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Biomedical subjects

J A Thompson

Publications and source records attributed to J A Thompson.

At least 343 records · Page 19Linked to original sources
PubMed1975

Multiple sclerosis and elevation of cerebrospinal fluid vaccinia virus antibody.

Thirty percent of 33 patients with a clinical diagnosis of multiple sclerosis and an elevation of cerebrospinal fluid (CSF) immunoglobulin G/albumin ratio greater than 2 standard deviations above the mean had elevation of the CSF vaccinia neutralizing antibody titer. Elevated titers were found in 1 of 23 patients with non-multiple sclerosis neurologic diseases and in none of the normal control patients. No linear correlation was found between the magnitude of the relative or absolute CSF immunoglobulin G concentration and the magnitude of the CSF vaccinia neutralizing antibody titers.

Antibodies, Viral↗
PubMed1975

Gas-chromatographic/mass-spectrometric identification and quantitation of tetronic and deoxytetronic acids in urine from normal adults and neonates.

Gas chromatographic/mass spectrometric/computer analyses of trimethylsilyl derivatives of urine extracts, prepared by an anion-exchange procedure, reveal the presence of several tetronic and deoxytetronic acids. Identifications were confirmed by comparing gas-chromatographic methylene unit values and mass spectrometric characteristics with those of chemically synthesized samples. In addition, several 1,4-lactones corresponding to the acids were detected in small amounts. The acids were measured in groups of adults and neonates by gas chromatographic/computer determination of peak areas and the use of calculated response factors. In urines from adults, 4-deoxythreonic, threonic, and erythronic acids were present in relatively large amounts. 4-Deoxyerythronic and 2-deoxytetronic acids were present in small to moderate amounts; 3-deoxytetronic and 2-methylglyceric acids were only trace constituents. These latter two acids, in addition to 4-deoxyerythronic, were also trace constituents of several urines from neonates but could not be detected in others. Expressed in terms of creatinine excretion, both groups excreted similar amounts of 4-deoxythreonic acid and neonates excreted significantly more 2-deoxytetronic, erythronic, and threonic acids.

Adult↗
PubMedDate not supplied

Spinal and radicular pain in pseudotumor cerebri.

A 4 1/2-year-old girl presented with cervical spine and radicular pain with hypoactive biceps and brachioradialis stretch reflexes. A diagnosis of pseudotumor cerebri was made. The patient's symptoms resolved following the reduction of the elevated intracranial pressure. Abnormalities of the cervical spine and spinal cord were not detected. A mechanism to explain this "false localizing" sign is discussed.

Child, Preschool↗
PubMedDate not supplied

Fate of free radicals generated during one-electron reductions of 4-alkyl-1,4-peroxyquinols by cytochrome P-450.

Free radicals resulting from the one-electron reduction and subsequent homolytic cleavage of oxygen-oxygen bonds by heme proteins are likely to be responsible for some aspects of the toxicity of organic hydroperoxides. In the present work, effects of the 4-alkyl substituent of 2,6-di-tert-butyl-4-alkyl-4-hydroperoxycytohexa-2,5-dienones (1,4-peroxyquinols) on radical production were investigated with microsomal cytochrome P-450 from rat liver. Quinoxy radicals from homolysis of the peroxyquinols underwent beta-scission to produce a quinone and an alkyl radical, and this process occurred with increasing frequency as the stability of the alkyl radical increased. The fate of benzyl and 2-phenylethyl radicals generated from the appropriately substituted peroxyquinols was investigated also. The former was converted to benzyl alcohol, benzaldehyde, and toluene and the latter to 2-phenylethanol, phenylacetaldehyde, ethylbenzene, styrene, and benzaldehyde. Oxygen-18 labeling studies demonstrated that 80-85% of the benzyl alcohol incorporated oxygen from the hydroperoxide and the balance from molecular oxygen. This indicates that the predominant reaction pathway involved recombination between the benzyl radical and the iron-bound hydroxyl radical of the P-450 intermediate complex. By contrast, about 50% of 2-phenylethanol from the 2-phenylethyl radical incorporated oxygen from water and the balance from O2. Two alternative mechanisms are proposed to explain the formation of 2-phenylethanol that contained oxygen from water and the concurrent formation of styrene: (a) oxygen exchange of the P-450 intermediate with water, followed by hydrogen abstraction and radical recombination reactions with the P-450 complex, or (b) oxidation of the radical to the 2-phenylethyl cation followed by proton elimination and hydration.

