population at risk. The need for a national screening program and early diagnosis of COPD in people at risk is needed.
Abstract: We used oligonucleotide microarrays with probe sets to 22,283 genes to analyze the gene expression profile of lung adenocarcinoma. Cancerous and noncancerous tissue samples were obtained from 23 patients with stage I or II lung cancer; 18 tissue pairs and 5 cancerous tissues. A list of 2065 genes that differentiate between cancerous and noncancerous tissues was generated using Winsorized paired t-tests. We analyzed CDK5RAP3 and CCNB2, which are involved in cell cycle progression, and RAGE. The first 2 of these 3 genes proved to be overexpressed in tumor tissue, whereas the RAGE gene was suppressed in tumor tissue. When CDK5RAP3 and CCNB2 were examined in individual patients we found that in cases where one of these genes was only slightly overexpressed the other was highly overexpressed. The combined expression of the 2 cell cycle genes was found to be statistically significant for differentiating between cancerous and noncancerous tissues. Inclusion of the data for the RAGE gene made the differentiation more powerful. The gene expression ratio gave a clear result: when CDK5RAP3 was expressed more than RAGE, the tissue was carcinomatous, and vice versa. We therefore conclude that these 3 genes may be used as a very reliable biomarker of lung adenocarcinoma.
Abstract: STUDY OBJECTIVE: Noninvasive ventilation has been shown to be effective in patients with acute respiratory failure due to pulmonary edema and exacerbations of COPD. Its role in an acute asthmatic attack, however, is uncertain. The purpose of this pilot study was to compare conventional asthma treatment with nasal bilevel pressure ventilation (BPV) [BiPAP; Respironics; Murrysville, PA] plus conventional treatment in patients with a severe asthmatic attack admitted to the emergency department. DESIGN: A prospective, randomized, placebo-controlled study. SETTING: An emergency department at a university hospital. PATIENTS: Thirty patients with a severe asthma attack were recruited from a larger group of 124 asthmatic patients seen in the emergency department. Fifteen patients were randomly assigned to BPV plus conventional therapy and 15 patients to conventional therapy alone. The two groups had similar clinical characteristics on hospital admission. Mean (+/- SD) FEV(1) on recruitment was 37.3 +/- 10.7% in the BPV group and 33.8 +/- 10.2% in the control group (p = not significant). Interventions and measurements: BPV with predetermined inspiratory and expiratory pressures was applied for 3 h in the BPV group; in the control group, a similar sham device with subtherapeutic pressures was applied for 3 h. Bedside lung function test results and vital signs were obtained at baseline, and during and at the completion of the study protocol. RESULTS: The use of BPV significantly improved lung function test results. Eighty percents of the patients in the BPV group reached the predetermined primary end points (an increase of at least 50% in FEV(1) as compared to baseline), vs 20% of control patients (p < 0.004). Mean rise in FEV(1) was 53.5 +/- 23.4% in the BPV group and 28.5 +/- 22.6% in the conventional treatment group (p = 0.006). The intention-to-treat analysis of the secondary end point rate of hospitalization included 33 patients. Hospitalization was required for 3 of 17 patients (17.6%) in the BPV group, as compared with 10 of 16 patients (62.5%) in the control group (p = 0.0134). CONCLUSION: In selected patients with a severe asthma attack, the addition of BPV to conventional treatment can improve lung function, alleviate the attack faster, and significantly reduce the need for hospitalization.
Abstract: OBJECTIVE: To determine the feasibility, safety and efficacy of bilevel positive airway ventilation (BiPAP) in the treatment of severe pulmonary edema compared to high dose nitrate therapy. BACKGROUND: Although noninvasive ventilation is increasingly used in the treatment of pulmonary edema, its efficacy has not been compared prospectively with newer treatment modalities. METHODS: We enrolled 40 consecutive patients with severe pulmonary edema (oxygen saturation <90% on room air prior to treatment). All patients received oxygen at a rate of 10 liter/min, intravenous (IV) furosemide 80 mg and IV morphine 3 mg. Thereafter patients were randomly allocated to receive 1) repeated boluses of IV isosorbide-dinitrate (ISDN) 4 mg every 4 min (n = 20), and 2) BiPAP ventilation and standard dose nitrate therapy (n = 20). Treatment was administered until oxygen saturation increased above 96% or systolic blood pressure decreased to below 110 mm Hg or by more than 30%. Patients whose conditions deteriorated despite therapy were intubated and mechanically ventilated. All treatment was delivered by mobile intensive care units prior to hospital arrival. RESULTS: Patients treated by BiPAP had significantly more adverse events. Two BiPAP treated patients died versus zero in the high dose ISDN group. Sixteen BiPAP treated patients (80%) required intubation and mechanical ventilation compared to four (20%) in the high dose ISDN group (p = 0.0004). Myocardial infarction (MI) occurred in 11 (55%) and 2 (10%) patients, respectively (p = 0.006). The combined primary end point (death, mechanical ventilation or MI) was observed in 17 (85%) versus 5 (25%) patients, respectively (p = 0.0003). After 1 h of treatment, oxygen saturation increased to 96 +/- 4% in the high dose ISDN group as compared to 89 +/- 7% in the BiPAP group (p = 0.017). Due to the significant deterioration observed in patients enrolled in the BiPAP arm, the study was prematurely terminated by the safety committee. CONCLUSIONS: High dose ISDN is safer and better than BiPAP ventilation combined with conventional therapy in patients with severe pulmonary edema.
