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Biomedical subjects

C L Williams

Publications and source records attributed to C L Williams.

At least 19 recordsLinked to original sources
PubMed1999

M3 muscarinic acetylcholine receptors regulate cytoplasmic myosin by a process involving RhoA and requiring conventional protein kinase C isoforms.

Although muscarinic acetylcholine receptors (mAChR) regulate the activity of smooth muscle myosin, the effects of mAChR activation on cytoplasmic myosin have not been characterized. We found that activation of transfected human M3 mAChR induces the phosphorylation of myosin light chains (MLC) and the formation of myosin-containing stress fibers in Chinese hamster ovary (CHO-m3) cells. Direct activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate (PMA) also induces myosin light chain phosphorylation and myosin reorganization in CHO-m3 cells. Conventional (alpha), novel (delta), and atypical (iota) PKC isoforms are activated by mAChR stimulation or PMA treatment in CHO-m3 cells, as indicated by PKC translocation or degradation. mAChR-mediated myosin reorganization is abolished by inhibiting conventional PKC isoforms with Go6976 (IC50 = 0.4 microM), calphostin C (IC50 = 2.4 microM), or chelerythrine (IC50 = 8.0 microM). Stable expression of dominant negative RhoAAsn-19 diminishes, but does not abolish, mAChR-mediated myosin reorganization in the CHO-m3 cells. Similarly, mAChR-mediated myosin reorganization is diminished, but not abolished, in CHO-m3 cells which are multi-nucleate due to inactivation of Rho with C3 exoenzyme. Expression of dominant negative RhoAAsn-19 or inactivation of RhoA with C3 exoenzyme does not affect PMA-induced myosin reorganization. These findings indicate that the PKC-mediated pathway of myosin reorganization (induced either by M3 mAChR activation or PMA treatment) can continue to operate even when RhoA activity is diminished in CHO-m3 cells. Conventional PKC isoforms and RhoA may participate in separate but parallel pathways induced by M3 mAChR activation to regulate cytoplasmic myosin. Changes in cytoplasmic myosin elicited by M3 mAChR activation may contribute to the unique ability of these receptors to regulate cell morphology, adhesion, and proliferation.

ADP Ribose Transferases↗
PubMed1999

Granule cells in aging rats are sexually dimorphic in their response to estradiol.

Normal aging comprises cognitive decline, including deterioration of memory. It has been suggested that this decline in memory is sexually dimorphic because of the cessation in gonadal steroid secretion that occurs during reproductive aging in female, but not male, mammals. We wondered whether neurons in brain regions associated with learning and memory underwent morphological changes that were dimorphic as well and whether cessation of the secretion of gonadal steroids influenced these morphological changes. To explore these questions, we deprived and restored estrogens to young and old gonadectomized females and males and studied the morphology of dentate granule cells by intracellular dye filling in a lightly fixed slice preparation. We found the following: (1) Aged female dentate granule cells deprived of gonadal steroids long-term have a paucity of dendritic spines compared with young females deprived short-term; however, aged male dentate granule cells deprived of gonadal steroids long-term have no decrease in dendritic spines compared with young males deprived short-term. (2) Aged female dentate granule cells with long-term estrogen replacement at either high or low levels still had a decline in spine density. (3) Aged female dentate granule cells with short-term estradiol replacement had spine density increased to levels normally observed in young adults, whereas aged males with short-term estradiol replacement had decreased spine density. These data suggest that the response of rat dentate granule cells to aging and estradiol is sexually dimorphic and that, in females, the responsiveness of granule cells depends on the temporal pattern of estradiol replacement.

Aging↗
PubMed1999

Activation of transfected M1 or M3 muscarinic acetylcholine receptors induces cell-cell adhesion of Chinese hamster ovary cells expressing endogenous cadherins.

