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Biomedical subjects

D C Thompson

Publications and source records attributed to D C Thompson.

At least 109 records · Page 6Linked to original sources

Involvement of capsaicin-sensitive afferent neurones in a vagal-dependent interaction between leukotriene D4 and histamine on bronchomotor tone.

Leukotriene D4 (LTD4, 0.1-0.5 micrograms/kg, i.v.), administered 20 s before histamine (H, 1-4 micrograms/kg, i.v.), enhanced the bronchoconstrictor response to H by between 105 and 168%. Bilateral vagotomy, atropine or indomethacin each attenuated, whereas hexamethonium completely prevented, this enhancement. LTD4 failed to enhance the bronchoconstrictor effects of either acetylcholine (ACh) or electrical stimulation of the vagi. Capsaicin pretreatment reduced bronchoconstrictor responses to electrical stimulation of the vagi, but did not affect depressor responses. There was no interaction between LTD4 and H on bronchomotor tone in capsaicin-pretreated guinea-pigs. It is concluded that LTD4 enhances H-induced bronchoconstriction by a mechanism which involves an increased activity of efferent cholinergic nerves innervating the airways. However, the failure of LTD4 to enhance bronchoconstriction due to ACh or vagal stimulation, together with the prevention of the interaction between LTD4 and H by capsaicin-pretreatment, suggests that the site of the interaction may be on capsaicin-sensitive afferent neurones.

Airway Resistance↗

Leukotriene D4 potentiates histamine-induced bronchoconstriction in guinea-pigs.

Histamine concentration-response curves performed on isolated airways smooth muscle preparations were unaffected by threshold constrictor concentrations of LTD4 (194 +/- 34 pM for parenchymal strips and 1940 +/- 480 pM for isolated trachea, respectively). In contrast, LTD4, when administered between 2 and 60 s beforehand, potentiated bronchoconstrictor responses to histamine in anaesthetized, artificially ventilated guinea-pigs. Doses of LTD4, which did not produce direct effects on airways resistance, potentiated histamine-induced bronchoconstriction to a lesser degree than those having small direct effects. This potentiation was prevented by bilateral vagotomy. In addition, the antagonists atropine (100 micrograms/kg), FPL55712 (5 mg/kg) and indomethacin (1 mg/kg) effectively prevented the interaction. It is suggested that the interaction between LTD4 and histamine involves a specific leukotriene receptor, possibly linked to the generation of a cyclo-oxygenase metabolite and requires intact cholinergic innervation of airways smooth muscle. Furthermore, these results are consistent with the hypothesis that LTD4 may be a mediator of bronchial hyperreactivity.

Airway Resistance↗

Vitreous: an inhibitor of retinal extract-induced neovascularization.

One of the major problems in assessing neovascularization in mammalian experimental animal models is the immunologic response of the host to stimuli from nonautologous species. Hence, crude bovine vitreous and retinal extracts may produce a complex immune reaction when tested in the rabbit. To circumvent this problem, the chicken chorioallantoic membrane (CAM) assay is most appropriate. In this study the CAM assay for angiogenesis has been modified to study antiangiogenic substances. The modified assay is described in detail and used to demonstrate for the first time the inhibition by adult bovine vitreous of neovascularization induced by extracts of adult bovine retina. In addition to vitreous, three common glycosaminoglycans (keratan sulfate, chondroitin sulfate C, and hyaluronic acid) were assayed for antiangiogenic activity. The results indicate that vitreous inhibition of retinal extract-induced neovascularization is dose dependent, while the sulfated glycosaminoglycans tested had no antiangiogenic activity. A commercial preparation of bovine vitreous hyaluronic acid exhibited a slight, but not statistically significant, inhibitory activity. When vitreous extracts were digested with hyaluronidase, no loss of antiangiogenic activity occurred. These results suggest that the inhibitor of angiogenesis from adult vitreous is probably not a common glycosaminoglycan. The results are consistent with the hypothesis that antiangiogenic substance(s) in vitreous and angiogenic components from retina may act as natural antagonists in controlling the process of retinal neovascularization.

Animals↗

Domestic violence and primary care. Attitudes, practices, and beliefs.

OBJECTIVE: To assess the attitudes and beliefs of the primary care provider team (physicians, physician assistants, nurses, and medical assistants) toward the identification and management of abused patients and perpetrators of domestic violence (DV). DESIGN: Survey of the health care team using a confidential questionnaire. SETTING AND SUBJECTS: Five primary care clinics with 240 providers at a large urban health maintenance organization. RESULTS: The response rate was 86% (206 respondents). Fifty percent of clinicians and 70% of nurses/assistants believed that the prevalence of DV in their practice was 1% or loss; 1 in 10 clinicians and nearly half of nurses/assistants had never identified an abused person; 45% of clinicians never or seldom asked about DV when examining injured patients; and all participants were much less confident in asking about DV than about smoking or consuming alcohol. Twenty-five percent believed the abused person's personality led to the violence; 28% believed they did not have strategies to help abused persons; and 20% were concerned for their personal safety in discussing DV. Only 10% believed they had management information, but 77% had not attended any educational programs on DV in the past year. CONCLUSIONS: This study provides important information about current knowledge, attitudes, and beliefs of health care providers toward the diagnosis and management of DV. This information should prove useful to all who attempt to design clinical strategies and educational programs to address this issue.

