D. Keith Payne

A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions.

The purpose of this study was to compare the effectiveness and safety of a chronic indwelling pleural catheter with doxycycline pleurodesis via tube thoracostomy in the treatment of patients with recurrent symptomatic malignant pleural effusions (MPE).

Translational regulation of vascular permeability factor by eukaryotic initiation factor 4E: Implications for tumor angiogenesis

Studies aimed at elucidating the function of the protein synthesis factor eukaryotic initiation factor 4E (elF‐4E) have demonstrated that overexpression of this protein results in marked cell phenotypic and proliferative changes, including neoplastic transformation of cells. These data suggest that elF‐4E may somehow participate in the development and progression of tumors in vivo. In order to determine how elF‐4E exerts its transforming effects, we examined vascular permeability factor (VPF) levels in cells transfected with an elF‐4E vector. Cells overexpressing elF‐4E showed an increase in intracellular, and an average 130‐fold increase in secreted VPF protein levels (CHO 0.13 ± 0.12 ng/ml; CHO‐4E 20.5 ± 12.5 ng/ml) over control cells. HUVEC growth induction revealed these VPF levels to be biologically active. Northern analysis revealed no difference in VPF transcript between the 2 cell lines. Polysome analysis showed that the VPF message in elF‐4E‐transfected cells was associated with the heavy polysomal regions, whereas the VPF message was associated with light polysomes in control cells. These data strongly suggest that enhanced VPF expression is achieved through translational regulation rather than transcriptional regulation in cells overexpressing elF‐4E. This indicates that elF‐4E‐induced VPF expression may be an important factor in some forms of tumor angiogenesis and development.

The Pathogenesis of Chronic Obstructive Pulmonary Disease

Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD). An accelerated rate of lung function decline that causes clinically significant COPD, however, is present in only a minority of smokers. In addition to the cumulative amount of cigarettes smoked, other environmental and genetic properties contribute to this variable physiological response. This article reviews the role of airway hyperresponsiveness, mucus hypersecretion, infection, and proteases in the development of COPD.

MODULATION OF ENDOTHELIAL CELL PERMEABILITY BY LUNG CARCINOMA CELLS: A Potential Mechanism of Malignant Pleural Effusion Formation

This study examined the hypothesis that tumor cells metastatic to the pleura secrete a soluble factor(s) that directly increases endothelial cell permeability. Nitrocellulose filters were endothelialized with bovine pulmonary artery endothelial cells and exposed to conditioned media from either human lung adenocarcinoma (Calu-3), human lung squamous cell carcinoma (SK-MES-1), or control media for 16 h. The diffusional permeability (Pd × 10−5 cm/sec) to [14C]albumin was then determined for each monolayer with Ussing-type chambers. Both adenocarcinoma conditioned media (ACCM) and squamous cell carcinoma conditioned media (SCCM) caused a two- to threefold increase in endothelial monolayer permeability. The addition of indomethacin (10 μg/ml) blocked the observed permeability increase in ACCM but not in SCCM, suggesting that the increase in permeability by ACCM was secondary to the production of prostaglandins. To confirm this, a variety of prostanoids previously shown to be produced by the Calu-3 cell line were added directly to the endothelial monolayer. Prostaglandin F2α (PGF2α) in both low (10 ng/ml) and high (100 ng/ml) concentrations for 16 h resulted in a three- to fourfold increase in permeability. Prostaglandin E2 (PGE2) resulted in a small increase in [14C]albumin permeability but only at high concentrations (100 ng/ml). PGF2α production by the two tumor cell lines was measured using radioimmunoassay. Baseline adenocarcinoma production of PGF2α was 117.5 pmol/106 cells and fell to 24.2 pmol/106 cells hours following incubation with indomethacin. The decrease in PGF2α occurred in parallel with the changes in permeability. Concomitant, reversible changes in cell shape and F-actin distribution were detected in endothelial cells exposed to ACCM. No significant production of PGF2α by the squamous cell carcinoma cell line was detected. These results suggest that both adenocarcinoma and squamous cell carcinoma secrete a soluble factor(s) that directly increases endothelial cell permeability to albumin and that in the case of adenocarcinoma this soluble factor may be a prostanoid such as PGF2α.This study examined the hypothesis that tumor cells metastatic to the pleura secrete a soluble factor(s) that directly increases endothelial cell permeability. Nitrocellulose filters were endothelialized with bovine pulmonary artery endothelial cells and exposed to conditioned media from either human lung adenocarcinoma (Calu-3), human lung squamous cell carcinoma (SK-MES-1), or control media for 16 h. The diffusional permeability (Pd × 10−5 cm/sec) to [14C]albumin was then determined for each monolayer with Ussing-type chambers. Both adenocarcinoma conditioned media (ACCM) and squamous cell carcinoma conditioned media (SCCM) caused a two- to threefold increase in endothelial monolayer permeability. The addition of indomethacin (10 μg/ml) blocked the observed permeability increase in ACCM but not in SCCM, suggesting that the increase in permeability by ACCM was secondary to the production of prostaglandins. To confirm this, a variety of prostanoids previously shown to be produced by the Calu-3 cell line were added directly to the endothelial monolayer. Prostaglandin F2α (PGF2α) in both low (10 ng/ml) and high (100 ng/ml) concentrations for 16 h resulted in a three- to fourfold increase in permeability. Prostaglandin E2 (PGE2) resulted in a small increase in [14C]albumin permeability but only at high concentrations (100 ng/ml). PGF2α production by the two tumor cell lines was measured using radioimmunoassay. Baseline adenocarcinoma production of PGF2α was 117.5 pmol/106 cells and fell to 24.2 pmol/106 cells hours following incubation with indomethacin. The decrease in PGF2α occurred in parallel with the changes in permeability. Concomitant, reversible changes in cell shape and F-actin distribution were detected in endothelial cells exposed to ACCM. No significant production of PGF2α by the squamous cell carcinoma cell line was detected. These results suggest that both adenocarcinoma and squamous cell carcinoma secrete a soluble factor(s) that directly increases endothelial cell permeability to albumin and that in the case of adenocarcinoma this soluble factor may be a prostanoid such as PGF2α.

