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Biomedical subjects

J L Wright

Publications and source records attributed to J L Wright.

At least 109 records · Page 6Linked to original sources
PubMed1994

Suppression of a yeast mitochondrial RNA processing defect by nuclear mutations.

The S. cerevisiae strain h56 is a temperature-sensitive mit- mutant containing a single nucleotide substitution in the region 5' to the reading frame of the mitochondrial var1 gene. The mutation decreases the efficiency of processing of a precursor RNA such that little var1 mRNA is produced at the restrictive temperature, 36 degrees C. This communication reports the isolation and characterization of several strains carrying nuclear mutations which suppress the temperature-sensitivity of h56. Both dominant and recessive suppressor mutations were isolated. One dominant suppressor strain (h56-S4) was characterized biochemically, and the mechanism of suppression shown to involve a restoration of precursor RNA processing at the restrictive temperature, with a concomitant increase in the synthesis of the var1 protein. It appears likely that the suppressing allele encodes a component of an RNA processing endoribonuclease active on var1 transcripts. A genomic library was constructed from the h56-S4 strain, and several plasmids showing suppressed activity were isolated. A preliminary analysis of these plasmids is presented.

Alleles↗
PubMed1994

Blood-brain barrier changes following intracerebral injection of human recombinant tumor necrosis factor-alpha in the rat.

Human recombinant tumor necrosis factor-alpha (rTNF-alpha) was administered to normal Fischer 344 rats by stereotaxic intracerebral (IC) injection. Animals receiving a single injection of either 6 x 10(4) U rTNF-alpha or an equivalent volume of excipient (vehicle) in their right parietal lobe. In order to demonstrate any effects rTNF-alpha might have on the blood-brain barrier (BBB), two studies were conducted, one employing exogenous horseradish peroxidase (HRP,44 kD) as a tracer of BBB permeability and the other using endogenous IgG (150 kD). Rats given rTNF-alpha showed transitory BBB permeability to HRP by 24 hours post-injection; this BBB compromise was determined to be no longer than 60 hours. In the other study, IgG was seen to cross the BBB by 48 hours post-rTNF-alpha injection. Alternatively, rats injected IC with excipient showed only limited BBB opening as a result of injection-induced trauma. We conclude that human rTNF-alpha, injected IC into normal rats triggers a temporary breakdown in BBB integrity which begins sometimes between 12 and 24 hours post-injection, is large enough to permit macromolecules of at least 150 kD to pass, and resolves by 72 hours post-injection.

Animals↗
PubMed1994

Lung structure and function in cigarette smokers.

BACKGROUND: Cigarette smoking produces an inflammatory response in the airways of everyone but only 15-20% of smokers develop airways obstruction. The present study concerns the relative importance of peripheral airways inflammation and the emphysematous destruction of the parenchymal support of the airways in the pathogenesis of this obstruction. METHODS: A total of 407 patients with a diagnosis of lung tumour performed pulmonary function tests a day or two before a lung or lobar resection. The specimens were fixed in inflation and analysed at the gross and microscopic level to determine the extent and severity of the emphysematous process, the number of alveoli supporting the outer walls of the airways, and the average distance between alveolar walls. The severity of the inflammatory process in the respiratory and nonrespiratory bronchioles was also assessed using a previously established grading system. RESULTS: The lung function test showed that a decline in FEV1 was associated with an increase in residual volume and a decrease in the diffusing capacity for carbon monoxide and a reduction in the lung maximum elastic recoil pressure. The prevalence of grossly visible emphysema increased as FEV1 declined, but the extent and severity of these lesions and the number of alveoli supporting the outer walls of the peripheral airways was similar at all levels of FEV1. The system used to grade inflammatory response in the peripheral airways failed to identify a specific defect responsible for the physiological abnormalities. CONCLUSION: The reduction in FEV1 associated with chronic cigarette smoking can be partially explained by loss of lung elastic recoil pressure which reduces the force driving air out of the lung. This loss of elastic recoil pressure is attributed to microscopic enlargement of the air spaces rather than to grossly visible emphysema. The exact nature of the lesions responsible for the peripheral airways obstruction remains to be identified.

Aged↗
PubMed1994

Relation of smoking to immunoreactive endothelin in the bronchiolar epithelial cells.

BACKGROUND: Endothelin is a potent bronchoconstrictor which appears to be important in asthma. To ascertain whether cigarette smoking is associated with any alteration in the proportion of bronchiolar epithelial cells which express endothelin immunoreactivity, the airways in the lungs of non-smokers and smokers were analysed. Since an increase in immunoreactivity has been found in the bronchial epithelial cells of asthmatic subjects, cigarette smokers with and without evidence of airway hyperresponsiveness were also selected. METHODS: A point counting method which examined the proportion of endothelin immunoreactive epithelial cells in membranous and respiratory bronchioles was used. RESULTS: Neither smoking itself nor evidence of airway hyperresponsiveness altered the percentage of endothelin immunoreactive epithelial cells in the membraneous and respiratory bronchioles. CONCLUSIONS: Cigarette smoke does not induce endothelin production in bronchiolar epithelial cells, and the airway hyperresponsiveness seen in some patients with lung disease induced by cigarette smoking is not related to exaggerated endothelin production in epithelial cells.

