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Biomedical subjects

J A Graham

Publications and source records attributed to J A Graham.

At least 37 records · Page 2Linked to original sources
PubMed1993

Direct measurement of pulmonary microvascular distensibility.

Pulmonary vascular distensibility has an important influence on pulmonary hemodynamics. Although many measurements of distensibility have been made on large pulmonary vessels, there is less information on microvascular distensibility. We have measured the distensibility of the smallest (< 70-microns-diam) precapillary arterioles and postcapillary venules. Isolated dog lobes, at 2.5 cmH2O transpulmonary pressure, were perfused at low flows, which caused the arteriovenous pressure gradient to be very small and thereby permitted accurate estimation of microvascular pressure. As microvascular pressure was systematically varied between 0 and 30 mmHg, subpleural microvascular diameters were determined from computer-enhanced images obtained by videomicroscopy. Arteriolar and venular distensibilities were not different from each other. The microvascular pressure-diameter relationship was alinear with distensibility coefficients of 1-3% mmHg-1, values that are of the same order of magnitude as previously measured distensibilities of 100- to 1,000-microns-diam canine pulmonary vessels.

Animals↗
PubMed1992

Epithelial injury and interstitial fibrosis in the proximal alveolar regions of rats chronically exposed to a simulated pattern of urban ambient ozone.

Electron microscopic morphometry was used to study the development of lung injury during and after chronic (78 weeks) exposure to a pattern of ozone (O3) designed to simulate high urban ambient concentrations that occur in some environments. The daily exposure regimen consisted of a 13-hr background of 0.06 ppm, an exposure peak that rose from 0.06 to 0.25 ppm, and returned to the background level over a 9-hr period, and 2-hr downtime for maintenance. Rats were exposed for 1, 3, 13, and 78 weeks. Additional groups of rats exposed for 13 or 78 weeks were allowed to recover in filtered clean air for 6 or 17 weeks, respectively. Rats exposed to filtered air for the same lengths of time were used as controls. Samples from proximal alveolar regions and terminal bronchioles were obtained by microdissection. Analysis of the proximal alveolar region revealed a biphasic response. Acute tissue reactions after 1 week of exposure included epithelial inflammation, interstitial edema, interstitial cell hypertrophy, and influx of macrophages. These responses subsided after 3 weeks of exposure. Progressive epithelial and interstitial tissue responses developed with prolonged exposure and included epithelial hyperplasia, fibroblast proliferation, and interstitial matrix accumulation. The epithelial responses involved both type I and type II epithelial cells. Alveolar type I cells increased in number, became thicker, and covered a smaller average surface area. These changes persisted throughout the entire exposure and did not change during the recovery period, indicating the sensitivity of these cells to injury. The main response of type II epithelial cells was cell proliferation. The accumulation of interstitial matrix after chronic exposure consisted of deposition of both increased amounts of basement membrane and collagen fibers. Interstitial matrix accumulation underwent partial recovery during follow-up periods in air; however, the thickening of the basement membrane did not resolve. Analysis of terminal bronchioles showed that short-term exposure to O3 caused a loss of ciliated cells and differentiation of preciliated and Clara cells. The bronchiolar cell population stabilized on continued exposure; however, chronic exposure resulted in structural changes, suggesting injury to both ciliated and Clara cells. We conclude that chronic exposure to low levels of O3 causes epithelial inflammation and interstitial fibrosis in the proximal alveolar region and bronchiolar epithelial cell injury.

Administration, Inhalation↗
PubMed1992

Health effects of atmospheric acid aerosols: a model problem in inhalation toxicology and air pollution risk assessment.

A symposium entitled, Health Effects of Atmospheric Acid Aerosols: A Model Problem in Inhalation Toxicology and Air Pollution Risk Assessment, was held at the 30th Annual Meeting of the Society of Toxicology (SOT) in Dallas, Texas. The symposium was sponsored by the Inhalation Toxicology Specialty Section of SOT, and was organized to integrate evidence from various disciplines concerning health effects from acid aerosols in ambient air.

Acids↗
PubMed1992

Antithrombin III deficiency and cerebrovascular accidents in young adults.