Heparin-Induced Thrombotic Thrombocytopenia

OBJECTIVE: To report a case of heparin-induced thrombotic thrombocytopenia (HITTS) and discuss the incidence, possible mechanisms, complications, and treatment for this syndrome. DATA SOURCES: Case reports and review articles identified by MEDLINE from 1980 through 1991. Older articles located by manual searches. DATA EXTRACTION: Data were extracted and reviewed from published sources. Cases were selected on the basis of case presentation, time of disease onset, pathophysiology of disease, and therapeutic options. SETTING: A 600-bed university teaching hospital and an affiliated community hospital. PATIENT: A 36-year-old woman with insulin-dependent diabetes mellitus, sepsis, adult respiratory distress syndrome, diabetic ketoacidosis, oliguric renal failure developed HITTS and subsequent gangrene of her right arm. INTERVENTION: Immediate cessation of all heparin use and amputation of the patients right arm. RESULTS: The patients condition improved progressively over the following 60 days and she was discharged to outpatient care. CONCLUSIONS: Heparin has been associated with thrombocytopenia and thrombotic events. Laboratory tests for HITTS are unreliable and the diagnosis is usually suspected by the clinical presentation of the patient. Platelet counts should be monitored closely during heparin use. In the event of a marked decrease in platelet count associated with venous or arterial thrombosis, heparin therapy should be stopped immediately. If further anticoagulation is necessary, oral anticoagulants such as warfarin may be used instead. As the onset of warfarin may take several days to become therapeutic, aspirin, dipyridamole, or both may be used effectively. Healthcare workers should be aware that in these patients, the use of even small amounts of heparin can produce catastrophic results.

Outpatient Management of Chronic Obstructive Pulmonary Disease

The outpatient management of chronic obstructive pulmonary disease (COPD) is designed to limit the decline in respiratory function over time, to relieve the symptoms and improve the patients functional status, and to manage complications when they arise. Factors that predispose to airway inflammation, including cigarette smoking and respiratory infections, are prevented by behavioral modification programs, measures such as exercise and nutrition to improve general health, and regular vaccination. Symptoms are relieved by bronchodilator and anti-inflammatory therapy, based upon the specific needs of the patient. Hypoxemia and acute infections are treated with oxygen administration and the use of antibiotics when necessary. The management of acute exacerbations of COPD is addressed elsewhere in this symposium (ie, choice of antibiotics is not discussed here). Also, certain aspects of management, such as surgical procedures, chest physical therapy, and other aspects of pulmonary rehabilitation, are also subjects of subsequent articles in this series. Although none of these modalities, except for smoking cessation and oxygen administration, have been shown to alter the course of COPD, the careful choice of the therapeutic measures discussed here can lead to significant relief of symptoms in the patient with chronic airway obstruction.

Surgical Treatment of Chronic Obstructive Pulmonary Disease

Over the past several decades, a number of surgical techniques have been developed for the treatment of chronic obstructive pulmonary disease. Many of these procedures have been abandoned because of lack of efficacy and/or high morbidity and mortality. At the present time, lung transplantation, reduction pneumoplasty for giant bullous emphysema, and lung volume reduction surgery are being performed in a number of centers. Data concerning the effectiveness of these procedures is accumulating and will ultimately need careful analysis to determine long-term outcomes in this group of patients.

