RESUMEN
Lunar material returned from the first manned landing on the moon was assayed for the presence of replicating agents possibly harmful to life on earth. Ten species of lower animals were exposed to lunar material for 28 days. No pathological effects attributable to contact with lunar material were detected.
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Acute lung injury (ALI) is characterized by fibrin deposition in the tissue and vascular spaces. Coagulation is activated after exposure to endotoxin or bacteria, and a procoagulant environment rapidly develops in the vascular, interstitial, and alveolar spaces of the lung. These changes are tissue factor (TF)-dependent and associated with increases in inflammatory cytokines. Procoagulant changes also occur in the lungs of patients with the acute respiratory distress syndrome (ARDS), suggesting that epithelial inflammation activates the extrinsic pathway. Many inflammatory mediators have specific effects on coagulation; however, the role of TF in regulation of pulmonary inflammatory responses is less clear. Here we report initial data on blockade of TF-initiated coagulation in baboons with Escherichia coli sepsis-induced ALI, using active site-inactivated FVIIa (FVIIai ASIS). Treatment with FVIIai prevented plasma fibrinogen depletion and attenuated fibrin deposition in the tissues. The drug also decreased systemic cytokine responses and inflammatory changes in the lung, including neutrophil infiltration, and decreased edema. Coagulation blockade with FVIIai improved lung function by preserving gas exchange and compliance, decreased pulmonary hypertension, and enhanced renal function. These results show that TF-FVIIa complex is an important regulatory site for the pathologic response of the lung to sepsis.
Asunto(s)
Síndrome de Dificultad Respiratoria/metabolismo , Tromboplastina/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Papio , Síndrome de Dificultad Respiratoria/microbiología , Síndrome de Dificultad Respiratoria/fisiopatología , Tromboplastina/fisiologíaRESUMEN
Energy metabolism during sepsis is incompletely understood, but alterations in mitochondrial structure and function appear important. We measured time-dependent changes in mitochondrial structure during sepsis using serial skeletal muscle biopsies in anesthetized baboons injected with 10(10) CFU/kg of live Escherichia coli (LD(100)). Skeletal muscle biopsies were taken before bacterial challenge (0 h controls) and at 12 h, 24 h, and death. By qualitative electron microscopy, the organelles became enlarged with distorted cristae and developed electron lucent areas within the matrix. With advanced injury the inner membrane became fragmented. Quantitative morphometric analysis showed a 50% increase in mean cristal membrane surface density by 24 h (p < .05) accompanied by a 100% increase in intermembrane space (p < .01). Matrix volume density decreased progressively (p < .01). These changes in mitochondrial ultrastructure occur within 12 h after the onset of the bacterial insult. This damage, including destruction or reorganization of both membrane and matrix proteins, is severe enough to compromise oxidative metabolism in muscle in Gram-negative sepsis.
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Bacterias Gramnegativas , Mitocondrias/ultraestructura , Músculo Esquelético/ultraestructura , Sepsis/patología , Animales , Masculino , Microscopía Electrónica , Mitocondrias/patología , Músculo Esquelético/patología , PapioRESUMEN
Cytokine mediators and leukocyte-endothelial cell adhesion molecules are critical and interdependent components of the acute inflammatory response in sepsis. We hypothesized that the administration of monoclonal antibodies to intercellular adhesion molecule-1 (CD54) or E- and L-selectin (CD62E/L) would decrease serum levels of the proinflammatory cytokines interleukin-1beta (IL-1), IL-6, and IL-8 and tumor necrosis factor receptor (TNFR-1) in baboons during sepsis. Adult male baboons received infusions of 1 x 10(9) colony forming units (CFU)/kg heat-killed Escherichia coli (E. coli) followed 12 h later by live E. coli (1 x 10(10) CFU/kg). At the time of live bacterial infusion, six septic animals were treated with a monoclonal antibody to CD54 and six with an antibody to CD62E and L (1 mg/kg). Eight untreated septic animals served as controls. Sequentially drawn serum samples were assayed for IL-1, IL-6, IL-8, and TNFR-1 using enzyme-linked immunoassay (ELISA). Data were compared using Mann-Whitney U tests and Chi-square analyses. Median survival was decreased in both treatment groups compared to controls (P < 0.05). Peak IL-1 level was higher than controls in septic animals treated with anti-CD54 but not anti-CD62E/L (P < 0.05, P = NS, respectively). Elevations in IL-6, IL-8, and TNFR-1 were increased and prolonged in both antibody treated groups compared to controls (P < 0.05). These results provide the first in vivo evidence that leukocyte-endothelial adhesion molecules CD54 and CD62E/L regulate cytokine production in sepsis.