A young man with antithrombin III (AT-III) deficiency sustained a cerebellar venous infarct and recovered following treatment with AT-III concentrate. A family study showed that other members were affected. AT-III deficiency in this family was found to be due to a new variant AT-III TRURO 1. Young patients with strokes should be screened for thrombophilia.

Adult↗
PubMed1992

Diphenhydramine toxicity in a child with varicella. A case report.

Varicella may be associated with serious complications including encephalitis, Reye's syndrome, and drug toxicity. In this case, a 19-month-old child with varicella was brought to the family practice clinic by her parents when she began behaving abnormally. At the time of presentation the child exhibited dilated pupils, ataxia, urinary retention, and facial grimacing. The child's parents had treated her with acetaminophen, diphenhydramine syrup, colloidal oatmeal baths, and frequent applications of Caladryl lotion. The results of her immediate laboratory tests were within normal limits, and she was admitted to the hospital for observation. She recovered without therapeutic intervention. Although not available at the time of admission to the hospital, her diphenhydramine serum level was 1948 ng/mL. Diphenhydramine levels above 100 ng/mL have been associated with toxicity.

Administration, Oral↗
PubMed1991

Alveolar epithelial cell injuries by subchronic exposure to low concentrations of ozone correlate with cumulative exposure.

Electron microscopy morphometry has been used to study the effects of cumulative exposure of low levels of inhaled O3 on lung proximal alveolar tissue. Six-week-old Fisher 344 rats were exposed to O3 in two different subchronic low-level exposure patterns. The first was a 12 hr/day exposure for 6 weeks and included two O3 concentrations, 0.12 and 0.25 ppm. The second consisted of an exposure profile having a background level of 0.06 ppm with an exposure peak 5 days each week that went from 0.12 to 0.25 ppm and back to 0.12 ppm over a 9-hr period. Rats given the second exposure pattern were exposed for either 3 or 13 weeks. Changes in the volumes of alveolar epithelium were found to be consistent and reproducible markers for cell injury and/or response. Results from the first study indicated that the relative volume of the type I epithelium increased 13 and 23% over the control value (p less than 0.05) following exposures for 6 weeks to 0.12 and 0.25 ppm, respectively. The magnitude of the increases were clearly concentration related. Similarly, when a fixed exposure concentration was employed the relative volume of type I epithelium was found to increase in proportion to the exposure time. In the second exposure, increases of 9 and 33% in relative volume of type I epithelium were found respectively after 3 and 13 weeks of exposure. If the total exposure determined by the product of O3 concentration (including background) and exposure time is plotted against the relative volume of type I epithelium from both the 0.12 ppm (60.5 ppm-hr) and 0.25 ppm (126 ppm-hr) exposures and the 3-week (45.3 ppm-hrs) and 13-week (196.2 ppm-hr) exposures, a linear relationship between increases in type I cell volume and the concentration X time product is observed. The coefficient of correlation (r2) for the linear regression of the animal means is 0.72. Changes in the volume of Type II epithelial cell also correlate with the concentration X time product (r2 = 0.66). This suggests that epithelial cell reactions to low-level subchronic exposure of O3 are directly related to the cumulative oxidant concentration. The pattern of exposure did not appear to affect the resulting degree of injury. Furthermore, a low level of background exposure may contribute to the epithelial cell injuries.

Animals↗
PubMed1990

Pulmonary effects due to subchronic exposure to oil fog.

Male and in some cases female rats were exposed to an oil fog generated by flash vaporization and subsequent condensation of light-weight lubricating oil. Exposures were for 3.5 h/d, 4d/wk for 13 wk. Males were exposed at concentrations of 1.5, 0.5, 0.2 or 0.0 mg/l (1500, 500, 200, and 0 mg/m3) and a particle size of approximately 1 micron (mass median aerodynamic diameter). A number of biologic endpoints were assessed the day after the last exposure and, in some cases, after a 4 wk recovery period. Effects of 1.5 mg/l on male and female rats were compared. Diffuse accumulation of macrophages in the alveoli was observed in all oil fog exposed groups. The degree of severity was concentration dependent. Histopathologic changes were more prominent in males than in females and represented the most notable gender-related differences. Histologic effects observed one day and 4 wk post exposure were similar. Minimal histopathologic changes and minimal increase in lavage fluid protein were the only effects observed at the 0.2 mg/l exposure level. There was a significant increase in lavage fluid protein, percent lavagable polymorphonuclear leukocytes and lung wet and dry weight following exposure to both 0.5 and 1.5 mg/l. At the highest exposure concentration effects on lung weights were still evident 4 wk post exposure. Pulmonary function endpoints including total lung capacity, vital capacity, residual volume, diffusing capacity to CO, compliance, and end expiratory volume (EEV) were unaffected by oil fog exposure with the exception of EEV in males exposed at the 1.5 mg/l level. All of the changes observed following oil fog exposure were consistent with a mild inflammatory edema.

