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Biomedical subjects

L L Smith

Publications and source records attributed to L L Smith.

At least 55 records · Page 3Linked to original sources
PubMed1998

Gender differences on negative affectivity: an IRT study of differential item functioning on the Multidimensional Personality Questionnaire Stress Reaction Scale.

Item response theory methods were used to study differential item functioning (DIF) between gender groups on a measure of stress reaction. Results revealed that women were more likely to endorse items describing emotional vulnerability and sensitivity, whereas men were more likely to endorse items describing tension, irritability, and being easily upset. Item factor analysis yielded 5 correlated factors, and the DIF analysis, in turn, revealed differential gender mean differences on these factors. This finding illustrates how even in an essentially unidimensional scale, comparison of group mean differences can be affected by multidimensionality caused by item clusters that share similar content. Results do not support arguments that measures of negative affective dispositions "artificially" produce gender mean differences by focusing on specific selected content areas.

Adult↗
PubMed1998

Differential white cell count after two bouts of downhill running.

The purpose of this study was to compare blood markers associated with eccentrically biased exercise and muscle damage, after two bouts of downhill running. Nine active, untrained males performed 2 x 45 min bouts of downhill running (-0.16 radians), at a speed that would elicit 70% of each subjects VO2max, on a level grade; runs were spaced 14d apart (RUN1, RUN2). Blood samples were obtained before, after, and every hour for 12 h after exercise, as well as every 24 h for 5 d, to assess numbers of circulating neutrophils, monocytes, and lymphocytes, serum cortisol, creatine kinase (CK); subjective sensations of delayed onset muscle soreness (DOMS) were monitored. To control for diurnal variation, two weeks prior to the RUN1, subjects had blood draws performed at the same time as would occur after exercise, but did no exercise (CONTROL). During the 5 d after exercise, DOMS and CK were significantly greater (p < 0.05) after RUN1 compared to RUN2 and CONTROL. During the 12 h after RUN1 and RUN2, neutrophils showed similar responses compared to CONTROL. However, neutrophils were significantly elevated at 96 h after RUN1 and 24 h after RUN2. Monocytes were significantly elevated during 5-11 h after RUN1 and RUN2, compared to CONTROL. Cortisol showed a similar significant diurnal decrease for all three conditions during the 12 h following exercise. The significantly lower levels of CK and DOMS seen after RUN2, compared with the initial run is consistent with the literature. The similar changes in neutrophils and monocytes during the 12 h following RUN1 and RUN2, followed by disparate responses over the subsequent 5 d, requires further investigation.

Adult↗
PubMed1998

Evaluation of tamoxifen and alpha-hydroxytamoxifen 32P-post-labelled DNA adducts by the development of a novel automated on-line solid-phase extraction HPLC method.

A novel HPLC system has been developed that has allowed the separation of tamoxifen DNA adducts formed in the livers of rats and mice treated with this drug. At least 13 different peaks have been separated from 32P-post-labelled DNA, with two major peaks jointly accounting for >60% of the total adducts formed by tamoxifen in the livers of treated rats and mice. This is a great improvement on the resolution obtained by thin layer chromatography, which separates the adducts into one main product consisting of a group of major adduct spots eluting together, plus several other minor spots. Identification of the nature of some of the peaks has been investigated. Comparisons of the products formed when alpha-acetoxytamoxifen is reacted with DNA in vitro with 32P-post-labelled liver DNA adducts from rats treated with tamoxifen or alpha-hydroxytamoxifen in vivo, appear to confirm that a major route of activation of tamoxifen in vivo is via alpha-hydroxylation. The resolving power of this HPLC system has further extended this result to show that six of the peaks, including the two major peaks, are formed by the reaction of an activated alpha-hydroxytamoxifen with DNA. Activation of 4-hydroxytamoxifen by the peroxidase/H2O2 system in vitro gives a more polar DNA adduct seen only at trace levels in liver DNA from tamoxifen-treated rats and mice.

Animals↗
PubMed1998

Expertise in caring: a source of power.

1. Caring generates power in relationships with patients and helps them to evolve. 2. Caring is more than an emotional response. It is acting in ways that demonstrate that people, relationships, and issues are important. 3. Continuity of care providers across settings help yield positive outcomes for patients.

Catchment Area, Health↗
PubMed1998

Effective peer responses to impaired nursing practice.

Chemical dependency within the nursing profession continues to be a significant problem affecting health care delivery. This article presents up-to-date information on responding to a peer who is demonstrating impaired nursing practice. Specific information on the scope and impact of the problem, indicators of impairment, return to practice, and fitness to practice issues are addressed. In addition, the authors share their insight regarding progress, trends, and challenges in responding to impaired practice.