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Citocinas/sangre , Selectina E/inmunología , Mediadores de Inflamación/sangre , Molécula 1 de Adhesión Intercelular/inmunología , Selectina L/inmunología , Sepsis/inmunología , Sepsis/terapia , Animales , Anticuerpos Monoclonales/uso terapéutico , Antígenos CD/sangre , Escherichia coli/inmunología , Escherichia coli/patogenicidad , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/terapia , Interleucina-1/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Papio , Receptores del Factor de Necrosis Tumoral/sangre , Receptores Tipo I de Factores de Necrosis TumoralRESUMEN
Diffuse lung injury from hyperoxia is accompanied by low compliance and hypoxemia with disruption of endothelial and alveolar epithelial cell layers. Because both function and content of surfactant in diffuse lung injury decrease in animals and in humans, changes in the extent of injury during continuous hyperoxia were evaluated after treatments with a protein-free surfactant in primates. Ten baboons were ventilated with 100% O2 for 96 h and five were intermittently given an aerosol of an artificial surfactant (Exosurf). Physiological and biochemical measurements of the effects of the surfactant treatment are presented in a companion paper (Y.-C. T. Huang, A. C. Sane, S. G. Simonson, T. A. Fawcett, R. E. Moon, P. J. Fracica, M. G. Menache, C. A. Piantadosi, and S. L. Young. J. Appl. Physiol. 78: 1823-1829, 1995.) After O2 exposures, lungs were fixed and processed for electron microscopy. The cellular responses to O2 included epithelial and endothelial cell injuries, interstitial edema, and inflammation. Morphometry was used to quantitate changes in lungs of animals treated with the artificial surfactant during O2 exposure and to compare them with the untreated animals. The surfactant decreased neutrophil accumulation, increased fibroblast proliferation, and decreased changes in the volume of type I epithelial cells. Surfactant-treated animals also demonstrated better preservation of endothelial cell integrity. These responses indicate ameliorating effects of the surfactant on the pulmonary response to hyperoxia, including protection against epithelial and endothelial cell destruction. Significant interstitial inflammation and fibroblast proliferation remained, however, in surfactant-treated lungs exposed to continuous hyperoxia.