Aerosols↗
PubMed1990

Interdisciplinary approach to assessing the health risk of air toxic chemicals: an overview.

To assist the regulatory branch of the Environmental Protection Agency in addressing the risk assessment of air toxics, the Health Effects Research Laboratory initiated a comprehensive inhalation toxicology program to provide key health effects data missing from the current data base. A priority ranking of chemicals based on the potential for substantial human exposure and the need for health effects data was developed to identify candidate chemicals for toxicological research. The major goal of the program is to evaluate the concentration-response from acute, intermittent and subchronic inhalation exposures to developmental, genetic, hepatic, immunologic, neurologic, pulmonary and reproductive toxicity in a manner that provides data for the regulatory health assessment of air toxic chemicals. Extrapolation and dosimetry research is also conducted to improve the basis for human risk assessment. Determination of biological endpoints to be examined will be decided on a compound-by-compound basis, depending on the physical, chemical and structural characteristics of the chemical and evaluation of the existing health data base. Although the main emphasis is on inhalation as the primary route of exposure, some of the laboratories will compare inhalation to other routes, such as oral, to better understand the influence of route of exposure and hence the potential applicability of existing health data. Acute and intermittent exposures will be done for all compounds. Upon evaluation of the acute results, a decision will be made as to whether subchronic studies are needed. Endpoints that show unusual sensitivity may be investigated in greater detail. The total length of exposure will vary from 1 to 21 days. The daily length of exposure will range from 1 to 8 hr. If adverse effects are observed at ambient levels, the time to recovery after exposure will be investigated.

Administration, Inhalation↗
PubMed1989

Effects of inhaled hexachlorobenzene aerosols on rat pulmonary host defenses.

Pulmonary bactericidal activity, macrophage phagocytic activity, alveolar macrophage (AM) enzyme activity, and T- and B-cell mitogenesis of lymphocytes from lung associated lymph nodes (LALN) or mesenteric lymph nodes (MESLN) were assessed in Sprague-Dawley rats exposed 4 hr/d, 4 days/wk for 1, 4, or 16 days to hexachlorobenzene (HCB) aerosols. Pulmonary bactericidal activity was depressed after 1 or 4 but not 16 exposures to 35 mg/m3 of HCB. AM phagocytosis of 51Cr-RBC in vitro was increased after 4 but not 1 or 16 exposures to HCB, and no effect was observed in peritoneal macrophages. HCB significantly enhanced mitogenesis in MESLN to the B-cell mitogen Salmonella typhimurium lipopolysaccharide (STM) after 4 exposures; LALN STM mitogenesis and LALN and MESLN mitogenesis to phytohemagglutinin (PHA) were not affected. After 16 exposures, however, the PHA responses in LALN and MESLN were significantly increased and decreased, respectively.

Administration, Intranasal↗
PubMed1989

Review, discussion, and summary: toxicology.