Bronchi↗
PubMed1994

Cigarette smoke causes rapid cell proliferation in small airways and associated pulmonary arteries.

To determine whether smoke could directly affect the cells of the small airways and the small vessels, we exposed Sprague-Dawley rats to the whole smoke of 7 cigarettes/day for 1, 2, or 7 days. Three hours before the rats were killed, 5-bromo-2'-deoxyuridine (BrdU) was administered. Labeled nuclei were counted in histological sections stained with antibodies to BrdU. In smokers, pulmonary artery walls at the level of the membranous bronchioles (MB), respiratory bronchioles (RB), and alveolar ducts (AD) showed significant increases in labeled nuclei at all three times; increases in endothelial labeling were only present in vessels associated with AD. Significantly increased labeling was also seen in the epithelium and walls of MB and RB themselves at all time periods. However, there was no correlation between labeling indexes in matched pairs of airways and vessels. Smoke had no effect on the labeling of mesothelial and submesothelial cells. We conclude that cigarette smoke rapidly causes proliferation of intrinsic cells in the airways and small vessels; this effect may lead eventually to airway wall muscular hyperplasia and fibrosis (small airways disease) and to vascular changes associated with pulmonary hypertension. However, the lack of correlation between labeling indexes in the vessels and airways suggests that different mediators are involved at these two sites. At least over the time course of this experiment, smoke does not cause proliferation of mesothelial or submesothelial cells.

Animals↗
PubMed1994

Effect of smoking cessation on pulmonary and cardiovascular function and structure: analysis of guinea pig model.

To assess the pulmonary structural and functional effects of smoking cessation, we exposed groups of guinea pigs to cigarette smoke for 4 and 8 mo and included a group of animals in which smoke exposure was stopped at 4 mo (ex-smokers). We found that, compared with control nonsmokers, the smokers at both 4 and 8 mo showed airflow obstruction with alterations in lung volume and morphological evidence of emphysema with increased alveolar air space size and decreased alveolar surface area-to-volume ratio. There was an alteration in the pulmonary vascular structure, with increased numbers of muscularized arterioles, in the smokers at both time periods, and this was associated with significantly increased pulmonary arterial pressure at 8 mo. Cessation of smoke exposure appeared to halt, but not reverse, these structural changes. The smokers at 8 mo showed clear evidence for a "healthy smoker" effect, underscoring the necessity for longitudinal studies even when using an animal model. We conclude that cessation of exposure to cigarette smoke is associated with an apparent halt, but not a reversal, of emphysematous lung enlargement and pulmonary arteriolar muscularization. However, the magnitude of improvement in pulmonary function is not as great as the apparent structural differences would imply, and there is no clear effect on the pulmonary arterial pressure.

Airway Obstruction↗
PubMed1994

Persistence of natural mineral fibers in human lungs: an overview.

Virtually all available data on persistence of naturally occurring mineral fibers in human lungs have been derived from studies of asbestos fiber loads. These studies indicate that, although both amphibole and chrysotile asbestos fibers are found in the lungs of the general population and exposed workers, amphibole fibers are universally present in disproportionately large and chrysotile fibers in disproportionately small amounts compared to their known abundance in the original inhaled dusts. Why this should be remains unclear. Most reports have shown that fiber accumulation is proportional to measured exposure for amphiboles, but this is not generally true for chrysotile. Very little information is available on actual fiber clearance rates from human lungs. For amosite and crocidolite, estimated clearance half-times are measured in years to decades, whereas for chrysotile the available, rather indirect, data suggest that the vast majority of fibers are cleared within months, although some fibers may be sequestered and very slowly cleared. Overall these studies suggest that the differences between amphibole and chrysotile fiber burdens in man reflect much faster clearance of chrysotile fibers, rather than a failure of chrysotile deposition. A variety of other naturally occurring fibers are commonly found in human lungs, but there are no data on their rates of accumulation or disappearance.

Animals↗
PubMed1993

An anti-okadaic acid-anti-idiotypic antibody bearing an internal image of okadaic acid inhibits protein phosphatase PP1 and PP2A catalytic activity.