Absenteeism↗
PubMed1998

Antiestrogen therapy: uncertainties and risk assessment.

Tamoxifen is by far the most clinically tested antiestrogenic drug currently used as adjuvant therapy for breast cancer and it continues to provide considerable benefit in this setting. The balance from clinical trials indicates a strong association between the use of tamoxifen and an increase in uterine tumors (three to sixfold). In rats, tamoxifen is a mutagenic, genotoxic hepatocarcinogen. These actions are not related to its estrogen antagonist activity but have been shown to be as a result of metabolic activation of this drug by cytochrome P450 enzymes, resulting in irreversible binding to cellular DNA. The mechanism of endometrial cancer associated with tamoxifen treatment is unclear, although there are two plausible hypotheses: (1), tamoxifen causes damage and mutation to DNA in uterine cells or (2), it promotes the development of endometrial tumors through its estrogen agonist activity. The evidence for a genotoxic effect of tamoxifen in the uterus is highly contentious and, on balance, we have concluded that it is more likely that the estrogenic effects of tamoxifen promote tumor development.

Animals↗
PubMed1997

Eprinomectin: a novel avermectin for control of lice in all classes of cattle.

Eight trials were conducted in the United States to determine the efficacy of eprinomectin applied topically against four common species of lice in cattle. In two dose titration trials, eprinomectin dosages of 125 to 750 mcg/kg body weight applied topically were compared to untreated controls. In dose confirmation studies, animals treated topically with eprinomectin applied at the rate of 500 mcg/kg were compared to vehicle-treated controls. Four species of lice were present in these trials: Linognathus vituli, Haematopinus eurysternus, Solenopotes capillatus, all sucking lice, and Damalinia (Bovicola) bovis, the cattle biting louse. Louse counts were made on six to nine predilection sites (the same number of sites in all animals in the same trial) prior to treatment. The same sites were counted again seven days after treatment and weekly thereafter until trial termination eight weeks after treatment. When no lice were found in the predilection sites, a modified whole body search was conducted. Each species of lice was present on at least six animals in each treatment group on at least one counting date in two or more trials. No lice were found on any animal treated topically with eprinomectin at a dosage of > or = 500 mcg/kg after 14 days posttreatment until termination of the trials eight weeks after treatment.

Animals↗
PubMed1997

Comparisons of the binding of [14C]radiolabelled tamoxifen or toremifene to rat DNA using accelerator mass spectrometry.

Tamoxifen, widely used as adjuvant therapy in the treatment of breast cancer, is now undergoing trials as a cancer chemopreventative agent. Previous work has shown an association between 32P-postlabelled adducts in rat liver DNA and the development of liver tumours. With the use of accelerator mass spectrometry, [14C]tamoxifen was shown to bind to liver DNA of female rats in a dose-dependent manner and was linear over 0.1-1 mg/kg, compatible with the therapeutic dose used in women (20 mg/person per day). Radiolabel could also be detected in extrahepatic organs, including reproductive and GI-tract, where levels were about 18 and 46%, respectively those seen in liver. Following enzymatic hydrolysis of liver DNA, normal nucleotides by HPLC showed < 2% incorporation of the [14C]radioactivity while > 80% appeared as non-polar products. In contrast, when animals were given an equivalent dose of [14C]toremifene, binding to DNA was an order of magnitude lower than that seen with tamoxifen and no evidence of non-polar adducted nucleotides following HPLC. However, in vitro, using human, rat or mouse liver microsomal preparations, NADPH-dependent binding of both toremifene and tamoxifen to calf thymus DNA could be demonstrated, suggesting that under favourable circumstances toremifene is capable of undergoing conversion to reactive intermediates.

Animals↗
PubMed1997

Tamoxifen causes gene mutations in the livers of lambda/lacI transgenic rats.

Tamoxifen, a rat liver carcinogen, was administered to female lambda/lacI transgenic rats at a dose of 20 mg/kg body weight by gavage for 6 weeks, and the animals were sacrificed 2 weeks later. Tamoxifen induced liver DNA adducts and caused a significant increase in mutation frequency (MF) of approximately 3-fold at the lacI gene in liver DNA. Liver DNA from animals dosed with tamoxifen at 10 mg/kg also showed a similar increase in MF. The mutations were characterized by a raised proportion of: (a) G:C to T:A transversions; (b) insertions of base pairs; and (c) deletions of pairs of G:C base pairs. These observations indicate that tamoxifen induces a distinct spectrum of mutations compared with that found in controls. Toremifene, a noncarcinogenic analogue of tamoxifen with similar estrogenic/antiestrogenic properties examined at 20 mg/kg body weight using the same dosing regime as tamoxifen was not mutagenic. A single oral dose of the rat liver carcinogen aflatoxin B1 (0.5 mg/kg) also significantly raised the MF. In conclusion, although tamoxifen is not mutagenic in regulatory short-term tests, it is a gene mutagen in the rat liver.

