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Biomedical subjects

C Harris

Publications and source records attributed to C Harris.

At least 163 records · Page 9Linked to original sources
PubMed1991

Role of glutathione and hsp 70 in the acquisition of thermotolerance in postimplantation rat embryos.

Studies were initiated to determine the extent to which reduced glutathione (GSH) may be involved in the capacity of cultured rat embryos to develop heat-induced tolerance to the deleterious effects of exposure to high temperatures (heat shock). Investigations of the modulation of dysmorphogenic responses of embryos to heat shock (43 degrees C, 30 min) as well as to the expression of the hsp70 gene and subsequent formation of hsps indicated that the acquisition of thermotolerance by rat embryos could be significantly influenced by the inhibition of GSH synthesis. Treatment of conceptuses with L-buthionine-S,R-sulfoximine (BSO) reduced intracellular GSH concentrations and compromised the capacity of embryos to mount a thermotolerance response as assessed by alterations in indices of growth and development. Embryonic thermotolerance elicited by preexposure to 42 degrees C for 30 min was accompanied by increases in GSH to levels greater than those measured in control embryos at 37 degrees C just prior to the subsequent 43 degrees C heat exposure. Expression of hsp70 mRNA was detectable soon after elevation of the temperature to 42 degrees C and reached its highest level of accumulation 1.5 hr after the 43 degrees C heat shock. BSO treatment had little if any effect on hsp70 message levels or on the synthesis of hsp70. The fact that BSO-treatment attenuated the thermotolerance response but did not produce a decrease in hsp70 RNA or the synthesis of hsp70 suggests that hsp70 alone is not sufficient to confer thermotolerance upon cultured rat embryos.

Animals↗
PubMed1991

Cytochrome P450-dependent bioactivation of prodysmorphogens in cultured conceptuses.

These investigations were undertaken to determine the extent to which tissues of cultured rat conceptuses contain cytochrome P450 isoforms in sufficient quantities to significantly influence the capacity of certain chemicals to elicit dysmorphogenic effects in vitro. Investigations with highly sensitive probe substrates/inhibitors and with immunologic methods enabled the detection of at least four separate P450 isoforms in tissues of the visceral yolk sac, ectoplacental cone, and embryo proper. One of the isoforms was identified as P450IA1 and was found to be inducible by polycyclic aromatic hydrocarbons in all three tissues. Other isoforms exhibited properties differing from characterized adult rat hepatic isoforms. Each of the isoforms was detectable in conceptuses on gestational days 10, 11, 12, and 14 and was present in the highest concentrations in the visceral yolk sac. Conceptal P450IA1 catalyzed the conversion of dysmorphogenically inactive 2-acetylaminofluorene to 7-hydroxy-2-acetylaminofluorene, a proximate dysmorphogen. Investigations with microinjections suggested that visceral yolk sac hydroxylation was largely responsible for the bioactivation reaction in vitro. The same isoform exhibited no capacity to influence the dysmorphogenic activity of cyclophosphamide. The results demonstrated that tissues of cultured rat conceptuses may contain P450 isoforms in sufficient amounts to markedly influence the dysmorphogenic activity of substrates of the corresponding isoforms.

Animals↗
PubMed1991

The will and the ways: development and validation of an individual-differences measure of hope.

Defining hope as a cognitive set that is composed of a reciprocally derived sense of successful (a) agency (goal-directed determination) and (b) pathways (planning of ways to meet goals), an individual-differences measure is developed. Studies demonstrate acceptable internal consistency and test-retest reliability, and the factor structure identifies the agency and pathways components of the Hope Scale. Convergent and discriminant validity are documented, along with evidence suggesting that Hope Scale scores augmented the prediction of goal-related activities and coping strategies beyond other self-report measures. Construct validational support is provided in regard to predicted goal-setting behaviors; moreover, the hypothesized goal appraisal processes that accompany the various levels of hope are corroborated.