The research presented in the toxicology session of the Symposium on the Health Effects of Acid Aerosols significantly advances our understanding of the health effects of acid aerosols and clearly illustrates the importance of animal inhalation toxicology to risk assessment. The description of the effects of acid on airway mucus buffering capacity and viscosity helps explain some of the mechanisms responsible for the effects of sulfuric acid on mucociliary clearance and pulmonary function observed in man and animals. Several of the papers illustrate that other pollutants interact with sulfuric acid (H2SO4), causing concern about exposure risks and helping in elucidating the effects observed in epidemiology studies that have not yet been duplicated in a laboratory. For example, H2SO4 absorbed in zinc oxide (ZnO) particles appears to be about a log more potent than H2SO4 alone in causing pulmonary function decrements. Low levels of H2SO4 and O3 were found to be synergistic in increasing collagen synthesis, implying a risk in development of lung fibrosis. More complex mixtures containing H2SO4 cause a variety of interactions, depending upon the end points examined and the chemistry of the mixture. Other reports indicate that dose rate and length of exposure issues are critical to toxicological outcomes. Animal data on mucociliary clearance, which parallels that of human data, was extended to show that concentration of exposure was more important than time of exposure in eliciting a response, although time played a significant role. A recent chronic study showed that H2SO4 caused effects that also can occur in the development of chronic bronchitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Rain↗
PubMed1989

The psychology of appearance in the elderly.

Appearance counts heavily in human affairs. The good-looking have many advantages. These benefits also extend to old age. Elderly persons who preserve a youthful appearance (look young for their age) are likely to be more optimistic, more outgoing, and more social. They rate themselves more highly on many psychologic dimensions. Those who look older than their stated age die earlier and are not as healthy physiologically. Cosmetics can help the elderly attain some of the benefits enjoyed by the physically attractive.

Aged↗
PubMed1988

Effects of low levels of NO2 on terminal bronchiolar cells and its relative toxicity compared to O3.

This report describes structural changes occurring in the terminal bronchioles of rats exposed to low levels of NO2 continuously for 6 weeks. In addition, the relative susceptibility of epithelial cells to oxidants and the comparative toxicity of NO2 and O3 are discussed. Terminal bronchioles isolated from rats exposed 5 days/week to 2.0 ppm NO2 (plus two 1-hr daily spikes to 6.0 ppm) were found to have 19% less ciliated cells per unit area of epithelial basement membrane. The remaining ciliated cells had a reduced mean surface area (-29%). The shape of the Clara cell changed with reduced size of the dome protrusions but increased cell contact with the basement membrane. These data indicate that exposure to 2.0 ppm NO2 (+ spikes) for 6 weeks caused injuries to cilia and ciliated cells and possible Clara cell differentiation in the terminal bronchioles of adult rats. Exposures of adult or juvenile rats to 0.5 ppm NO2 (+ two 1-hr daily spikes 5 days/week to 1.5 ppm) did not cause morphologically measurable injuries in the terminal bronchioles. The severity of the concentration-dependent epithelial cell reactions to NO2 and O3 in adult rat terminal bronchioles were compared to those occurring in the proximal alveolar regions (PAR). Epithelial cells in the PAR appeared to be more susceptible to oxidant insult since both 0.5 ppm NO2 and 0.25 ppm O3 were found to cause epithelial injury only in the PAR. Comparison of epithelial reactions to 6-week exposures to either NO2 or O3 indicated that 0.25 ppm O3 caused four times as much increase in the number of type I epithelial cells as did 2 ppm (+spikes) NO2. Therefore, O3 could be 40 times more toxic than NO2 in the PAR on the basis of the inspired concentration and the focal response. On the other hand, there was no loss of ciliated cells following the 0.25 ppm O3 exposure. This suggests that the ratio of O3 to NO2 toxicity in the terminal bronchioles is considerably less than 10. The relative toxicity of the two oxidant gases appears to be site specific.

Animals↗
PubMed1988

Research needs and advances in inhalation dosimetry identified through the use of mathematical dosimetry models of ozone.

Knowledge of the quantitative relationship between exposure concentration and delivered dose (i.e., dosimetry) is a fundamental starting point in the evaluation of the toxicity of chemicals, not only for intra- and interspecies comparisons but also for designing experiments that elucidate mechanisms of action and that identify issues or research areas for further study. To these ends a mathematical, lower respiratory tract dosimetry model for gases has been developed which, when linked to experimentally determined upper respiratory tract removal of a gas, can be used for dosimetric extrapolations between one test condition to a theoretical condition (e.g., animal-to-man, child-to-adult, high-to-low dose). This paper, using the ozone (O3) dosimetry model as an example, describes (1) the results of sensitivity analyses that have identified variables that can significantly influence the precision of model predicted doses, (2) research progress in improving the precision of those highly sensitive variables, and (3) approaches being used to validate the model. Results from studies of upper respiratory tract removal of O3 in animals and human are used as inputs into the mathematical model of the lower respiratory tract to illustrate applications of dosimetric extrapolations.