Aflatoxins↗
PubMed1997

Cost-effective evaluation and treatment for carotid disease.

OBJECTIVE: To compare carotid endarterectomy (CEA) based solely on Duplex ultrasonography (DU) with CEA based on DU and arteriography. DESIGN AND SETTING: Retrospective case series analysis in a regional tertiary care center. PATIENTS: Consecutive sample of 194 patients undergoing 218 CEAs from January 1, 1993, through June 30, 1995, with either preoperative DU plus arteriography (165 CEAs) or DU only (53 CEAs). MAIN OUTCOME MEASURES: Concordance of the 2 diagnostic imaging techniques and influence of these on the conduct of surgery, surgical outcome, and resource cost. RESULTS: There was agreement (kappa = 0.85) between DU and arteriography in the detection of a carotid occlusion or a stenosis greater than 45%. Arteriography demonstrated 26 aortic arch branch lesions (15.8%), 22 intracranial abnormalities (13.3%), and 6 type C ulcers (3.6%), in addition to 1 nonoccluded internal carotid artery (ICA) (0.61%) and 1 contralateral severe ICA stenosis (0.61%) inaccurately estimated by Duplex. These findings prompted 3 changes (1.8%) in surgical therapy, including 2 decisions in favor of CEA and 1 subclavian-carotid bypass added to CEA. There was no difference in the stroke and death rate for CEA based solely on DU compared with CEA based on DU and arteriography (P = .43). The mean total hospital cost was $5,534 for DU only CEA vs $7,608 for DU plus arteriogram CEA (mean difference = $2,074, P < .01). CONCLUSIONS: The addition of carotid arteriography to a diagnostic Duplex ultrasound study that already suggested the need for CEA did not change the operative plan in 98% (162/165) of the cases. Carotid endarterectomy based solely on DU is appropriate and cost-effective.

Adult↗
PubMed1997

The effectiveness of a single treatment with doramectin or ivermectin in the control of gastrointestinal nematodes in grazing yearling stocker cattle.

Four studies were conducted to a similar experimental design in the U.S. to evaluate the effectiveness of doramectin injectable administered to yearling stocker cattle in the control of gastrointestinal nematodiasis over the subsequent grazing period. Studies were conducted in Wisconsin (WI) and Arkansas (AR) during the summer season. The other two studies were conducted in Georgia (GA) and Mississippi (MS) during the winter/spring season. Doramectin was compared with both ivermectin injectable and ivermectin pour-on in the WI study, with ivermectin injectable alone in the GA study and with ivermectin pour-on alone in the other two studies. At each study site, an area of permanent pasture previously grazed by parasitized animals was subdivided by fencing into equal pasture units each with its own water supply. A treatment designation (non-medicated control, doramectin injectable, ivermectin injectable or ivermectin pour-on) was randomly assigned to each pasture unit. Weaned beef calves with confirmed gastrointestinal nematode infections were randomly allotted to a pasture unit and corresponding treatment group. Each treatment group consisted of three replicates of seven animals per pasture unit (total 21 animals) in the WI study, three replicates of four or six animals per pasture unit (total 16 animals) in the AR study, five replicates of six animals per pasture unit (total 30 animals) in the GA study and three replicates of 12 animals per pasture unit (total 36 animals) in the MS study. Treatments were 1% doramectin injectable solution, 1% ivermectin injectable solution, 0.5% ivermectin pour-on solution or non-medicated controls. The injectables were administered at a dose of 1 ml/50 kg body weight (200 micrograms doramectin or ivermectin/kg) by subcutaneous injection in the neck. Ivermectin pour-on solution was administered topically at a dose of 1 ml/10 kg body weight (500 micrograms ivermectin/kg). After receiving their prescribed treatment, animals were placed on their designated pasture unit where they remained for the entire grazing period (84-140 days). Fecal nematode egg counts and body weights were monitored at predetermined intervals throughout each study. Doramectin treatment reduced pretreatment egg counts by between 95 and 100% by 21 days post-treatment. Subsequent rises in egg output from exposure to infective pastures were delayed by two to four weeks resulting in substantial reductions in total egg deposition over the grazing period and, therefore, potential pasture recontamination. Doramectin treatment resulted in substantial average daily weight gain advantages (0.152-0.272 kg) over the grazing season compared to non-medicated controls. Advantages were statistically significant (P < 0.05) in three of the four studies. There were no significant differences (P > 0.05) in average daily gain between the doramectin and ivermectin injectable or ivermectin pour-on treated groups.