Adaptation, Psychological↗
PubMed1991

Pharmacokinetic study of lomefloxacin and its effect on the faecal flora of volunteers.

In a volunteer pharmacokinetic study mean peak serum concentrations of lomefloxacin of 7.19 mg/l were obtained 1.5 h after an oral dose of 400 mg. Women had higher concentrations than men. Urinary excretion was 34% in 6 h and 63% in 24 h and the mean peak concentration was 699 mg/l. Saliva concentrations were 37% of those in serum. Lomefloxacin was detectable in the faeces up to seven days after the last dose. The major effect of lomefloxacin on the faecal flora of volunteers following a four day course of 400 mg once daily was the elimination of strains of Enterobacteriaceae and an increase in the numbers of Gram-positive cocci, mainly streptococci. There was no effect on anaerobic bacteria or yeasts. Lomefloxacin was well tolerated and no side effects were recorded. No bacterial resistance was detected after treatment.

4-Quinolones↗
PubMed1991

Headache in HIV-1-related disorders.

To define the causes, clinical significance and characteristics of headaches in HIV-1-related disorders, we studied 49 consecutive HIV-1 infected patients who presented with headache. Work-up included CT scans, cerebrospinal fluid examinations (in the absence of a contraindication) and serologic studies. Overall, 40 of 49 patients (82 percent) had an identifiable serious cause of headache. Cryptococcal meningitis (39 percent) and CNS toxoplasmosis (16 percent) were the leading headache etiologies. Serious causes were more likely in patients diagnosed with AIDS prior to presentation but also occurred in most patients in early stages of infection. Based on this study, we suggest that patients with HIV-1 infection must be managed with a high index of suspicion when they present with new onset headaches.

Adult↗
PubMed1991

In-home respite care: a comparison of volunteers and paid workers.

Descriptive data using an administered questionnaire were obtained from fifteen in-home respite volunteers and from fifteen paid in-home respite workers. From each group, five volunteers and five paid workers and the families they served, were interviewed in depth. Independent t tests showed volunteers to be older, have more education, spend less time in respite and more time in the confidant role than paid workers. Volunteers were characterized as a family surrogate motivated by altruistic and substitutive needs. They were shown to be reliable, competent, creative, and nurturant. Paid workers were found to be motivated by a liking for people and financial need. Though their services were also shown to be reliable, competent and nurturant, paid workers were characterized more as an extension of the family care-giver.

Adult↗
PubMed1991

Efficacy of acemannan in treatment of canine and feline spontaneous neoplasms.

Forty-three dogs and cats with spontaneous tumors were treated with the immunostimulating polysaccharide acemannan by intraperitoneal and intralesional routes of administration. Tumors from 26 of these animals showed histopathological evidence of immunological attack as shown by marked necrosis or lymphocytic infiltration. Thirteen showed moderate to marked tumor necrosis or liquefaction. Twenty-one demonstrated lymphoid infiltration, and seven demonstrated encapsulation. Twelve animals showed obvious clinical improvement as assessed by tumor shrinkage, tumor necrosis, or prolonged survival; these included five of seven animals with fibrosarcomas. It is believed that acemannan exerts its antitumor activity through macrophage activation and the release of tumor necrosis factor, interleukin-1, and interferon.

Adjuvants, Immunologic↗
PubMed1991

The evaluation of patients with human immunodeficiency virus-related disorders and brain mass lesions.

In patients at risk for acquired immunodeficiency syndrome who present with a mass lesion, a dilemma arises as to whether to treat empirically for toxoplasmosis or perform a brain biopsy. We present data that further define the indications for performing brain biopsy vs empiric treatment. We reviewed charts on 59 patients with acquired immunodeficiency syndrome--related disorders and cerebral mass lesions. Thirty-two patients met diagnostic criteria for toxoplasmosis. Bayesian analysis demonstrated that the prior probability of toxoplasmosis was increased by the presence of contrast enhancement on computed tomographic scans (0.68) and toxoplasmosis titers greater than 1:64 (0.81). Features associated with decreasing probabilities of toxoplasmosis included the absence of contrast enhancement on computed tomographic scans (0.29) and toxoplasmosis titers less than or equal to 1:64 (0.14). Ten percent of patients had complications of brain biopsy. Treatment with pyrimethamine and sulfadiazine produced complications in 29% and serious complications in 8% of treated patients. These data favor empiric therapy for patients with typical features of toxoplasmosis and brain biopsy for defined subsets of patients with atypical features.

