Anti-endotoxin monoclonal antibodies.
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Antibodies, Monoclonal↗
Biomedical subjects
A P Wheeler
Publications and source records attributed to A P Wheeler.
Effect of cyclooxygenase inhibition on amphotericin B-induced lung injury in awake sheep.
Amphotericin therapy in humans has been reported to cause severe pulmonary dysfunction in some patients, and these abnormalities have been reproduced in unanesthetized sheep. To determine the role of cyclooxygenase products in this response, paired, random-order experiments in 11 sheep were done using the cyclooxygenase inhibitor ibuprofen. Ibuprofen blunted increases in pulmonary artery pressure (Ppa) after amphotericin (peak Ppa 38 +/- 3 cm H2O in amphotericin-alone group vs. 30 +/- 1 cm H2O in ibuprofen + amphotericin group, P less than .05) and reduced peak lung lymph flow to approximately 170% of baseline compared with 350% of baseline in amphotericin-alone group (P less than .05). In addition, the increase in airflow resistance across the lung and the decrease in partial pressure of oxygen seen after amphotericin was blocked by ibuprofen. Therefore, amphotericin-induced lung dysfunction is produced in part through the generation of cyclooxygenase products of arachidonic acid metabolism and can be ameliorated by pretreatment with the cyclooxygenase inhibitor ibuprofen.
6-Ketoprostaglandin F1 alpha↗
The role of cyclooxygenase products in lung injury induced by tumor necrosis factor in sheep.
Tumor necrosis factor-alpha (TNF alpha) has been proposed as a mediator of endotoxin-induced lung injury. When given to sheep, TNF alpha mimics endotoxin (LPS) causing hypoxemia, pulmonary hypertension, leukopenia, reduced dynamic compliance (Cdyn), increased resistance to airflow (RL), exudation of lung lymph, and enhanced airway reactivity. TNF alpha also induces rapid release of thromboxane A2 (TxA2), prostaglandin E2 (PGE2), and prostacyclin (PGI2). We hypothesized that the inflammatory effects of TNF alpha are due at least in part to cyclooxygenase products, and therefore cyclooxygenase inhibition would have similar effects on TNF alpha-induced lung injury as has previously been demonstrated for LPS-induced lung damage. Using awake sheep with chronic lung lymph fistulas, we measured Cdyn, RL, and FRC using a whole-body plethysmograph. Pulmonary artery (Ppa), left atrial (PLA), and systemic arterial (Psa) pressures were recorded continuously. Arterial blood gases (for calculating AaPO2), leukocyte counts, and lymph samples (for prostanoid levels) were collected every 30 min. Eleven animals underwent paired random-order experiments receiving ibuprofen (14 mg/kg) 1 h before human recombinant TNF alpha (10 micrograms/kg), or an identical dose of TNF alpha alone. Within 15 min of initiating TNF alpha, Ppa doubled and remained elevated for 4 h. Ibuprofen prevented the early rise in Ppa after TNF alpha. In the group receiving TNF alpha alone, increases in Ppa were accompanied by a 60% decline in leukocyte count and a 50% increase in AaPo2 within 30 min. Ibuprofen prevented increases in AaPo2, but it had no effect on leukopenia or late increases in lymph flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Tumor necrosis factor's effects on lung mechanics, gas exchange, and airway reactivity in sheep.