Alkylation↗
PubMedDate not supplied

Formation and reactivity of alternative quinone methides from butylated hydroxytoluene: possible explanation for species-specific pneumotoxicity.

Previous work has shown that butylated hydroxytoluene [2,6-di-tert-butyl-4-methylphenol (BHT)] undergoes pi-oxidation in liver microsomes to form the quinone methide 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone (QM). This electrophilic species binds covalently to glutathione and protein thiols and is believed to initiate pulmonary toxicity in mice. In the present investigation, we identified another quinone methide metabolite of BHT, 6-tert-butyl-2-(hydroxy-tert-butyl)-4-methylene-2,5-cyclohexadienone (QM-OH), formed subsequent to the microsomal hydroxylation of BHT at a tert-butyl group. Mouse liver and lung microsomes generate the two quinone methides, and evidence was obtained that both metabolites also are formed in vivo. In contrast, rat microsomes produce QM almost exclusively, with only traces of QM-OH formed in liver and none in lung. Studies of the chemical reactivities of the two quinone methides with GSH demonstrated that QM-OH reacts about 6-fold faster than QM. Infrared spectra, 1H NMR spectra, and electrochemical measurements all support the proposal that the enhanced electrophilicity of QM-OH is due to intramolecular hydrogen bonding of the ring oxygen with the side-chain hydroxyl. The results provide evidence, therefore, that the previous metabolic scheme for bioactivation of BHT to a pulmonary toxin should be amended to include tert-butyl hydroxylation and subsequent pi-oxidation to the activated electrophile QM-OH. This scheme is consistent with published data concerning BHT-induced pulmonary toxicity and provides an explanation for the species specificity of this effect.

Animals↗
PubMedDate not supplied

The enzymatic formation and chemical reactivity of quinone methides correlate with alkylphenol-induced toxicity in rat hepatocytes.

The effects of o-alkyl substituents on both the cytochrome P450-catalyzed oxidation of phenols to p-quinone methides (QM's; 4-methylene-2,5-cyclohexadien-1-ones), and on the rates of nucleophilic additions to the 4-methylene carbon of QM's were investigated. The derivatives of 4-methylphenol studied were BHT (2,6-di-tert-butyl), BHTOH [6-tert-butyl-2-(hydroxy-tert-butyl)], BDMP (2-tert-butyl-6-methyl), BMP (2-tert-butyl), TMP (2,6-dimethyl), and DMP (2-methyl). QM formation was estimated to be in the range 0.17-0.70 nmol/(nmol of P450.min) in rat liver microsomes and 16-62 pmol/(10(6) cells.min) in isolated rat hepatocytes. QM's derived from BHT (BHT-QM), BHTOH (BHTOH-QM), BDMP (BDMP-QM), and TMP (TMP-QM) were synthesized and their rates of reaction with water and reduced glutathione (GSH) determined. BDMP-QM and TMP-QM were the most reactive, BHT-QM was consumed relatively slowly, and BHTOH-QM displayed intermediate reactivity. These variations in rate were rationalized by differences in hydrogen bonding with the carbonyl oxygen, which affects positive charge density at the site of nucleophilic attack. The loss of hepatocyte viability during incubations with BMP, BDMP, and BHTOH was preceded by GSH depletion. Pretreatment of hepatocytes with diethyl maleate exacerbated alkylphenol toxicity, and metyrapone protected the cells. These data, together with information on the formation and reactivity of QM's, strongly support the proposal that QM's mediate the toxicity of alkylated 4-methylphenols in rat hepatocytes.