Bayes Theorem↗
PubMed1990

Non-mydriatic retinal photography as a screening service for general practitioners.

Non-mydriatic retinal photography was offered as a screening service to 37 general practitioners providing diabetes care in their practices. Of 84 patients photographed, 22 had appearances of diabetic retinopathy and these were compared with 25 of the remainder without retinopathy. In only seven of 11 patients with maculopathy or proliferative retinopathy had this been detected by their GP and, likewise, only six of 11 cases of probable background retinopathy had been detected. The mean annual examination rate in general practice was 33 (95% Cl 18-47)%. Of the 18 cases in whom action in response to recommendations for follow-up or referral could be ascertained, 15 (83%) had had the recommendations implemented. Thus, despite the potential risks of false-negative screening using non-mydriatic retinal photography, the technique may improve the comprehensiveness of screening in patients under the care of their GPs.

Diabetic Retinopathy↗
PubMed1990

Dysmorphogenesis elicited by microinjected acetaminophen analogs and metabolites in rat embryos cultured in vitro.

Direct additions of acetaminophen (APAP), 3,5-dimethylacetaminophen, 3-hydroxyacetaminophen or 3-methoxyacetaminophen to the medium of cultured embryos each produced an increased incidence of morphologically similar, abnormally open anterior neuropores. Approximate concentrations required to produce an equal incidence were 0.5 mM, 1.0 mM, 0.1 mM and 0.75 mM, respectively. In contrast, 2.6-dimethylacetaminophen and N-acetyl-p-benzoquinoneimine failed to produce elevated incidences of abnormal neurulation unaccompanied by marked growth retardation. However, with intra-amniotic microinjections, 3-hydroxyacetaminophen and N-acetyl-p-benzoquinoneimine were roughly equipotent for eliciting abnormal neurulation, whereas 3-methoxyacetaminophen required greater than 30-fold higher concentrations. This suggests that N-acetyl-p-benzoquinoneimine does not readily transit the visceral yolk sac and would likely not be a major factor in APAP-elicited neural tube abnormalities unless generated in target tissues. The differential effects produced by two dimethylated (2.6 and 3.5) APAP analogs further suggest that sulfhydryl oxidation is associated more closely than sulfhydryl conjugation with the neurulation defect. Intra-amniotic microinjections of large quantities (3500 ng) of 7-hydroxy-2-acetylaminofluorene (7-OH-AAF) or APAP failed to produce the specific neurulation defect. Microinjections of 7-OH-AAF into the exocoelomic cavity effected the characteristic abnormal neurulation. Conversion by conceptal homogenates of 7-OH-AAF was roughly 7- to 8-fold more rapid than conversion of APAP to respective catechol metabolites, and specific activities in yolk sac tissues were greater than those in the embryo. Rates of conceptal conversion to the quinoneimine were approximately 2- to 3-fold lower than catechol generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1989

Influence of electrophilic character and glutathione depletion on chemical dysmorphogenesis in cultured rat embryos.