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Alcoholes Grasos/uso terapéutico , Enfermedades Pulmonares/tratamiento farmacológico , Pulmón/patología , Oxígeno/toxicidad , Fosforilcolina , Polietilenglicoles/uso terapéutico , Surfactantes Pulmonares/uso terapéutico , Aerosoles , Animales , Análisis de los Gases de la Sangre , División Celular/efectos de los fármacos , Combinación de Medicamentos , Endotelio/efectos de los fármacos , Endotelio/patología , Alcoholes Grasos/administración & dosificación , Hemodinámica/efectos de los fármacos , Pulmón/ultraestructura , Enfermedades Pulmonares/patología , Enfermedades Pulmonares/fisiopatología , Masculino , Microscopía Electrónica , Papio , Polietilenglicoles/administración & dosificación , Alveolos Pulmonares/patología , Surfactantes Pulmonares/administración & dosificaciónRESUMEN
Prolonged hyperoxia causes lung injury and respiratory failure secondary to oxidative tissue damage mediated, in part, by the superoxide anion. We hypothesized that aerosol treatment with recombinant human manganese superoxide dismutase (rhMnSOD) would attenuate hyperoxic lung damage in primates. Adult baboons were anesthetized and ventilated with 100% oxygen for 96 h or until death. Six animals were treated with aerosolized rhMnSOD (3 mg . kg-1 . day-1 in divided doses), and six control animals did not receive enzyme therapy. Physiological variables were recorded every 12 h, and ventilation-perfusion ratio relationships were evaluated by using the multiple inert-gas elimination technique. After the experiments, surfactant composition and lung edema were measured. We found that rhMnSOD significantly decreased pulmonary shunt fraction (P < 0.01) and preserved arterial oxygenation (P < 0.01) during hyperoxia. The rhMnSOD increased lung phospholipids, phosphatidylcholine and disaturated phosphatidylcholine, and decreased lung edema in this model. Testing of higher and lower doses of MnSOD (1 and 10 mg . kg-1 . day-1) in two other groups of baboons produced variable physiological protection, suggesting a "window" of effective dosage. We conclude that aerosolized MnSOD (3 mg . kg-1 . day-1) affords significant preservation of pulmonary gas exchange during hyperoxic lung injury.
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Hiperoxia/patología , Pulmón/patología , Superóxido Dismutasa/farmacología , Aerosoles , Animales , Hemodinámica , Humanos , Hiperoxia/metabolismo , Hiperoxia/fisiopatología , Pulmón/metabolismo , Pulmón/fisiopatología , Masculino , Papio , Edema Pulmonar/etiología , Intercambio Gaseoso Pulmonar , Surfactantes Pulmonares/química , Proteínas Recombinantes , Respiración , Análisis de Supervivencia , Relación Ventilacion-PerfusiónRESUMEN
Hyperoxia damages lung parenchyma via increased cellular production of reactive oxygen species that exceeds antioxidant defenses. We hypothesized that aerosolized human recombinant manganese superoxide dismutase (rhMnSOD) would augment extracellular antioxidant defenses and attenuate epithelial injury in the lung during hyperoxia in primates. Twenty-four adult male baboons were anesthetized and mechanically ventilated with 100% oxygen for 96 h. The baboons were divided equally into four groups. Oxygen alone and oxygen plus rhMnSOD given at 3 mg . kg-1 . day-1 were compared to assess efficacy of the drug. Subsequently, aerosolized rhMnSOD was given at 1 or 10 mg . kg-1 . day-1 to study dose effects and toxicity. Quantitative morphometry showed protection of alveolar epithelium from hyperoxia by 3 mg . kg-1 . day-1 rhMnSOD (P < 0.05). In addition, interstitial fibroblast volumes were increased in the treatment group (P = 0.06). This effect appeared greater at the two higher doses of the rhMnSOD. The aerosolized drug was localized to the surface of airways and air spaces and macrophages by immunolabeling studies, suggesting efficacy via physicochemical properties that localize it to cell surfaces or by effects on alveolar macrophage function.