The macrophage- and monocyte-produced cytokine tumor necrosis factor alpha (TNF alpha) has been proposed as a major mediator of endotoxin-induced injury. To determine if TNF alpha could reproduce the effects of endotoxin on the lung, we intravenously administered 10 micrograms/kg of human recombinant TNF alpha into five chronically instrumented unanesthetized sheep on two occasions to characterize the TNF alpha response and its reproducibility. We assessed changes in lung mechanics, pulmonary and systemic hemodynamics, gas exchange, and the number and type of peripheral blood leukocytes. We also determined airway reactivity by use of aerosolized histamine before and after TNF alpha infusion. Pulmonary arterial pressure (Ppa) peaked within 30 min of initiating the TNF alpha infusion [47.7 +/- 2.2 vs. 15.9 +/- 0.4 (SE) cmH2O at base line] and then returned toward base line over 4 h. There was a brief decline in left atrial pressure after TNF alpha. Pulmonary hypertension was accompanied by leukopenia, neutropenia, and increases in the alveolar-arterial O2 difference (AaDO2). Dynamic lung compliance (Cdyn) declined after TNF alpha, reaching a nadir within 15 min of the initiation of the TNF alpha infusion [0.045 +/- 0.007 vs. 0.093 +/- 0.007 (+/- SE) l/cmH2O at base line]. Resistance to airflow across the lung (RL) increased from 1.2 +/- 0.2 cmH2O.l-1.s at base line, peaking at 5.4 +/- 1.3 cmH2O.l-1.s 30 min after the start of the TNF alpha infusion. Alterations in Cdyn and RL persisted for 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Airway Resistance↗
Studies of an antiendotoxin antibody in preventing the physiologic changes of endotoxemia in awake sheep.
In sheep, endotoxin (LPS) causes pulmonary hypertension, hypoxemia, leukopenia, exudation of protein-rich lung lymph, reduced dynamic compliance (Cdyn), and increased resistance to airflow (RL), changes similar to those seen in human sepsis and sepsis-induced ARDS. We used well-described methods in the awake sheep-endotoxin model to evaluate the effectiveness of a commercially manufactured antibody to prevent the physiologic changes of endotoxemia. In awake sheep with chronic lung lymph fistulas, we used a whole-body plethysmograph to measure Cdyn, RL, and FRC. Pulmonary artery, left atrial, and systemic arterial pressures were recorded continuously. Arterial blood gases (for calculating AaPO2), leukocyte counts, and lymph samples were collected every 30 min. Animals received a 30-min (2 mg/kg) infusion of antiendotoxin antibody 4 h before LPS (0.75 micrograms/kg) challenge (n = 4), or were given a mixture of LPS (0.75 micrograms/kg) and antibody (2 mg/kg) that had been incubated in vitro at 37 degrees C for 30 min before infusion (n = 6). A control group given only 2 mg/kg of antibody (n = 4) showed no change in any measured parameter, whereas control animals receiving LPS alone (n = 6) exhibited a typical endotoxin response. In all animals receiving endotoxin, Cdyn declined by approximately 50% within 30 to 60 min, and RL increased approximately sixfold over a similar time course. Accompanying the abnormalities in lung mechanics were pulmonary hypertension, leukopenia, and widening of the AaPO2.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
A model for the objective assessment of clinical training programs: the initial application to two pulmonary medicine fellowship programs.
A model is presented for the objective assessment of clinical training programs. The model documents the clinical trainee's experience by the diagnoses seen and procedures performed during a full year of experience. It also surveys faculty impressions of the trainee's experience and their judgment of what is necessary to constitute an adequate experience. In the pilot study applying this model to two pulmonary medicine fellowship programs, several important observations were made: (1) faculty members may not have an accurate perception of the fellow's actual clinical experience, (2) faculty impressions of the fellow's experience often do not correspond to their own conception of an adequate clinical experience, (3) interprogram variability exists, (4) pulmonary fellows may have inadequate experience with certain invasive procedures. These observations suggest that wilder application of such a model could provide valuable information to program directors and subspecialty boards. In addition, directors of pulmonary disease training programs have been asked by the American Board of Internal Medicine to establish systems to evaluate, document, and substantiate those components of overall clinical competence considered essential for certification in the subspecialty. The model presented here provides an accurate and efficient means for such evaluation and documentation.
Clinical Competence↗
Atypical mycobacterial infections.
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Acquired Immunodeficiency Syndrome↗
Fatal hemoptysis: aortobronchial fistula as a preventable cause of death.