Animal Feed↗
PubMed1997

Identification and mechanism of formation of potentially genotoxic metabolites of tamoxifen: study by LC-MS/MS.

On-line high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-ESI MS) and tandem mass spectrometry (MS/MS) have been applied to the study of tamoxifen metabolism in liver microsomes and to the identification of potentially genotoxic metabolites. The results showed that the hydroxylated derivatives, including 4-hydroxytamoxifen and alpha-hydroxytamoxifen are detoxication metabolites, while arene oxides, their free radical precursors or metabolic intermediates, are the most probable species involved in DNA-adduct formation.

Chromatography, High Pressure Liquid↗
PubMed1997

Peroxidase activation of 4-hydroxytamoxifen to free radicals detected by EPR spectroscopy.

4-Hydroxytamoxifen is a major metabolite of the antiestrogenic drug tamoxifen used in the treatment of women with breast cancer. 4-Hydroxytamoxifen is broken down by a horseradish peroxidase/H2O2 system very much more rapidly than tamoxifen and causes much greater DNA damage determined by 32P-postlabelling. EPR spin trapping of 4-hydroxytamoxifen reaction products in the presence of the free radical trap 5,5-dimethyl-1-pyrroline N-oxide, together with glutathione as a hydrogen donor, resulted in the generation of a species with the characteristics of the glutathione thiyl radical (aN approximately 15.3 G, aH approximately 16.2 G). Support for the creation of thiyl radicals comes from the close to stoichiometric time dependent formation of glutathione disulfide concomitant with the loss of glutathione. Similar results were obtained using 4-hydroxytoremifene but no radical formation or glutathione loss could be detected using 3-hydroxytamoxifen (droloxifene). On-line LC-ESI MS analysis of the incubation products from 4-hydroxytamoxifen has identified three products with a protonated molecular mass of 773, consistent with the formation of dimers of 4-hydroxytamoxifen. The role that radical mechanisms have in the carcinogenic effects of tamoxifen in the endometrium or other target organs of women taking this drug remains to be established.

DNA Adducts↗
PubMed1997

Investigation of the formation and accumulation of liver DNA adducts in mice chronically exposed to tamoxifen.

Tamoxifen was administered to three strains of female mice (B6C3F1, C57BL/6 and DBA/2) in short- and long-term studies to determine their ability to activate tamoxifen and cause hepatic DNA damage. 32P-Postlabelling of liver DNA from mice treated for 4 days showed a group of major adducts that increased in a dose-dependent manner and co-chromatographed with the major adducts detected in rat liver. On cessation of dosing, the majority of adducts were cleared within 3 days. Binding of [14C]tamoxifen to DNA nucleotides was demonstrated by the use of accelerator mass spectrometry. In long-term studies of 12 months to 2 years duration, dependent on strain, tamoxifen was administered continuously in the diet to give a daily dose of approximately 40 mg/kg. DNA adducts were detected after 3 months, although the number of adducts decreased with time and by 2 years were not detectable in the tamoxifen treated mice. None of the treated groups showed a significantly increased incidence of liver tumours, with or without phenobarbital promotion and there was no sustained liver cell proliferation. Tamoxifen was detected in the mouse livers, but at levels 50 times lower than those reported in a comparable rat study. These results suggest that, in contrast to the rat, tamoxifen is non-carcinogenic in mice because it does not cause sufficient cumulative DNA damage, or act as a promoter by causing cell proliferation.

Animals↗
PubMed1997

Clastogenic and aneugenic effects of tamoxifen and some of its analogues in hepatocytes from dosed rats and in human lymphoblastoid cells transfected with human P450 cDNAs (MCL-5 cells).