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Hiperoxia/patología , Pulmón/patología , Superóxido Dismutasa/farmacología , Animales , Relación Dosis-Respuesta a Droga , Humanos , Pulmón/efectos de los fármacos , Masculino , Microscopía Electrónica , Papio , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/patología , Proteínas RecombinantesAsunto(s)
Medio Ambiente Extraterrestre , Animales , Crustáceos/efectos de los fármacos , Cyprinidae/efectos de los fármacos , Exposición a Riesgos Ambientales , Euglena/efectos de los fármacos , Moscas Domésticas/efectos de los fármacos , Insectos/efectos de los fármacos , Intestinos/anatomía & histología , Moluscos/efectos de los fármacos , Paramecium/efectos de los fármacos , Turbelarios/efectos de los fármacosAsunto(s)
Medio Ambiente Extraterrestre , Animales , Crustáceos/efectos de los fármacos , Cyprinidae/efectos de los fármacos , Exposición a Riesgos Ambientales , Euglena/efectos de los fármacos , Moscas Domésticas/efectos de los fármacos , Insectos/efectos de los fármacos , Intestinos/anatomía & histología , Moluscos/efectos de los fármacos , Paramecium/efectos de los fármacos , Turbelarios/efectos de los fármacosRESUMEN
PURPOSE: The effects of prolonged positive pressure ventilation on lung ultrastructure are not well defined in primates. This study was designed to measure cardiopulmonary and morphological responses to 4 days of positive pressure ventilation in normal baboons. MATERIALS AND METHODS: Six adult male baboons were mechanically ventilated on air for 96 hours with 2.5 cm positive end-expiratory ventilation and a tidal volume of 12 to 15 mL/kg. Physiological measurements were obtained every 12 hours and serial measurements of ventilation-perfusion (VA/Q) were performed using the multiple inert gas elimination technique. Quantitative morphotometry, lung dry-to-wet ratio, and surfactant analysis were performed at the end of the experiment. RESULTS: Cardiovascular variables, except for a small increase in mean pulmonary artery pressure at 84 and 96 hours, were not significantly affected by positive pressure ventilation. Arterial Po2 decreased, and shunt fraction increased from 0.7% of cardiac output to 5.4% (P < .01). Dispersion of perfusion increased threefold (P < .01), and dispersion of ventilation doubled (P < .01) indicating increased VA/Q mismatch mismatch. Respiratory system compliance decreased by 30% (P < .01). There was no lung edema or change in surfactant composition. Lung morphometry showed increases in polymorphonuclear cells and type II cell volume. Vacuolated endothelial cells and bare basement membrane were observed consistently. CONCLUSION: Four days of positive pressure ventilation decreases lung compliance and worsens gas exchange by increasing shunt and VA/Q mismatch in healthy baboons. These effects are accompanied by only minor ultrastructural changes and mild inflammatory responses in the lung.
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Pulmón/fisiología , Papio , Respiración con Presión Positiva , Animales , Membrana Basal/ultraestructura , Biopsia , Análisis de los Gases de la Sangre , Lavado Broncoalveolar , Cromatografía en Capa Delgada , Ensayo de Inmunoadsorción Enzimática , Pulmón/cirugía , Masculino , Microscopía Electrónica , Consumo de Oxígeno , Fosfolípidos/análisis , Proteínas/análisis , Presión Esfenoidal Pulmonar , Respiración Artificial , Volumen de Ventilación PulmonarRESUMEN
Ipsilateral and contralateral middle-component AERs (8-90 ms) were recorded from 20 normal neonates. AERs were elicited with either 500-Hz or 3000-Hz tone-pips presented monotically at 10, 30, and 50 dB HL. AERs also were obtained for silent control conditions. In general, latencies decreased and amplitudes increased with increasing stimulus level. Responses to 500-Hz tone-pips were larger than those for 3000 Hz. The results are similar to those obtained from adults. The neonates' middle-components, however, differ from those of adults in terms of the small contribution of the electroencephalic activity beyond 60 ms, and in the asymmetry between the ipsilateral and contralateral AERs.
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Audiometría de Respuesta Evocada/métodos , Audiometría/métodos , Estimulación Acústica , Potenciales Evocados Auditivos , Humanos , Recién Nacido , Tiempo de ReacciónRESUMEN
Tone-pips, centered at 1,000 Hz, were used to elicit middle component averaged electroencephalic responses (AERs) (8 to 90 ms) from five normal neonates. The stimuli were presented monaurally at 10-, 30-, and 50-dB HL, with regard to adult behavioral thresholds. Averaged electroencephalic responses were also derived for no-stimulus control conditions. The initial portion of the stimulus-elicited AER waveforms was similar to that obtained from adults. An objective, scoring procedure, based on predetermined rules, was used to determine peak latencies and to quantify point-to-point amplitudes. Inspection of the scored data revealed that latencies decreased and amplitudes increased as the stimulus magnitude increased, as has also been reported for adults. Unlike adult responses, the middle components from the neonates in this study were identifiable only when recorded from the side of the head ipsilateral to the ear stimulated.
