A Piece of my mind. Sunday rounds.
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Aged↗
Biomedical subjects
J L Wright
Publications and source records attributed to J L Wright.
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↗
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↗
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↗
Detection of new 7-O-acyl derivatives of diarrhetic shellfish poisoning toxins by liquid chromatography-mass spectrometry.
A novel method for the detection of acylated diarrhetic shellfish poisoning toxins is reported. Direct determination of these compounds is possible using high performance liquid chromatography coupled with ion-spray mass spectrometry. An extract, purified from the digestive glands of toxic mussels (Mytilus edulis) contaminated with okadaic acid, dinophysistoxin-1, and a recently reported analog, dinophysistoxin-2, was also shown to contain small amounts of dinophysistoxin-3, a mixture of 7-O-acyl ester derivatives of dinophysistoxin-1. In addition, acyl ester derivatives of okadaic acid and dinophysistoxin-2 were also detected by direct LC-MS analysis and confirmed by analysis of their hydrolysis products. This is the first report of the detection of other naturally occurring 7-O-acyl esters similar to dinophysistoxin-3.
Acylation↗
Diseases of the small airways.
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Bronchi↗
Effects of cigarette smoke on the clearance of short asbestos fibres from the lung and a comparison with the clearance of long asbestos fibres.
Long asbestos fibres are generally considered to have greater disease-producing potential than short asbestos fibres. However, recent reports have suggested that short fibre asbestos appears to be as effective an inducer of macrophage growth factors and toxic oxygen species as long fibre asbestos, but that short fibres are readily removed from lung and do not gain access to tissues. Because smoke is believed to impair the clearance of asbestos fibres from lung, we examined the clearance of a short (geometric mean length 1.3 microns) amosite preparation administered by intratracheal instillation to guinea-pigs. Half the animals in each group were exposed to the smoke of 10 cigarettes daily. Animals were sacrificed 1 day, 1 week, or 1 month later, the macrophages recovered by lavage, and fibre concentrations and sizes determined by analytical electron microscopy in macrophages and lung tissue. A 30-fold increase was seen in total numbers of fibres retained in macrophages in smokers compared to non-smokers by 1 month, and there was an eightfold increase in retention of short fibres in the lung tissue by 1 month. By contrast, a long fibre amosite preparation (geometric mean length 8.9 microns) showed approximately the same increase in fibre retention in macrophages, but only a twofold increase in tissue retention. We conclude that (1) cigarette smoke markedly impairs the clearance of short amosite fibres from the lung with enhanced retention of fibres in both macrophages and tissue; (2) the effects of smoke on short fibre tissue retention appear to be greater than those on long fibre retention; (3) with the long fibre preparation, smoke causes increased tissue retention of relatively shorter fibres; (4) for both fibre size experiments, the increase in total fibres in macrophages in smoke-exposed animals reflects an increase in the total number of fibre-containing macrophages, rather than an increase in the number of fibres phagocytized per macrophage; (5) enhanced short fibre retention markedly increases total fibre surface area, a parameter which has been suggested as a measure of fibre toxicity, to the point where short fibres might under some circumstances have roughly the same potential toxicity as long fibres. These observations suggest that short asbestos fibres could play an important role in the pathogenesis of some types of asbestos-related disease in cigarette smokers.
Animals↗
A piece of my mind. Soliloquy.
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Attitude of Health Personnel↗
Acute effects of human recombinant tumor necrosis factor-alpha on the cerebral vasculature of the rat in both normal brain and in an experimental glioma model.
The effects of intravenous (IV) infusion of human recombinant tumor necrosis factor-alpha (rTNF-alpha, Cetus) on normal brain and malignant glioma in rats were examined. Twelve Fischer 344 rats were given either a single injection of 10(6) U rTNF-alpha or injections of 5 x 10(5) U rTNF-alpha for three days. One day post-rTNF-alpha injection(s), rats were injected IV with horseradish peroxidase (HRP) to determine blood-brain barrier (BBB) breakdown and, one hour later, were perfused with an aldehyde fixative and processed for histologic examination. Treatment of normal rats with rTNF-alpha by either dosage or schedule caused no remarkable histopathologic changes in the brain and no alteration in BBB integrity. Human glioma models were produced by intracerebal inoculation of 10(4) syngeneic RT-2 glioma cells into the right parietal lobe of 30 rats. Animals received single IV injections of 10(6) U human rTNF-alpha or its excipient (TNF-E) as above on day 3, 7, or 10 post-tumor inoculation or multiple injections of 5 x 10(5) U rTNF-alpha beginning on day 7, 10, or 12 post-tumor inoculation. With a single IV injection of either rTNF-alpha or its excipient, 3-day models showed a similar pattern of HRP extravasation limited to the extracellular space of the tumor inoculation site. In 7-day models treated with a single IV injection of rTNF-alpha or TNF-E, HRP extravasated throughout the tumor, but did not exceed peritumoral margins. In 10-day models treated with a single injection of TNF-E, HRP was found only in the tumor and immediate peritumoral regions while rTNF-alpha-treated rats showed more extensive areas of BBB breakdown with HRP evident throughout the entire right hemisphere and extending via the corpus callosum into the contralateral hemisphere. Pericapillary halos were also evident around the small blood vessels within the edematous areas of the corpus callosum. Within tumors, hemorrhagic necrosis and adherence of neutrophils to vessels was observed only in animals treated with rTNF-alpha at 10 days post-tumor inoculation. Multiple IV injections of rTNF-alpha in 7 and 10-day models triggered widespread hemorrhagic necrosis, neutrophil adherence and infiltration in the tumor. There was also extravasation and diffusion of HRP from the site of glioma into the contralateral hemisphere. Twelve-day models treated with multiple rTNF-alpha injections, in addition, showed irregular luminal surfaces and gaps between adjacent endothelial cells of tumor vasculature.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Long-term pulmonary hypertension produced by cigarette smoking is associated with subendocardial fibrosis and inflammation of the right ventricle: a morphometric analysis in the guinea pig model.