Administration, Inhalation↗
PubMed1988

Pulmonary function in juvenile and young adult rats exposed to low-level NO2 with diurnal spikes.

Pulmonary function was examined for juvenile and young adult Fischer 344 rats that were continuously exposed to NO2 (0.5, 1.0, or 2.0 ppm) for up to 6 wk. The exposure included twice daily 1-h spikes equal to 3 times the baseline concentration. This spike-to-baseline ratio was chosen to simulate morning and evening urban rush-hour conditions. Juvenile rats were examined after 3 and 6 wk of NO2 exposure, whereas young adult rats were examined after 1-, 3-, and 6-wk intervals. Lung volumes, compliance, and efficiency of ventilation distribution were evaluated. Lung volumes increased in the juvenile rats after 3- and 6-wk exposures to 1.0 and 2.0 ppm NO2, but were unchanged in young adult rats. Lung compliance increased in juvenile rats exposed to 1.0 or 2.0 ppm NO2 for 3 wk. However, it was unchanged in juvenile rats exposed for 6 wk or in young adult rats exposed for 1 or 3 wk. Compliance decreased in young adult rats exposed to 2.0 ppm NO2 for 6 wk and was correlated to an overall thickening of alveolar interstitium and septal tissue. However, the observed changes in pulmonary function were marginal and reversible, since lung-function measurements were not different from controls after a 3-wk recovery period.

Animals↗
PubMed1987

Effects of inhalation of ethylene dichloride on pulmonary defenses of mice and rats.

The effects of single or multiple inhalation exposures to ethylene dichloride (DCE) on the pulmonary defense systems of mice and rats were evaluated. Single exposures of mice to the threshold limit value of DCE (10 ppm) resulted in decreased pulmonary bactericidal activity to inhaled Klebsiella pneumoniae and increased mortality from Streptococcus zooepidemicus respiratory infection. A single exposure to 5 ppm DCE caused increased mortality from streptococcal pneumonia although bactericidal activity was not affected. Neither of these two parameters changed following single or five consecutive daily exposures to 2.5 ppm DCE. Single exposures to 10 or 100 ppm DCE did not affect mouse alveolar macrophage (AM) inhibition of the proliferation of a tumor target cell in vitro or AM in vitro phagocytosis of red blood cells. In rats, no effects were observed on pulmonary bactericidal activity. AM in vitro phagocytosis, AM cytostasis and cytolysis of tumor target cells, AM ectoenzymes, or blastogenesis of mitogen-stimulated rat T- and B-lymphocytes from lung-associated, mesenteric, and popliteal lymph nodes following single exposure to 100 or 200 ppm DCE or after twelve 5-hr exposures to 10, 20, 50, or 100 ppm DCE.

Administration, Inhalation↗
PubMed1987

Effects of NiCl2 and CdCl2 on susceptibility to murine cytomegalovirus and virus-augmented natural killer cell and interferon responses.

Female C3H/HeJ or CD-1 mice were infected with a sublethal dose of murine cytomegalovirus (MCMV) and then exposed to nickel chloride (NiCl2) or cadmium chloride (CdCl2) intramuscularly (im) or by inhalation. Effects of these treatments on disease susceptibility, virus-augmented and spontaneous natural killer (NK) cell activity, and virus induction of interferon (IFN) were determined. NiCl2 (20 mg/kg, im) enhanced mortality due to MCMV in both mouse strains, and a reduction in virus-augmented NK cell activity was seen at doses as low as 10 mg NiCl2/kg im. At 6.25 mg CdCl2/kg im there was a significant depression of NK cell activity, but there was no effect on mortality due to infection. Effects on NK activity did not appear to be due to effects on IFN production since neither of the metal treatments caused depression of this response. Neither metal when given by inhalation had any effect on these parameters.

Aerosols↗