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Percepción Auditiva , Recién Nacido , Umbral Auditivo , Potenciales Evocados , Lateralidad Funcional , HumanosRESUMEN
Articles in recent dental journals are strongly advising our dentist customers to require their laboratories to provide them with information regarding in-laboratory cross contamination control procedures. New strains of infectious diseases are emerging. Because of over use, some antibiotics are losing their effectiveness. The Center for Disease Control and The World Health Organization assert that emerging infections represent a global threat. Disinfection (use of glutaraldehyde, iodophors, and chlorine compounds) is generally less lethal to pathogenic organisms than sterilization. By using an autoclave in our laboratory we have taken the logical "next step" to protect our dentists and their patients.
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Control de Infección Dental/instrumentación , Laboratorios Odontológicos , Infección de Laboratorio/prevención & control , Esterilización/instrumentación , Equipo Dental , HumanosRESUMEN
Speech-language-hearing professionals need to develop a proactive posture regarding legislative issues. The first steps must begin at the local level. The state association is a reasonable and logical organization from which broader issues may be addressed, issues affecting the professionals as well as the patients/clients/students who require their services. The ideas that we generate at conferences and meetings to improve our educational and health care systems can be funneled into meaningful legislative action. The legislative issues of today become the governing regulations of tomorrow. Involvement in the legislative process helps strengthen our collective voices.
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Audiología/legislación & jurisprudencia , Sociedades , Patología del Habla y Lenguaje/legislación & jurisprudencia , California , Humanos , Maniobras Políticas , PolíticaRESUMEN
CONTEXT: Focus groups are becoming an important method for conducting qualitative research in health care. This strategy enables information to be gathered on the perceptions, beliefs, and values of a group's participants and is particularly well suited to addressing cultural characteristics that impact on a population's health status. As nations become more culturally diverse, qualitative research will likely play a growing role in helping health professions educators develop appropriate educational programs and in helping researchers better understand the needs of minorities and other vulnerable populations who are experiencing disparities in health care. OBJECTIVES: The purposes of this paper are to introduce the usefulness of a qualitative research strategy as an adjunct to quantitative survey research, and to describe briefly how researchers and educators at the Charles R. Drew University of Medicine and Science (Drew) have utilized this strategy when conducting combined qualitative and quantitative research. DISCUSSION: Focus group research has been successfully used to develop culturally adapted surveys, to develop educational programs, and to conduct needs assessments at Drew, which serves a culturally diverse urban population.
RESUMEN
Middle-component AERs (8-90 msec) to tone-pips from 10 normal-hearing adults were subjected to three objective methods of response identification. Threshold was then determined for each subject according to four different rules. The criterion score, which considers conjointly latency and amplitude values across the middle-component peaks, was developed as a single-value measure for response-identification and subsequent threshold-determination procedures. One of the response-identification methods was applied to 10 hearing-impaired subjects; the results of the threshold-determination procedures were encouraging. Further directions toward improving objective response analysis are discussed.
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Audiometría de Respuesta Evocada/métodos , Audiometría/métodos , Umbral Auditivo/fisiología , Potenciales Evocados , Trastornos de la Audición/fisiopatología , Humanos , Factores de TiempoRESUMEN
The middle components of the evoked cortical response (8-50 msec) were examined under improved signal processing conditions. 512 click stimuli were presented at 5 rates ranging from 1-16/sec to 10 normal-hearing subjects. The influence of stimulus numbers of 32, 64, 128 and 512 and stimulus rates of 1, 2, 4, 8 and 16/sec was examined. Identifiable and repeatable responses were found with as few as 128 stimuli. Stimulus rate had little effect on middle component waveform or its identifiability. An enhancement of signal-to-noise ratio through improved filter conditions is suggested as one reason for the ability to identify middle components to fewer stimuli.