Abstract: T-cell types are important in maintaining immune homeostasis in the lung and their imbalance may be associated with several diseases. We examined the relationship between bronchoalveolar lavage (BAL) T-cell subset profiles and the clinical course of 46 patients with idiopathic pulmonary fibrosis (IPF). A flow cytometry cell sorter (FACS) was used to analyse the T-cell subsets. Pulmonary function tests (PFT) were performed at baseline and 6-12 months later. Patients were divided into two groups according to their CD4/CD8 ratio: CD4/CD8 >1 (group 1, n=21); and CD4/CD8 <1 (group 2, n=25). A lower percentage of lymphocytes, a higher percentage of CD8/S6F1 cells (cytotoxic T-lymphocytes) and a higher percentage of neutrophils were found in the BAL in group 2 compared to group 1 (11+/-7.5% versus 19+/-13.2%; p=0.024 and 29.8+/-17.6% versus 13.3+/-6.9%; p=0.068, respectively for lymphocytes and cytotoxic T-lymphocytes; and 8+/-11% versus 29+/-27%; p=0.003 for neutrophils). Inversely, in the peripheral blood, the distribution of CD8/S6F1 cells was lower in group 1 than in group 2 (8.3+/-6.9% versus 33.4+/-16.5%; p=0.0048). The patients were followed over a period of 1 yr in order to test whether those findings could determine efficacy of therapy. The baseline transfer factor of the lung for carbon monoxide (TL,CO) capacity in group 1 and group 2 was 59+/-22% and 51+/-21%, respectively (p=0.29), but only in group 1 was the TL,CO capacity improved significantly in response to steroids treatment after 6-12 months. IPF patients with a higher percentage of lymphocytes, a lower percentage of neutrophils, CD4/CD8 >1 and a low percentage of CD8/S6F1 may have a more benign course of disease. These parameters may identify an early stage of reversible disease responsive to therapy. We conclude that these measurements may be a useful tool in monitoring response to treatment in patients with idiopathic pulmonary fibrosis.
Abstract: BACKGROUND: One of the enigmas in asthma is that our improved understanding of the pathophysiology and the introduction of new modalities to treat asthma has not led to a parallel decrease in asthma mortality. On the contrary, morbidity and mortality from asthma have increased since the mid-seventies in most of the western countries. This trend of increased asthma mortality rate was not observed in Israel in a survey that examined the changes in asthma mortality rate in Israel during 1960-1986. A small but statistically insignificant increase in asthma mortality rate during the last years of that survey solicited for reexamination and extension of the survey. OBJECTIVES: The purpose of the present study was to evaluate the changes in the asthma mortality rate in Israel during the years 1971-1990. METHODS: We extracted the statistical data on asthma mortality rate in Israel during the 1971-1990 period. Because of the small numbers each year and the variations in asthma mortality rate between years, the data were analyzed after grouping the asthma mortality rate into 5-year periods. RESULTS: The rates, expressed as deaths per 100,000 population per year, were 0.43, 0.18, 0.39, and 0.40 in the 5- to 34-year-old group for the periods 1971-1975. 1976-1980, 1981-1985, and 1986-1990, respectively. We found a statistically significant increase in asthma mortality rate during the 1981-1985 and 1986-1990 periods as compared with 1975-1980 in the young (<34 years old) population. The increase in asthma mortality rate was greater among males. The mortality rate in the older population (35-64 year olds) decreased during 1976-80 as compared with 1971-1975 but did not change thereafter. The rates were 10.4, 4.8, 4.5, and 4.4 cases per 100,000 for 1971-1975, 1976-80, 1981-85, and 1986-90, respectively. CONCLUSIONS: Asthma mortality rate increased in Israel in the young age group (5-34 years) during 1980-1990. This is similar to reports from many other countries with advanced medical care systems. The decrease of asthma mortality rate in 1976-80 probably reflect the general improvement in medical care in Israel during these years.