Okadaic acid (OA), produced by marine phytoplankton, is the parent compound of a family of marine toxins responsible for diarrheic shellfish poisoning (DSP). A monoclonal antibody to OA (6/50) (Ab1) has been raised and in turn used for immunization of syngeneic animals. Mice inoculated with the 6/50 idiotype produced both anti-idiotypic antibodies (Ab2) and OA binding antibodies (Ab3). The selected anti-idiotypic antibody 1/59 bound to the immunizing 6/50 idiotype but not to F(ab')2 fragments of pooled normal mouse Ig. It inhibited the binding of OA to solid-phase attached F(ab')2 of 6/50 IgG as well as the binding of 6/50 IgG to a solid-phase bound OA. Like OA, 1/59 anti-idiotypic antibody inhibited protein phosphatase 1 and 2A catalytic subunits in a 32P-phosphorylase a phosphatase radioassay. Thus, 1/59 IgG is a novel internal image anti-idiotypic antibody (Ab2 beta) and can serve as a surrogate of OA in biological assays.

Animals↗
PubMed1993

Pediatric acepromazine poisoning: the importance of child-resistant packaging for veterinary drugs.

The first reported case of acepromazine ingestion in a pediatric patient is presented. It is an aliphatic phenothiazine that is structurally similar to chlorpromazine (thorazine). In our case, a 2 1/2-year-old male ingested 3 to 4 of his 80-pound Doberman's 25-mg tablets. The pills were stored in a vial without a child-resistant closure. The child displayed signs and symptoms of phenothiazine toxicity. There is no federal law which requires veterinary medicines to be dispensed in special packaging. All prescription medications should require child-resistant packaging.

Acepromazine↗
PubMed1993

An unusual form of pulmonary aspergillosis in two patients with the acquired immunodeficiency syndrome.

Two cases of an unusual pathologic form of pulmonary aspergillosis in patients with the acquired immunodeficiency virus are reported. Each was characterized by chronic cavitary disease with involvement of small bronchioles and extension into subtending alveoli. It is suggested that this variant would best be described as chronic cavitary and invasive bronchopulmonary aspergillosis. A prominent feature in each case was the presence of numerous cytomegalovirus inclusions adjacent to the cavities and affected airways. The significance of this association is not known.

AIDS-Related Opportunistic Infections↗
PubMed1993

Relationship of pulmonary arterial pressure and airflow obstruction to emphysema.

Guinea pigs were exposed to cigarette smoke for 6 mo, after which lung and cardiac function and lung morphology were examined. The smoke-exposed animals were divided into two groups on the basis of final pulmonary arterial pressure. We found that the smoke-exposed animals with increased pulmonary arterial pressure had a moderate degree of airflow obstruction compared with the normotensive smoke group, which showed only mild airflow obstruction, and with the control group. Both smoke groups had similar degrees of emphysema. Although both smoke groups had an increased percentage of muscularized small arterioles, only the group with increased pulmonary arterial pressure had an altered flow-pressure response to dobutamine. We conclude that although cigarette smoke appears to induce changes in the vascular structure and to produce emphysematous lung destruction, the increased pulmonary arterial pressure in guinea pigs chronically exposed to smoke is not directly related to either of these findings. Instead, it appears that there is a dynamic alteration of both the airways, producing airflow obstruction, and the vasculature, producing increased pulmonary arterial pressure.

Airway Obstruction↗
PubMed1993

Fiber burden and patterns of asbestos-related disease in chrysotile miners and millers.

To examine how fiber type, fiber concentration, and fiber size correlate with the presence of asbestos-related disease in workers with heavy chrysotile exposure, we used analytic electron microscopy to determine the fiber content of the lungs of 94 long-term chrysotile miners and millers from the region of Thetford Mines, Quebec. Mesothelioma, airway fibrosis, and asbestosis were strongly associated with a high tremolite fiber concentration, whereas pleural plaques and carcinoma of the lung showed no relationship to tremolite burden. Similar patterns were seen for chrysotile concentration, but further analysis suggested that the apparent effect of chrysotile probably was due to the high correlation (r = 0.70) between chrysotile and tremolite concentration rather than to an independent effect of chrysotile. Increased tremolite-chrysotile ratio was marginally associated with the presence of pleural plaques but not with any other disease. Very high correlations (r > 0.90) between the concentrations of fibers longer or shorter than 8 microns prevented assessment of the effects of long compared with short fibers. Pleural plaques were very strongly associated with higher mean tremolite fiber aspect ratios, but no differences in mean fiber size (length, width, aspect ratio, surface area, and mass) were seen for any other disease. Total fiber size measures (total fiber length/g and others) showed differences similar to fiber concentration for mesothelioma, airways fibrosis, and asbestosis, but no one measure was clearly better than another or better than fiber concentration. We conclude that, in this population of heavily exposed chrysotile miners and millers, the presence of airways fibrosis and asbestosis and, probably, mesothelioma reflects high tremolite burden.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Inhalational lung injury causing bronchiolitis.