To examine the importance of reduced intracellular glutathione (GSH) in the modulation of dysmorphogenesis and to gain insight into the electrophilic character of the embryotoxic intermediates generated in the rat embryo from N-acetoxy-2-acetylaminofluorene (AAAF) and acetaminophen (APAP) in cultured embryos, the effects of GSH depletion on the embryotoxicity, dysmorphogenesis and covalent binding of these agents were examined. Both AAAF (90 microM) and APAP (500 microM) produced concentration-dependent, statistically significant (P less than or equal to 0.05) decreases in embryonic length as well as embryonic and visceral yolk sac protein content when rat embryos were exposed in vitro between days 10 and 11 of gestation. The predominant malformations observed upon exposure to AAAF and APAP were prosencephalic hypoplasia and abnormal neurulation respectively. Exposure of conceptuses to [3H]APAP followed by separation and fractionation of the cellular RNA, DNA and protein via density gradient centrifugation resulted in detectable binding in fractions that contained protein, but not DNA or RNA. This suggested that the rat conceptus is capable of bioactivating APAP to a soft electrophile that selectively arylates protein. In contrast, conceptuses exposed to [3H]AAAF exhibited detectable binding to RNA, DNA and protein, indicative of conversion to both hard and soft electrophiles. Depletion of GSH was accomplished by pretreating conceptuses with 500 microM L-buthionine-S,R-sulfoximine (BSO) from the start of the culture period (day 9.5) until the morning of day 10. When conceptuses were depleted previously of GSH by BSO, exposure to APAP resulted in significant potentiation (relative to APAP alone) of the observed embryotoxicity. These conceptuses displayed further decreases in both embryonic size and protein content of the embryo and yolk sac, as well as increased incidence of abnormally open anterior neuropores and increased binding (3-fold) of [3H]APAP to protein. In contrast, pretreatment with BSO did not potentiate the AAAF-elicited decreases in embryonic size or protein content, nor the severity of prosencephalic hypoplasia, although a slight increase in binding of [3H]AAAF to DNA was observed. Taken together, these data are consistent with the concept that abnormal neurulation elicited by APAP results from the generation of one or more soft electrophilic species, whereas elicitation of prosencephalic hypoplasia by AAAF appears to be a consequence of conversion to a relatively hard electrophile(s).

2-Acetylaminofluorene↗
PubMed1989

Modulation of the embryotoxicity and cytotoxicity elicited by 7-hydroxy-2-acetylaminofluorene and acetaminophen via deacetylation.

Acetaminophen (APAP) and 7-hydroxy-2-acetylaminofluorene (7-OH-AAF) each produced a similar incidence of, as well as a qualitatively similar, abnormal closure of the anterior neuropore at similar concentrations when added to the medium of cultured rat embryos. At concentrations producing a 50-65% incidence of abnormal neurulation, the affected embryos displayed relatively complete embryonic development as assessed from measurements of protein, axial rotation, and embryonic length. The neural tube defect produced by these agents consisted of elevated neural folds remaining separated by approximately 45 degrees as well as the presence of a mitotically active neural epithelium. In contrast, the nonacetylated structures, p-aminophenol (PAP) and 7-hydroxyaminofluorene (7-OH-AF), were embryotoxic at concentrations 10-fold lower than the corresponding acetylated compounds; each produced a greater incidence of abnormal axial rotation and a greater decrease in embryonic protein than APAP or 7-OH-AAF. In addition, the embryos exposed to PAP or 7-OH-AF were morphologically and histologically dissimilar to those exposed to the acetylated compounds. The neural folds of the latter remained elevated and in apposition, but lacked complete fusion of the folds of neural epithelium and were accompanied by marked cytotoxicity. Addition of active deacetylase sources (guinea pig liver microsomes or commercially obtained, purified carboxylic-ester hydrolase) to the culture medium of conceptuses exposed to 7-OH-AAF or APAP resulted in an increased embryotoxicity which was indistinguishable from that produced by the nonacetylated compounds alone. The increases in toxicity were effectively blocked by the addition of paraoxon, indicating that catalysis of the deacetylation of APAP and 7-OH-AAF was the causative factor. No evidence could be found for deacetylation of 7-OH-AAF or APAP mediated by the Day 10 conceptus itself. When examined for cytotoxicity in F9 embryonal carcinoma cells, APAP and 7-OH-AAF each produced observable cell death only if reduced glutathione (GSH) had previously been depleted and if a deacetylase source were present; this cytotoxicity was also blocked by addition of paraoxon. The nonacetylated metabolites were directly cytotoxic, although GSH depletion greatly increased the incidence of cell death. Therefore, deacetylation of APAP and 7-OH-AAF produced an increase in generalized embryotoxicity and cytotoxicity relative to abnormal neurulation, suggesting that APAP and 7-OH-AAF are capable of eliciting neural tube defects via a mechanism(s) that is distinguishable from the generalized embryotoxicity or cytotoxicity produced by their nonacetylated counterparts.