Abstract: IL-13, like IL-4, a product of activated T cells, has multiple biological actions, primarily on B cells and monocytes. The purpose of the present study was to compare the effects of IL-13 with those of IL-4 on the synthesis of complement proteins in fibroblasts. Dermal fibroblasts were developed from skin biopsies. Confluent monolayers were stimulated with the relevant cytokine or combinations of cytokines and biosynthetically labelled with 35S-methionine. The specific proteins were analysed using immunoprecipitation and SDS-PAGE. Addition of IL-13 to fibroblast cultures treated with TNF-alpha resulted in a dose-dependent increase in C3 protein biosynthesis and a concomitant down-regulation of factor B protein biosynthesis. In TNF-stimulated fibroblasts, the addition of IL-13, 100 ng/ml, induced a 2.45-fold increase in the synthesis of C3, while in the same cells under identical conditions the synthesis of factor B was only 42% of the level without IL-13. Similar effects of IL-13 were noted on IL-1-treated fibroblasts. These effects were specific for C3 and factor B, and no alteration of the constitutive or TNF-induced synthesis of C1s or C1 inhibitor proteins was observed. IL-13 altered the synthesis of C3 and factor B proteins also in fibroblasts stimulated with interferon-gamma (IFN-gamma) in addition to TNF, in the same direction as it did in cells stimulated with TNF alone. IL-13 has similar effects to those of IL-4 on the synthesis of C and factor B in TNF- and IL-1-stimulated fibroblasts. The observed effects of IL-13 are IL-4-independent, as anti-IL-4 antibody abrogates IL-4-induced effects, but has no effect on IL-13-induced responses. This interaction between different cytokines on the synthesis of proinflammatory and immunoregulatory proteins may have significance, particularly at local sites of inflammation, and may affect the synthesis of complement proteins in inflamed joint as in rheumatoid arthritis.
Abstract: A nonsmoker drill polisher with interstitial lung disease is presented. The environmental exposure was mainly to aluminum oxide, aluminum silicate, and hard metals. Bronchoalveolar lavage revealed high eosinophilia, and transbronchial biopsy specimen disclosed interstitial pneumonia with giant cell infiltrates and peribronchiolar accumulation of macrophages laden with opaque dust. Mineralogic studies done from the tissue revealed a high concentration of exogenous particles that were identified as hard metals and aluminum silicate. These findings are compatible with hard metal pneumoconiosis.
Abstract: We examined the effect of quinacrine, an anti-malarial drug which inhibits phospholipase A2, on phorbol myristate acetate (PMA) stimulated alveolar macrophage oxygen radical secretion. This drug suppressed 30% of radicals release, which was 70% of the amount inhibited by superoxide dismutase, a specific inhibitor of oxygen radicals. In addition, this reduction was at the same magnitude as dexamethasone. This and previous results on other inflammatory cells support the assumption that quinacrine may have a beneficial effect on bronchial asthma.
Abstract: A 22 year old male was admitted with haemoptysis. A chest X-ray showed bilateral confluent alveolar infiltrates. Bronchoscopy revealed blood oozing from all bronchopulmonary segments. Open lung biopsy disclosed bilateral effusions and large necrotizing nodules with pleural adhesions. Histological examination showed tumour cells, which were negative to epithelial and embryogenic markers but positive to factor VIII. This confirmed the diagnosis of an epithelioid haemangioendothelioma. This rare tumour, usually has an indolent course, whereas in our case it was complicated by alveolar and intrapleural bleeding.
Abstract: The expression of class II molecules (Ia) of the major histocompatibility complex by isolated alveolar macrophages (AM) and alveolar type II cells from the lungs of rats with bleomycin-induced pulmonary fibrosis was examined. The percentage of Ia-positive AM and type II cells from rats treated with bleomycin as detected by flow cytometry was increased three times and two times, respectively, over the values obtained from control rats. The relative density of Ia expression, determined with a radioimmunoassay technique, showed a 50% increase in Ia density on AM and a 35% increase on type II cells. Recombinant interferon-gamma increased the expression of Ia on type II cells in vitro by 35% to the level obtained on type II cells in bleomycin-induced lung disease. We conclude that the increase of Ia expression on cells of the immune system and on pulmonary epithelial cells may have an important role in the initiation and/or amplification of inflammatory reactions in the lung and may contribute to the development of pulmonary fibrosis.
Abstract: Pressure-volume (P-V) curves and total lung capacity (TLC) were measured in excised lung of mice using a water manometer and a closed system in which the humidity and temperature were controlled. In pathogen-free mice there are no significant differences in elastic properties of these lungs in relation to their age. The measured TLC in those normal mice was approximately 2.9 ml. This relatively simple apparatus which allows one to make sensitive and accurate measurements of pulmonary function in mice and other small animals.