Tamoxifen and its analogues 4-hydroxytamoxifen, toremifene, 4-hydroxytoremifene, clomifene and droloxifene were tested for clastogenic effects in a human lymphoblastoid cell line (MCL-5) expressing elevated native CYP1A1 and containing transfected CYP1A2, CYP2A6, CYP2E1 and CYP3A4 and epoxide hydrolase and in a cell line containing only the viral vector (Ho1). MCL-5 or Ho1 cells were incubated with 4-hydroxytamoxifen, 4-hydroxytoremifene, clomifene or droloxifene and the incidence of micronuclei estimated. With MCL-5 cells there was an increase in micronuclei with 4-hydroxytamoxifen, 4-hydroxytoremifene and clomifene but not with droloxifene. With Ho1 cells only 4-hydroxytamoxifen and 4-hydroxytoremifene caused an increase in micronuclei. MCL-5 cells were incubated with tamoxifen, 4-hydroxytamoxifen, toremifene, droloxifene, clomifene or diethylstilbestrol (0.25-10 microg/ml) for 48 h and subjected to 3 h treatment with vinblastine (0.25 microg/ml) to arrest cells in metaphase. The incidence of cells with chromosomal numerical aberrations (aneuploidy) was increased in cells treated with tamoxifen, 4-hydroxytamoxifen, toremifene, clomifene and diethylstilbestrol but not droloxifene. The frequency of cells with structural abnormalities (excluding gaps) was increased in cells treated with tamoxifen and toremifene but not 4-hydroxytamoxifen, clomifene, droloxifene or diethylstilbestrol. The clastogenic activities of tamoxifen (35 mg/kg), toremifene (36.3 mg/kg), droloxifene (35.2 mg/kg) and diethylstilbestrol (25 mg/kg) were compared in groups of four female Wistar rats. Each chemical was dissolved in glycerol formal, administered as a single dose by gavage and hepatocytes isolated by collagenase perfusion 24 h later. The cells were cultured in the presence of epidermal growth factor (40 ng/ml) for 48 h, colchicine (10 microg/ml) being added for the final 3 h of incubation. At least 100 chromosomal spreads were examined from each animal for the presence of numerical and structural abnormalities. The incidences of aneuploidy following treatment were: tamoxifen 81%, toremifene 46%, droloxifene 9.6%, diethylstilbestrol 45.7%, vehicle control 5.3%. The incidences of chromosomal structural abnormalities excluding gaps were: tamoxifen 4.3%, toremifene 0.8%, droloxifene 0.5%, diethylstilbestrol 0.8%, control 0.5%. The incidence of chromosomal structural aberrations excluding gaps in the treated animals was not statistically significantly different from controls except in the tamoxifen-treated group. Tamoxifen (35 mg/kg per os) and toremifene (36.3 mg/kg per os) were dosed to rats for 4 weeks and chromosomal spreads made from hepatocytes. The incidences of aneuploidy were: tamoxifen 94%, toremifene 57%, control 6.5%. The incidences of chromosomal aberrations excluding gaps were: tamoxifen 12%, toremifene 1%, control 0.5%. The incidence of tamoxifen-induced chromosomal structural abnormalities was significantly elevated compared with control levels. The results demonstrate that tamoxifen and toremifene are the only two drugs tested in the study that cause chromosomal structural and numerical aberrations in vitro and tamoxifen is the only drug that induces both these effects in rat liver cells stimulated to divide in culture following oral dosing. Since chromosomal mutations require cell division for their manifestation and tamoxifen is the only compound of those tested that causes hyperplasia in the rat liver, chromosomal aberrations and aneuploidy in the rat liver would only be expected to occur following treatment with tamoxifen alone, although aneuploidy could be induced by toremifene in conjunction with a promoter such as phenobarbitone.

Aneuploidy↗
PubMed1997

Efficacy of eprinomectin against mange mites in cattle.

OBJECTIVE: To determine whether eprinomectin was effective against mange caused by Chorioptes bovis and Sarcoptes bovis in cattle. ANIMALS: 80 cows naturally infested with C bovis and 30 cattle experimentally infested with S bovis. PROCEDURE: 6 trials were performed to determine efficacy against C bovis, and 2 trials were performed to determine efficacy against S bovis. In each trial, a group of untreated animals or of animals treated with vehicle alone was compared with a group of animals treated with a 0.5% formulation of eprinomectin applied topically (500 micrograms/kg). Number of mites in skin scrapings was determined prior to treatment and at weekly intervals for 8 weeks after treatment. Severity of skin lesions was evaluated when skin scrapings were obtained. In 5 trials, animals were weighed before and 56 days after treatment. RESULTS: Mite counts for treated cattle were significantly less than counts for control cattle from day 14 onwards in trials to determine efficacy against C bovis and from day 7 onwards in trials to determine efficacy against S bovis. Mites were not detected in scrapings collected from treated cattle on day 56. Mean weight gain of treated cattle was not significantly different from mean weight gain of control cattle in trials evaluating efficacy against C bovis but was significantly greater in trials evaluating efficacy against S bovis. CONCLUSION AND CLINICAL RELEVANCE: Eprinomectin was highly effective against C bovis and S bovis. Because eprinomectin can be administered to lactating cows, it may be useful for controlling mange in cattle.

Administration, Topical↗