Book Review: Handbook of Physiology Section 3: The Respiratory System, Volume IVHandbook of Physiology Section 3: The Respiratory System, Volume IV Edited by FishmanAlfred P., FarhiLeon E., TenneyS. Marsh, and GeigerStephen R.. Published by Waverly Press, Baltimore, 1987. Hardbound, xi + 468 pp. (28.5 × 22.2 cm),

New Cardiovascular Drugs 1987 is the fifth book in the series entitled New Drugs Annual: Cardiovascular Drugs, which has been published once a year since 1983. Keeping with the format of previous volumes, this volume profiles some of the more recent investigational cardiovascular drugs and is divided into multiple sections with single or multiple agents reviewed within a given section. The 42 contributing authors consist primarily of pharmaceutical industry researchers from the U.S., Europe, and Japan. In all, 12 new drugs are described and categorized into 5 sections: 6 antihypertensive agents, 1 peripheral vasodilator, 2 cardiac stimulants, 1 cerebral antihypoxic agent, 1 renal vasodilator, and 1 nasal decongestant. The focus of this text, which is expanded beyond the self-titled sections, are the antihypertensive agents: ketanserin (a serotonin antagonist); ramipril (an angiotensin-converting enzyme inhibitor); tiapamil (a calcium channel blocking agent); three beta blocking agents nipradilol, amosulalol, and carvedilol; cadralazine (a potent peripheral vasodilator); and fenoldopam (a dopamine receptor agonist that acts selectively as a renal vasodilator). The remaining chapters describe two positive inotropes, DPI 201-106 and isomazole; idebenone (a cerebral metabolism activator); and Abbott-57219 [SHC-40054], which is a unique nasal decongestant. In most cases, individual chapters are organized into sections describing the chemistry, pharmacology, preclinical studies (primary emphasis of chapter), pharmacokinetics, toxicology, and clinical evaluation or use of these agents. Although each year the editor focuses on a class of cardiotherapeutics that he believes is currently emphasized in research, the selection and subsequent categorization of individual agents are somewhat arbitrary. There are no introductory or concluding chapters linking the selected agents together, and the inclusion of the chapter summarizing research of a nasal decongestant seems out of place in a cardiovascular drug text. The scope of the text is limited in that it reviews a small number of drugs that are not routinely used by clinical pharmacists in the U.S., and the data presented are primarily preclinical in nature. The book does, however, present many descriptions (graphs, figures, and tables) of unpublished or difficult-to-find literature, as well as extensive reference lists that in many cases could aid drug information specialists and other health professionals interested in cardiovascular research. In conclusion, this text specializes in detailed information on a limited spectrum of cardiovascular drugs. Thus, New Cardiovascular Drugs 1987 is best suited to be part of a medical library collection, drug information center resource, or private collection of any health professional interested in new agents being evaluated in cardiopharmacologic research. SARAH A. SPINLER, Pharm.D. Cardiovascular Fellow Department of Pharmacy Practice College of Pharmacy University of Illinois at Chicago FREDERICK P. ZELLER, Pharm.D. Assistant Professor Department of Pharmacy Practice College of Pharmacy Instructor in Medicine Department of Medicine Section of Cardiology Abraham Lincoln College of Medicine University of Illinois at Chicago Chicago, Illinois 60612

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Water and protein movement across the pulmonary endothelial-visceral pleural membrane of spontaneously breathing anesthetized dogs was analyzed to determine if the protein concentration at the microvascular membrane (Cpro) influences microvascular permeability. The left lung was enclosed in a water-impermeable membrane, creating a visceral pleural space (VPS); fluid and solute fluxes were determined as the filtration or reabsorption of water and protein in the VPS. The plasma protein concentration was experimentally varied by plasmapheresis with saline replacement while the pleural fluid protein concentration was varied by introducing different concentrations of plasma mixed with saline into the VPS. Hydrostatic pressures were maintained within a physiologic range (pulmonary capillary pressure 12.1-16.1 mm Hg). The plasma protein concentration fell as low as 1.98 g/dl, and Cpro, calculated as the mean of the plasma and pleural fluid protein concentrations, ranged from 1.73 to 6.23 g/dl. The relationship between Cpro and the apparent homoporous diffusional permeability for protein (Phs), Phs(cm/sec X 10(-6] = 0.95 Cpro (g/dl) + 2.28, was highly significant (r = 0.87, P less than 0.01). In contrast, the hydraulic conductivity was not affected by a reduction in Cpro to this level (r = 0.21, P greater than 0.4). Although the solute concentration at the endothelial membrane should be considered when evaluating changes in protein permeability, under most experimental conditions the magnitude of this effect will be small.