Expression of endogenous cadherins by Chinese hamster ovary (CHO) cells has not been previously reported. However, we observed that CHO cells adhere to one another upon activation of transfected muscarinic acetylcholine receptors (mAChR), suggesting that the cells express endogenous cadherins. A 160-base pair RT-PCR product with 100% homology to the cytoplasmic domain of human E-cadherin was amplified from CHO cells. A second RT-PCR product amplified from these cells has 92% homology to the cytoplasmic domain of human cadherin-9 and 86% homology to the cytoplasmic domain of human cadherin-6. Western blotting indicates that CHO cells express a 165-kDa protein recognized by E-cadherin antibodies and a 120-kDa protein recognized by an antibody to the cadherin C-terminus sequence. The ability of transfected mAChR subtypes to regulate cadherin-mediated adhesion of CHO cells was tested by measuring the permeation of horseradish peroxidase across confluent CHO cell monolayers, by microscopic examination of the cells, and by aggregation assays. Cell-cell adhesion is induced within 15 min of activating transfected M1 or M3 mAChR which functionally couple to protein kinase C (PKC). In contrast, CHO cell adhesion is not affected by activating transfected M2 mAChR which functionally couple to other effectors. Activation of PKC with phorbol esters also induces cell-cell adhesion of all CHO sublines tested. Immunofluorescence assays reveal that endogenous cadherins redistribute on the plasma membrane of CHO cells following mAChR or PKC activation. Inactivation of cadherins by removal of extracellular Ca2+ abrogates adhesion induced by mAChR or PKC activation. Our demonstration that activation of only odd-numbered mAChR subtypes induces cadherin-mediated adhesion suggests that the unique responses of cells to M1 or M3 mAChR stimulation may involve cadherin activation.

Amino Acid Sequence↗
PubMed1999

Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial.

CONTEXT: Heterozygous familial hypercholesterolemia (HeFH) is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). OBJECTIVE: To assess the lipid-lowering efficacy, biochemical safety, and effect on growth and sexual development of lovastatin in adolescent boys with HeFH. DESIGN: One-year, double-blind, placebo-controlled, balanced, 2-period, 2-arm randomized trial. In the first period (24 weeks), lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period (24 weeks). The study was conducted between 1990 and 1994. SETTING: Fourteen pediatric outpatient clinics in the United States and Finland. PATIENTS: Boys aged 10 to 17 years with HeFH. Of 132 randomized subjects (67 intervention, 65 placebo), 122 (63 intervention, 59 placebo) and 110 (61 intervention, 49 placebo) completed the first and second periods, respectively. INTERVENTION: Lovastatin, starting at 10 mg/d, with a forced titration at 8 and 16 weeks to 20 and 40 mg/d, respectively, or placebo. MAIN OUTCOME MEASURES: The primary efficacy outcome measure was low-density lipoprotein cholesterol (LDL-C). Primary safety measures were growth and sexual development. RESULTS: Compared with placebo, LDL-C levels of patients receiving lovastatin decreased significantly (P<.001) by 17%, 24%, and 27% receiving dosages of 10, 20, and 40 mg/d, respectively, and remained 25 % lower than baseline at 48 weeks. Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks (P = .85) and 48 weeks (P = .33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect significant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation. CONCLUSIONS: This study in adolescent boys with HeFH confirmed the LDL-C-reducing effectiveness of lovastatin. Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks, although further study is required.

Adolescent↗
PubMed1999

Glucocorticoid receptor activation in the rat nucleus of the solitary tract facilitates memory consolidation: involvement of the basolateral amygdala.