2-Acetylaminofluorene↗
PubMed1989

Circulatory responses to laryngoscopy: the comparative effects of placebo, fentanyl and esmolol.

The circulatory response to a 30-second laryngoscopy followed by orotracheal intubation was recorded in 60 patients of ASA physical status III or IV undergoing a variety of non-cardiac surgical procedures. Patients were randomly allocated to either the placebo, esmolol (500 micrograms.kg-1.min-1 X 6 minutes, followed by 300 micrograms.kg-1.min-1 X 9 minutes), or fentanyl (0.8 microgram.kg-1.min-1 X 10 minutes) group, and the observer was blinded to the infusion administered. Esmolol blunted the heart rate (HR) response, while fentanyl decreased it below the baseline and maintained it there, in spite of laryngoscopy. Similarly, fentanyl decreased the systolic (SBP), mean (MBP) and diastolic blood pressures (DBP) significantly below the baseline, while these pressures were either retained at or elevated slightly above control in the esmolol group. In these doses, the HR response to laryngoscopy was more effectively blocked by fentanyl, while esmolol better retained perfusion pressure. There were no complications or ischaemic electrocardiographic changes in any patient.

Adrenergic beta-Antagonists↗
PubMed1989

Abnormal neurulation induced by 7-hydroxy-2-acetylaminofluorene and acetaminophen: evidence for catechol metabolites as proximate dysmorphogens.

Direct additions to culture media of either acetaminophen (APAP) or 7-hydroxy-2-acetylaminofluorene (7-OH-AAF) resulted in abnormal closure of the anterior neuropores of cultured rat embryos in the absence of an exogenous bioactivation system. Concentrations required to produce a 50% incidence of the defect were approximately 500 and 250 microM for APAP and 7-OH-AAF, respectively. Losses of viability were not evident at these concentrations but 7-OH-AAF elicited a somewhat greater effect on growth parameters and generalized embryotoxicity. Transplacental induction with 3-methylcholanthrene (MC) of P450IA1 in subsequently cultured rat embryos did not detectably alter the capacity of APAP or 7-OH-AAF to effect embryotoxicity or neuropore closure. However, additions to the culture medium of exogenous hepatic bioactivating systems (S9) from MC-induced vs phenobarbital (PB)-induced adult rats produced profoundly different effects on neuropore closure. Coincubation with S9 from MC-induced rats reduced the incidence of 7-OH-AAF-elicited abnormal neuropores from 45 to 19%, whereas coincubation with S9 from PB-induced rats increased the incidence to 77%. Coincubation with MC-induced S9 produced no statistically significant effect on APAP-elicited neuropore abnormalities but, with PB-induced S9, resulted in a significant increase from 60 to 86%. Additions of 3-OH-APAP (0.1-0.2 mM) but not N-acetyl-p-benzoquinoneimine (NAPQI, 0.1-0.5 mM) to the culture medium elicited the typical neuropore abnormality. Experiments with APAP and 7-OH-AAF as substrates demonstrated that embryonic enzymes catalyzed their conversion to the corresponding catechols. Considered together, the results provided evidence that embryonic conversion of APAP or 7-OH-AAF to the corresponding catechol metabolites may be instrumental in effecting the abnormal anterior neuropore closure observed after exposure of embryos to the respective parent compounds.

2-Acetylaminofluorene↗