Attitude of Health Personnel↗

Universal newborn hearing screening: summary of evidence.

CONTEXT: Each year, approximately 5000 infants are born in the United States with moderate-to-profound, bilateral permanent hearing loss (PHL). Universal newborn hearing screening (UNHS) has been proposed as a means to speed diagnosis and treatment and thereby improve language outcomes in these children. OBJECTIVES: To identify strengths, weaknesses, and gaps in the evidence supporting UNHS and to compare the additional benefits and harms of UNHS with those of selective screening of high-risk newborns. DATA SOURCES: We searched the MEDLINE, CINAHL, and PsychINFO databases for relevant articles published from 1994 to August 2001, using terms for hearing disorders, infants or newborns, screening, and relevant treatments. We contacted experts and reviewed reference lists to identify additional articles, including those published before 1994. STUDY SELECTION: We included controlled and observational studies of (1) the accuracy, yield, and harms of screening using otoacoustic emissions (OAEs), auditory brainstem response (ABR), or both in the general newborn population and (2) the effects of screening or early identification and treatment on language outcomes. Of an original 340 articles identified, 19 articles, including 1 controlled trial, met these inclusion criteria. DATA EXTRACTION: Data on population, test performance, outcomes, and methodological quality were extracted by 2 authors (D.C.T., H.M.) using prespecified criteria developed by the US Preventive Services Task Force. We queried authors when information needed to assess study quality was missing. DATA SYNTHESIS: Good-quality studies show that from 2041 to 2794 low-risk and 86 to 208 high-risk newborns were screened to find 1 case of moderate-to-profound PHL. The best estimate of positive predictive value was 6.7%. Six percent to 15% of infants who are missed by the screening tests are subsequently diagnosed with bilateral PHL. In a trial of UNHS vs clinical screening at age 8 months, UNHS increased the proportion of infants with moderate-to-severe hearing loss diagnosed by age 10 months (57% vs 14%) but did not reduce the rate of diagnosis after age 18 months. No good-quality controlled study has compared UNHS with selective screening of high-risk newborns. In fair- to poor-quality cohort studies, intervention before age 6 months was associated with improved language and communication skills by ages 2 to 5 years. These studies had unclear criteria for selecting subjects, and none compared an inception cohort of low-risk newborns identified by screening with those identified in usual care, making it impossible to exclude selection bias as an explanation for the results. In a mathematical model based on the literature review, we estimated that extending screening to low-risk infants would detect 1 additional case before age 10 months for every 1441 low-risk infants screened, and result in treatment before 10 months of 1 additional case for every 2401 low-risk infants screened. With UNHS, 254 newborns would be referred for audiological evaluation because of false-positive second-stage screening test results vs 48 for selective screening. CONCLUSIONS: Modern screening tests for hearing impairment can improve identification of newborns with PHL, but the efficacy of UNHS to improve long-term language outcomes remains uncertain.

Evidence-Based Medicine↗

The effects of antagonists of vasoactive intestinal peptide on nonadrenergic noncholinergic inhibitory responses in feline airways.

Relaxations of the feline intrapulmonary bronchus (IPB) induced by VIP or nonadrenergic noncholinergic (NANC) inhibitory nervous stimulation were unaffected by the VIP receptor antagonist [Ac-Tyr1,D-Phe2]-GRF (1-29) (30 microM). A second VIP antagonist, [pCl-D-Phe6,Leu17]-VIP (30 microM), also had no effect on NANC relaxation responses or IPB sensitivity to VIP. However, responses to three of the four highest VIP concentrations were inhibited by this antagonist. These results indicate that [Ac-Tyr1,D-Phe2]-GRF (1-29) and [pCl-D-Phe6,Leu17]-VIP are not effective competitive antagonists of VIP receptors in feline airways and, hence, have but limited applicability in determining the role of VIP in mediating airway NANC inhibitory responses in this tissue.

Acetylcholine↗

The toxicological implications of the interaction of butylated hydroxytoluene with other antioxidants and phenolic chemicals.

Butylated hydroxyanisole (BHA) enhanced both the in vitro peroxidase-catalysed covalent binding of butylated hydroxytoluene (BHT) to microsomal protein and the formation of BHT-quinone methide. Eugenol, methylparaben, vanillin, guaiacol, ferulic acid and several other phenolic compounds commonly used in food and cosmetic products also enhanced the metabolic activation of BHT. BHA was the most effective compound tested. Microsomes from lung, bladder, kidney medulla and small intestine of various animal species, including man, were also able to support this interaction of BHA and BHT using either hydrogen peroxide or arachidonic acid as the substrate. These in vitro observations were extended to an in vivo mouse lung model. Subcutaneous injections of BHA significantly enhanced the lung/body weight ratio of mice given intraperitoneal injections of subthreshold doses of BHT. The toxicological implications of the interactions of BHT with other antioxidants and phenolic chemicals and their potential relevance to human risk are discussed.