We have developed a guinea pig model of cigarette smoking induced lung disease, whereby animals exposed for several months to cigarette smoke develop emphysematous lung destruction as well as mild pulmonary hypertension with increased muscularization of the arterioles. To ascertain whether the animals with pulmonary hypertension had structural alterations of the right ventricle, we morphologically determined the volume proportion of inflammatory cells, fibrosis, and muscle cytoplasm and nuclei, and compared these values to those of age matched animals not exposed to smoke. We found that there was a significantly increased volume proportion of both fibrous tissue and inflammatory cells in the subendocardial myocardium after 12 months of cigarette smoke exposure, but not after 3 or 6 months. Since the degree of pulmonary hypertension, and the weight of the right ventricle were similar at the 3 time periods, we conclude that the inflammatory cell infiltrate and fibrosis in the subendocardial myocardium are manifestations of long term pulmonary hypertension, rather than any indication of co-existant damage to the myocardium as a result of the smoke exposure. These features would be compatible with the "right ventricular hypothesis" of Morrison (8) for the development of cor pulmonale, with the pathological changes seen as a result of a dysequilibrium between oxygen supply and demand in the right ventricle.
Animals↗
Diffusion in porous materials above the percolation threshold.
The diffusion of water-soluble solutes in water-soaked porous media was studied by following the release of benzoic acid from poly(vinyl stearate) matrices. The results were analyzed using a pseudo-steady-state diffusion model coupled with the fundamental concepts of percolation theory. The results of the study indicated that the relationship between the bulk diffusion coefficient of benzoic acid in the polymer matrix and the porosity was well described by percolation scaling laws. A very low percolation threshold (0.07) was experimentally observed for this system.
Benzoates↗
Active oxygen species mediate asbestos fiber uptake by tracheal epithelial cells.
To examine the mechanism whereby asbestos fibers penetrate tracheal epithelial cells, we exposed rat tracheal explants to amosite asbestos alone, or with varying concentrations of substances that scavenge active oxygen species (catalase and superoxide dismutase) or prevent formation of active oxygen species (deferoxamine). All three agents decreased asbestos fiber uptake in a dose-response fashion, but no agent provided complete protection against fiber penetration. We conclude that uptake of amosite asbestos fibers is mediated in part by active oxygen species (most likely OH.), but that other mechanisms of fiber uptake must also exist.
Animals↗
Surgical treatment of obliterative otitis externa.
Seven patients with fibrous obliteration of the ear canal due to long-standing otitis externa were seen at St Mary's Hospital during the past 10 years. Two patients underwent bilateral surgery making a total of 9 ear cases. Two patients developed early restenosis within 6 months of permeatal excision of the fibrous core and skin grafting, and one patient had late stenosis 4 years following postaural excision, meatoplasty and skin grafting. Two of these patients opted for revision surgery and a total of 6 patients (8 ear cases) underwent postaural excision with Körner flap canalplasty, enlargement of the bony ear canal and skin grafting. The average hearing gain was 25 dB in the speech frequencies and only one restenosis was seen at 3 years. This was successfully revised. Radical excisional surgery with a wide bony canalplasty is recommended in this condition.
Adult↗
Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig.
To investigate the long-term effect of cigarette smoke on pulmonary structure and function, we exposed groups of guinea pigs to the smoke of 10 cigarettes each day, 5 days per week, for 1, 3, 6, and 12 months. We found that the guinea pigs developed progressive lung destruction (emphysema) and alterations in their pulmonary function tests similar to that seen in humans with cigarette smoke-induced chronic obstructive lung disease. This method of smoke-induced lung destruction should provide a good model for the study of the early changes of emphysema.
Animals↗
Domoic acid toxicity. Panel discussion: short-term research priorities.
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Animals↗
Chemistry, biology, and toxicology of domoic acid and its isomers.
The causative agent of toxicity in cultured mussels from a localized area of eastern Prince Edward Island has been identified as domoic acid, a neuroexcitatory amino acid. The toxin was isolated by a number of different bioassay-directed separation techniques including high-performance liquid chromatography (HPLC), high-voltage paper electrophoresis (HVPE), and ion-exchange chromatography, and characterized by a number of spectroscopic techniques including ultraviolet, infrared, mass spectrometry, and nuclear magnetic resonance. The isolation and purification methods are described in detail and some new analytical data for domoic acid are reported. A plankton bloom at the time of the outbreak gave positive mouse bioassays and consisted almost entirely of the pennate diatom, Nitzschia pungens f. multiseries. A positive correlation was found between the number of N. pungens cells and the concentration of domoic acid in the plankton. N. pungens f. multiseries isolated from Cardigan Bay produced domoic acid de novo during stationary phase culture at levels (1 to 10 pg/cell) comparable to values estimated for N. pungens in the plankton samples. We conclude that N. pungens was the major source of the domoic acid in toxic mussels in eastern Prince Edward Island. The recurrence, in November 1988, of a monospecific bloom of N. pungens and the presence of domoic acid in plankton and mussels reinforces this conclusion.
Animals↗
Troubled orthodontic patients: the role of the social worker.
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Adolescent↗