Abstract: Silicosis is a chronic progressive granulomatous and fibrotic lung disease caused by inhaled silica. Although the causative agent is known, the pathogenesis, especially the immunologic response, is not well understood. We examined two important components of cell-mediated immune responses in the lungs of rats with silica-induced lung disease, i.e., class II (Ia) antigen expression and IL-1 production. The relative density of Ia was examined on isolated alveolar macrophages and type II cells with a solid-phase cellular radioimmunoassay and the percent of Ia positive cells was determined by an indirect immunofluorescent technique. There was a three-fold increase of Ia expression on the alveolar macrophages and nearly a two-fold increase on type II cells from rats with silicosis compared to normal rats. The percent of alveolar type II cells positive for Ia increased by 20%, and the alveolar macrophages increased by 40%. IL-1 in supernatants from cultured alveolar macrophage was measured by the amount of DNA synthesis in an IL-1 dependent cell line (D10). A six-fold increase in IL-1 secretion was noted in macrophage supernatants derived from silica-treated animals. We conclude that in this animal model of silicosis, a local amplification of cell-mediated immune responses may be instrumental in the pathogenesis.
Abstract: Class II antigens of the major histocompatibility complex (Ia) are important components in the investigation of cell-mediated immune responses. Several reports have indicated that anti-Ia monoclonal antibodies suppress disease development in animal models. In this paper, the expression of Ia and the effect of anti-Ia on IL-1 secretion from alveolar macrophages (AM) from silica-treated rats was examined. The results obtained showed that 45% of silicotic AM, but only 5% of AM from normal control rats, express Ia antigen. Anti-Ia treatment of silicotic AM reduced IL-1 secretion by 55%. We conclude that anti-Ia immune suppression may involve the inhibition of IL-1 secretion.
Abstract: Inflammatory cells and lymphocyte populations were examined in the bronchoalveolar lavage (BAL) fluid, lung tissues, and peripheral blood from rats at various times after the intratracheal instillation of silica. In lavage fluid, there was a rapid initial increase in the percentage and number of polymorphonuclear leukocytes (PMN), which slowly decreased during the course of the experiment. In addition, compared to controls, there was an increased number and percentage of lymphocytes throughout the 75 days of the experiment. The lymphocytic populations, which were determined by an indirect immunofluorescence method with monoclonal antibodies to lymphocyte surface markers, showed a predominance of the T-helper phenotype from Day 14 through the end of the experiment (Day 75). The number of PMNs obtained from collagenase digest of the lung was increased over control levels up to Day 7 after silica administration and remained at a relatively constant level until Day 14, after which time they decreased slightly in number. The total number of lymphocytes peaked on Day 14, with cells of the T-helper phenotype predominating after this time. In the peripheral blood, T-helper cells from silicotic rats were significantly increased over control rats on Days 7 and 14 but returned to normal control values after this time. The lymphocyte subsets in the BAL, but not in the peripheral blood, more closely reflect the lymphocyte patterns in the lung. The results of these experiments suggest that T-helper cells may play an important role in the inflammatory-fibrotic events in the lungs of rats with silicosis.
Abstract: Lung volume and the pressure-volume (PV) relationships of the lung were determined in excised lungs of an animal model of human systemic lupus erythematosus, which develops in NZB/W mice, and correlated with histopathologic changes. In young, 4-month-old NZB/W mice, and in nonautoimmune BALB/c mice at any age, there were minimal histologic changes or alterations in lung function. The NZB/W mice developed histologic changes with aging. Perivascular, peribronchial, and interstitial changes developed and were associated with a significant reduction in total lung capacity as well as changes in the pressure-volume characteristics of the lung, which are compatible with a restrictive process.
Abstract: Class II (Ia) molecules of the major histocompatibility complex are important in the presentation of antigen to T cells and in the regulation of the immune response. Recent studies have suggested that many epithelial cell types can express class II molecules. We examined rat alveolar type II epithelial cells, a cell which can synthesize and secrete pulmonary surface-active material, for the expression of class II antigens. Using an indirect immunofluorescent technique with a mouse anti-rat class II monoclonal antibody (OX-4), the majority of type II cells isolated from pathogen-free Sprague-Dawley rats expressed Ia antigens as determined by fluorescent microscopy and cell sorter analysis. In culture, the Ia expression was lost from type II cells. The addition of recombinant interferon-gamma to cultures of type II cells induced the expression of class II antigens. These findings suggest that class II antigen expression on type II cells may have relevance to immune responses occurring in the lung.
Abstract: The effect of the protein kinase C enzyme inhibitor H-7 on the noncardiogenic lung edema induced by phorbol myristate acetate (PMA) in mice was examined. Lung edema was assessed by measurement of 125I-labeled albumin leak into the lung. The results showed that pretreatment of mice with H-7 nearly prevents the albumin leak induced by PMA, whereas post-PMA treatment with H-7 had less of an effect on the albumin leak, although it was still significant.