Animals↗

Reactive intermediates formed during the peroxidative oxidation of anisidine isomers.

The ortho isomer of anisidine (2-methoxyaniline) causes urinary bladder tumors in both mice and rats while the para isomer (4-methoxyaniline) is inactive. Since the urinary bladder contains substantial peroxidase activity, we investigated the peroxidative metabolism of both o- and p-anisidine using horseradish peroxidase as a model enzyme. Both isomers were excellent reducing cofactors for the oxidized state of horseradish peroxidase (HRP), resulting in one-electron oxidation to free radicals. Using high-pressure liquid chromatography, we observed that HRP oxidized p-anisidine to a diimine metabolite which subsequently hydrolyzed to form a quinone imine. Also observed was a dimeric metabolite with an azo bond. Both the diimine and quinone imine metabolites were reactive toward nucleophiles. The quinone imine formed a conjugate with glutathione and was also reduced by glutathione or ascorbic acid. Higher concentrations of substrate (greater than 1 mM) led to the formation of polymeric products (tetramer). Similar metabolites (diimine, quinone imine, azo dimer, polymers) were observed with o-anisidine. Using tritium-labeled anisidine, we observed substantial metabolism-dependent covalent binding of both isomers to protein and DNA. These results demonstrate that horseradish peroxidase dependent metabolism of anisidine isomers yields similar metabolites, although some differences in reactivity of the respective intermediates with nucleophiles were observed.

Aniline Compounds↗

Quinone methide formation from para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol: relationship to toxicity.

The oxidative metabolism and toxicity of the para isomers of methylphenol (cresol), ethylphenol, and isopropylphenol were studied using male Sprague-Dawley rat liver microsomes and precision-cut liver slices. Reactive intermediates from each compound were trapped using radiolabeled glutathione and were detected and quantified by HPLC. Conjugates were collected and their structures determined by fast atom bombardment mass spectrometry and proton nuclear magnetic resonance. During microsomal incubations each test compound formed monoglutathione conjugates with structures which are consistent with the formation of quinone methide intermediates. In each case the glutathione moiety was attached to the benzylic carbon on the alkyl side chain of the phenol. With ethylphenol, which has a prochiral benzylic carbon, two isomeric conjugates were detected. The rate of formation of the glutathione conjugates in liver slice incubations was 4-isopropylphenol > 4-ethylphenol > 4-methylphenol. This correlated with the toxicity of the three compounds in liver slices. At equimolar concentrations 4-isopropylphenol was the most toxic while 4-methylphenol was the least toxic. Depletion of intracellular glutathione was observed in the presence of each test compound which preceded cell death. Enhancement of cellular thiol levels with N-acetylcysteine protected cells from the toxic effects of all three compounds as did inhibition of cytochrome P450 activity with metyrapone. These results suggest the formation of quinone methide intermediates from three alkylphenols during oxidative metabolism and demonstrate a correlation between the amount of reactive intermediate formed and toxicity observed in liver slices.

Animals↗

o-Methoxy-4-alkylphenols that form quinone methides of intermediate reactivity are the most toxic in rat liver slices.

The effects of p-alkyl substituents on the relative cytotoxicity of 4-alkyl-2-methoxyphenols were investigated in isolated rat liver slices. The derivatives of 4-alkyl-2-methoxyphenol studied were 4-methyl- (creosol), 4-ethyl-, 4-propyl-, 4-isopropyl-, 4-allyl-2-methoxyphenol (eugenol), as well as 4-allyl-2,6-dimethoxyphenol. The data were correlated with previous microsomal experiments which showed that all of the 4-alkyl-2-methoxyphenols were converted to quinone methides (QMs; 4-methylene-2,5-cyclohexadien-1-ones) via a cytochrome P450-catalyzed process [Bolton, J. L. Comeau, E., and Vukomanovic, V. (1995) Chem.-Biol. Interact., in press]. The present investigation showed little correlation between the rate of QM formation in microsomes and the relative toxicities of the alkylphenols, unless the QMs formed were of similar reactivity. In contrast, a plot of alkylphenol toxicity versus the relative hydrolysis rates of QMs derived from these phenols fit a parabolic equation with a minimum at the data for 4-isopropyl-2-methoxyphenol. These data suggest that in vivo oxidation of phenols to QMs which have lifetimes in the 10 s-10 min range results in cytotoxicity. QMs with reactivities outside this window are less toxic since the electrophile is either too stable for reaction with cellular nucleophiles or too reactive for nucleophilic cellular macromolecules to compete with solvent. These data suggest that a reactivity window exists for QMs which is a primary determinant of the extent of cytotoxic injury caused by these reactive electrophiles.

Animals↗