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Percepción Auditiva/fisiología , Potenciales Evocados , Estimulación Acústica , Adolescente , Adulto , Audiometría , Umbral Auditivo , Electroencefalografía , Femenino , Humanos , Masculino , Ruido , Factores de TiempoRESUMEN
The bases for variations of the middle-component (8-50 ms) auditory averaged electroencephalic response (AER) to clicks during the averaging process were explored by examining (1) the trend of the mean variance of the averaged waveform, (2) averaged waveforms generated by successive blocks of stimuli fractioned from a total of 512 stimuli, and (3) averaged waveforms generated by successive, but partially overlapping, blocks of responses recorded for a train of 512 stimuli. These analyses indicated no systematic changes in peak latencies or peak-to-peak amplitudes as stimulation progressed. Fluctuations in middle AER waveform are more readily explained by non-stationarity of the background electrophysiologic noise. Previously reported amplitude reduction with increasing stimulus number possibly can be explained by progressive reduction of the background noise on which the consistent-amplitude middle components are superimposed.
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Percepción Auditiva , Encéfalo/fisiología , Ruido , Estimulación Acústica , Adulto , Audiometría , Electroencefalografía , HumanosRESUMEN
Pseudomonas putrefaciens is an unusual cause of human disease. Since 1978 only five cases of bacteremia due to this organism have been reported. Within 12 recent months four cases of bacteremia due to P. putrefaciens were seen - two occurred in patients with chronic infections of a lower extremity, one in a patient with neutropenia, and one in a patient with fulminant septicemia and disseminated intravascular coagulation. Two of the patients had prostheses; in neither case did prosthetic infection or prosthetic failure occur. Two syndromes of bacteremic infection with P. putrefaciens are suggested. One syndrome is associated with chronic infection of a lower extremity, is fairly well tolerated, and responds to appropriate antimicrobial agents. The other syndrome is more fulminant and may be associated with severe underlying debility, liver disease, and malignancy. It is not yet known whether this is a meaningful distinction. The significance of the recent increase is the isolation of this organism is not clear at present.
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Infecciones por Pseudomonas , Sepsis/etiología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Infecciones por Pseudomonas/diagnóstico , Infecciones por Pseudomonas/terapia , Sepsis/diagnóstico , Sepsis/terapiaRESUMEN
Sepsis-induced tissue factor (TF) expression activates coagulation in the lung and leads to a procoagulant environment, which results in fibrin deposition and potentiates inflammation. We hypothesized that preventing initiation of coagulation at TF-Factor VIIa (FVIIa) complex would block fibrin deposition and control inflammation in sepsis, thereby limiting acute lung injury (ALI) and other organ damage in baboons. A model of ALI was used in which adult baboons were primed with killed Escherichia coli (1 x 10(9) CFU/kg), and bacteremic sepsis was induced 12 h later by infusion of live E. coli at 1 x 10(10) CFU/kg. Animals in the treatment group were given a competitive inhibitor of TF, site-inactivated FVIIa (FVIIai), intravenously at the time of the infusion of live bacteria and monitored physiologically for another 36 h. FVIIai dramatically protected gas exchange and lung compliance, prevented lung edema and pulmonary hypertension, and preserved renal function relative to vehicle (all p < 0.05). Treatment attenuated sepsis-induced fibrinogen depletion (p < 0.01) and decreased systemic proinflammatory cytokine responses, for example, interleukin 6 (p < 0.01). The protective effects of TF blockade in sepsis-induced ALI were confirmed by using tissue factor pathway inhibitor. The results show that TF-FVIIa complex contributes to organ injury in septic primates in part through selective stimulation of proinflammatory cytokine release and fibrin deposition.