Inhalational injury to the respiratory tract is common and can be subtle. The clinical features produced by these injuries are very similar, and pulmonary function tests usually show an obstructive profile. Pathologic reactions also appear to be similar, with the end result airway distortion by inflammation and fibrosis. Rather than postulating that there is a specific airway response to each of a broad range of agents, it is more likely that inflammation and fibrosis are nonspecific and stereotypic responses.

Air Pollutants↗
PubMed1992

Interaction of domoic acid and several derivatives with kainic acid and AMPA binding sites in rat brain.

We have determined the inhibitory potencies of domoic acid and a series of derivatives of domoic acid at kainic acid and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) binding sites in rat forebrain membranes. These derivatives of domoic acid differed in the configuration, stereochemistry, and degree of saturation of the side chain attached to C-4 of the prolyl ring. The binding data were analyzed in terms of one or two classes of sites as appropriate. Domoic acid and kainic acid displayed similar inhibition constants at [3H]kainic acid sites (IC50 = 5 and 7 nM, respectively). At both kainic acid and AMPA binding sites, all of the compounds tested were less potent than domoic acid itself. At high affinity [3H]kainic acid sites, the derivatives could be categorized into two groups; those with nanomolar affinity and those with micromolar affinity. All members of the former group possessed a side chain with the first double bond intact and in the Z (cis) configuration. The more distal atoms present in the extended side chain of domoic acid did not appear to contribute to the high affinity interaction with the kainic acid receptor. Although all the compounds tested were weaker inhibitors of [3H]AMPA binding compared to [3H]kainic acid binding, there was a high correlation between the rank order of potency of the seven domoic acid derivatives at [3H]kainic acid and at [3H]AMPA binding sites. The inhibition data for kainic acid at [3H]AMPA binding sites were described adequately in terms of a 1-site model, whereas the data for domoic acid required two classes of sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Analysis of the structure of the muscular pulmonary arteries in patients with pulmonary hypertension and COPD: National Institutes of Health nocturnal oxygen therapy trial.

We examined the cardiovascular function as well as the structure of the muscular pulmonary arteries in patients who had died while enrolled in the National Institutes of Health nocturnal oxygen therapy trial (NOTT). The cardiovascular function of the patients classified into groups based on the severity of the pulmonary hypertension was examined, and we compared the morphologic data in these groups to those obtained from age-matched controls who died with no evidence of cardiovascular disease. The groups with severe pulmonary hypertension had markedly increased pulmonary vascular resistance but similar cardiac index to the group with only mild hypertension. In the structural analyses, we found definite alterations in arterial structure from the control population: the patients who had pulmonary hypertension had markedly increased percentages of intima and media. These differences were most pronounced in the medium and larger muscular arteries. The degree of pulmonary hypertension did not appear to alter vascular structure consistently, although there was a trend towards an increase in muscle media in the smaller vessels. When the patients were classified into a group who responded to oxygen administration by a decrease in Ppa, and an age- and Ppa-matched group who did not respond, there were no differences in vascular structure between these groups, although both groups had greater percentages of intima and media compared to the control group. We conclude that, in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD), there are structural alterations of the muscular pulmonary arteries, but these do not correlate with either the severity of the pulmonary hypertension or the ability of the pulmonary vasculature to respond to oxygen administration.

Adult↗
PubMed1992

Histopathological effects of intracerebral injections of human recombinant tumor necrosis factor-alpha in the rat.

Human recombinant tumor necrosis factor-alpha (rTNF-alpha) was administered to normal Fischer 344 rats by stereotaxic intracerebral (IC) injection. Animals received a single injection of either 6 x 10(4) U rTNF-alpha or excipient in their right parietal lobe. Others received three consecutive daily injections of either 6 x 10(4) U rTNF-alpha or excipient to examine effects of higher accumulative doses. Histological examination of the brain revealed that both single and multiple IC injections of rTNF-alpha triggered an immigration of circulating leukocytes into the site of TNF-alpha injection. After one injection, this cell population was composed mainly of macrophages and neutrophils. Maximal leukocytic influx occurred by 48 h and was composed mostly of neutrophils which were limited to the injection site and perivascular space. Quantitation of the inflammatory reaction by measurement of tissue myeloperoxidase levels supported these histological observations. One day after multiple rTNF-alpha injections, leukocytic adhesion to endothelium, vascular cuffing and leukocytic infiltration into the neuropil was observed at levels comparable to those seen 3 days following a single rTNF-alpha injection. We conclude that while one or more IC injection(s) of 6 x 10(4) U rTNF-alpha was well tolerated in normal rats, at this dose the cytokine triggers a pronounced leukocytic infiltration at the site of injection. These results support a role for TNF-alpha as a mediator in inflammatory responses within the central nervous system.

Animals↗