Hemoptysis as a result of leaking aortic aneurysms occurs rarely and has a high fatality rate. A case of chronic hemoptysis resulting from an aortobronchial fistula in a patient with an aortic prosthesis is reported. Hemoptysis, even when chronic, should prompt investigation of the possibility of a leaking graft in patients with prosthetic aortic grafts. Chest x-ray and bronchoscopy usually yield nonspecific findings. Aortography may demonstrate an aortic aneurysm and is the preferred diagnostic procedure; however, an aggressive surgical approach is often necessary.
Adult↗
Physician practices in the treatment of pulmonary embolism and deep venous thrombosis.
To quantify physician practices in the care of patients with presumed pulmonary embolism or deep venous thrombosis, we analyzed heparin sodium orders, the intensity of anticoagulation, and complications in 65 patients with the diagnosis of deep venous thrombosis or pulmonary embolism. All patients were given heparin, for a mean (+/- SEM) period of 8.8 +/- 0.4 days. A high percentage of patients (60%) did not have a single partial thromboplastin time (PTT) greater than 1.5 times control within the first 24 hours of heparin therapy. Not until day 8 were 90% of PTTs in therapeutic range. We identified five common practices that led to delays in achieving a PTT greater than 1.5 times the laboratory control: (1) failure to start heparin therapy at the time of initial clinical suspicion, (2) choice of a heparin sodium bolus (mean, 5861 +/- 365 U) and continuous infusion (1026 +/- 148 U/h) insufficient to elevate the PTT to greater than 1.5 times control, (3) delay in obtaining the first PTT (mean, 11.7 +/- 1 h after start of heparin therapy), (4) insufficient heparin dosing in response to a low PTT, and (5) excessive and prolonged reductions in heparin therapy in response to a PTT greater than three times control, leading to subtherapeutic levels in 56% of subsequent PTTs. We think that poor understanding of heparin kinetics, overcautious behavior of physicians, and high heparin requirements in this selected population account for the findings.
Female↗
Histoplasmosis in AIDS.
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Acquired Immunodeficiency Syndrome↗
Fatal pneumococcal pneumonia.
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Acidosis, Respiratory↗
Campylobacter bacteremia, cholecystitis, and the acquired immunodeficiency syndrome.
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Acquired Immunodeficiency Syndrome↗
Pseudogout presenting with low synovial fluid glucose: identification of crystals by gram stain.
A man developed acute monoarticular ankle arthritis caused by calcium pyrophosphate dihydrate (CPPD) crystals. The clinical syndrome resembled that of a pyogenic arthritis. Synovial fluid analysis revealed a glucose concentration of 13 mg/dL and 99,000 white blood cells/mm3. Only one other report of an extremely low synovial fluid glucose associated with pseudogout could be found. The diagnosis of pseudogout was initially suggested when rhomboidal forms were seen during synovial fluid Gram stain examination. Synovial fluid examination with polarized microscopy was initially negative, but revealed numerous CPPD crystals when repeated on the third hospital day. This case serves to illustrate how pseudogout can mimic pyogenic arthritis in both clinical presentation and low synovial fluid glucose concentration. The examination of Gram-stained synovial fluid can reveal the rhomboidal forms of CPPD crystals. The appearance of these crystals is documented in this report.
Arthritis, Infectious↗
Subcellular localization and characterization of HCO3(-)-ATPase from the mantle of the freshwater clam, Anodonta cataracta.
1. HCO3(-)-stimulated ATPase activity was demonstrated in mantle tissue of the freshwater clam, Anodonta cataracta. 2. Calcium (1 mM) slightly inhibited and SCN- completely inhibited HCO3(-)-stimulation of the enzyme. 3. ATPase activity had a Km of 6.8 mM for HCO3(-)-activation and was inhibited at HCO3(-)-concentrations greater than 20 mM. 4. Subcellular fractionation studies revealed the presence of both a mitochondrial and a non-mitochondrial HCO3(-)-ATPase.
Adenosine Triphosphatases↗