Animals↗
PubMedDate not supplied

Role of quinone methide in the in vitro toxicity of the skin tumor promoter butylated hydroxytoluene hydroperoxide.

An electrophilic quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone, BHT-QM) functions in the toxicity of butylated hydroxytoluene (BHT) in both rodent liver and lung. BHT-QM has also been demonstrated to mediate tumor promotion in mouse skin by another metabolite of BHT, 2,6-di-tert-butyl-4-hydroperoxy-4-methyl-2,5-cyclohexadienone (BHTOOH). In the present study, the role of BHT-QM in the cytotoxicity of BHTOOH was investigated. The toxicity of BHTOOH was potentiated by glutathione depletion and inhibited by thiol compounds, indicating that BHTOOH is activated to a thiol-reactive, toxic intermediate. This activation process was suggested to be iron-dependent by the ability of an Fe(III)-specific chelator to inhibit BHTOOH toxicity. Comparative study of analogs of BHTOOH in which the 4-methyl group was substituted with CD3, ethyl, isopropyl or tert-butyl supported the hypothesis that BHT-QM mediates this toxicological response. The decreased rate of reactivity of quinone methides that occurs as the 4-alkyl group is enlarged was accompanied by a corresponding reduction in toxic potency. The structural requirements for quinone methide toxicity were also explored with a series of BHTOOH analogs substituted at the 2- and 6-positions of the molecule. Reducing the lipophilicity of the 2,6-tert-butyl groups is known to increase quinone methide reactivity with glutathione but does not diminish the rate of quinone methide formation from the hydroperoxide. Interestingly, alteration of only one of the tert-butyl groups did not change the toxic potency, whereas removal or replacement of both tert-butyl groups dramatically reduced the toxicity in control cells but not glutathione-depleted cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Evaluation of the Palmaz stent in the trachea and mainstem bronchi of normal dogs.

OBJECTIVE: This study evaluates the efficacy of the Palmaz balloon expandable intraluminal stent in the trachea and mainstem bronchi of normal dogs. STUDY DESIGN: Effects of the stent were evaluated by physical examination, thoracic radiography, respiratory tract fluoroscopy and endoscopy, tracheal diameter measurement, postmortem examination, and airway histomorphometry. ANIMALS OR SAMPLE POPULATION: Ten normal beagle dogs. METHODS: Stent size was estimated from thoracic radiographs in awake dogs. Group I dogs (n = 4) had two stents placed: one in the thoracic trachea (TT) plus a randomly chosen mainstem bronchus (MB). Group II dogs (n = 3) had stents placed in the MB (one stent), TT (one stent), and mid- or proximal cervical trachea (CT) (one or two stents). Three dogs were used as sham-operated controls (group III). Temperature, pulse, respiration, and cough were measured twice daily. Dogs were evaluated at 21 and 49 to 56 days after stent placement, euthanatized, and tissues were collected for histomorphometric analysis of stent integration and epithelial pathology. RESULTS: Mean tracheal diameters of awake (10.5 +/- 1.7 mm) and anesthetized dogs before stent implantation (13.9 +/- 2.0 mm) were significantly different (P < .01). Complications associated with stent placement included acute pulmonary edema (n = 2), stent migration (n = 7), stent collapse (n = 4 CT, 2 TT, and 1 MB), and positive tracheal culture (n = 10). Group II dogs coughed more at rest, exercise, and with tracheal palpation than dogs in other groups (P < .01). Group I dogs coughed more at rest than group III dogs (P < .01). Stent integration ranged from 0 to 91.3%. Squamous metaplasia and epithelial ulceration associated with stents ranged from 0 to 57.5% and 0 to 32.7%, respectively. CONCLUSIONS: Determination of stent size should be based on measurements taken on anesthetized dogs because use of inappropriately sized stents may promote stent migration, squamous metaplasia, and/or ulceration. Epithelialization over stent struts may occur if the stent is closely associated with tracheal epithelium. CLINICAL RELEVANCE: Palmaz stents do not appear to be appropriate for placement in the CT of dogs; however, with technical modifications, application in the TT and MB may be feasible.

Animals↗