These experiments examined the involvement of glucocorticoid receptors (GRs or type II) located in the A2-noradrenergic cell group of the rat nucleus of the solitary tract (NTS) in modulating memory storage. Bilateral intra-NTS infusions (0.5 microL) of the specific GR agonist RU 28362 (11beta, 17beta-dihydroxy-6, 21-dimethyl-17alpha-pregna-4,6-trien-20yn-3-one), in doses ranging from 0.01 to 10.0 ng, immediately after inhibitory avoidance training produced a dose-dependent enhancement of 48 h retention performance. Infusions of 0.1 or 1.0 ng of the agonist enhanced retention, whereas lower or higher doses were ineffective. Post-training infusions of the GR antagonist RU 38486 [17beta-hydroxy-11beta-(4-dimethylaminophenyl)-17alpha-(1-pr opynyl)-o estra-4,9-dien-3-one, 0.01-10.0 ng] into the NTS did not significantly affect retention performance, but shifted the dose-response effects of post-training systemic injections of the synthetic glucocorticoid dexamethasone to the right. These results indicate that activation of GRs in the NTS can influence memory formation for inhibitory avoidance training, and suggest that the effects of circulating glucocorticoids on memory are mediated, in part, by an activation of GRs in the NTS. Additionally, pretraining infusions of the beta1-adrenergic antagonist atenolol (0.5 microg in 0.2 microL) into the basolateral nucleus of the amygdala (BLA), a brain structure which receives noradrenergic projections from the NTS and is implicated in memory storage modulation, blocked the memory-enhancing effects of the GR agonist (1.0 ng) infused into the NTS. These findings provide evidence that memory storage is modulated by glucocorticoid binding to GRs in noradrenergic cell bodies in the NTS and suggest that these modulatory effects are conveyed by ascending projections to the BLA.

Amygdala↗
PubMed1999

Helicobacter pylori and endoscopy.

Helicobacter pylori is possibly the most common bacterial infection of humans and is now recognized as the most important acquired cause of peptic ulceration. Epidemiological evidence also recently implicated this bacterium in the pathogenesis of gastric cancer. The mechanism of spread of the organism, by either the faecal-oral or oral-oral route, raises the possibility of transmission of this organism from infected patients to hospital staff particularly those involved in endoscopy. The evidence for an increased risk to endoscopists is contradictory, varying from none to a five-fold increase. This review summarizes the evidence for mode of transmission and risk to hospital staff from this important bacterium.

Cross Infection↗
PubMed1999

Nutrient intake of Head Start children: home vs. school.

OBJECTIVE: To determine mean intake of energy and protein, total fat, saturated fat, percent energy from total and saturated fat, cholesterol, carbohydrate, calcium, iron, zinc, folate, vitamins A, C, E, B-6 and B-12, thiamin, niacin, riboflavin, magnesium, sodium and fiber of preschool Head Start children at school and away from school. DESIGN: Twenty-four-hour food intakes for 358 Head Start children were obtained by observing food intake at school and acquiring intake recalls from parents or guardians specifying food their children consumed for the balance of the day. After determining group estimates of energy and nutrient intake, mean intake was compared to standard nutrient recommendations for the entire 24-hour day, i.e., for the time the children were in school and for the remaining hours away from school ("home" intake). SUBJECTS: The 358 Head Start children attended school either half-day (2- to 3-hour AM and PM sessions) or all-day (5 to 6 hours). STATISTICAL ANALYSES: Differences in nutrient intake among class times were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test. Differences with a p-value <0.05 (two-tailed) were considered to be statistically significant. Total energy, protein, calcium, iron, zinc, vitamins A, C, E, B6, and B12, thiamin, niacin, riboflavin as well as folate and magnesium were compared to the Recommended Dietary Allowances for the 4- to 6-year-old age group. Other standards that were used for comparisons included the National Cholesterol Education Program (fat, saturated fat and cholesterol), the 1989 National Research Council's Diet and Health Report (carbohydrate and sodium) and the recommendation for fiber proposed by the American Health Foundation. RESULTS: At school, half-day children consumed up to 25% of the daily recommendation for energy and nutrients, while all-day children achieved at least a third of the recommended intakes. When intakes at home and school were combined, all three groups of children (AM, PM and all-day) exceeded dietary recommendations for protein, vitamins and minerals. Energy intake remained below 100% of the recommendation, while intake of total fat, saturated fat and cholesterol exceeded recommendations. APPLICATION: Further research is required to explore energy needs and determine nutritional status and nutrient needs of minority and low-income preschool children. Strategies are required to increase nutrient density, but not fat density, of meals and snacks served to children who attend day care for part of the day. Finally, school meals and nutrition education programs such as Team Nutrition should broaden their base to include healthful eating habits for all school children, including the very youngest children in preschool programs.

Child Nutritional Physiological Phenomena↗
PubMed1999

Evaluation of antipsychotic and concomitant medication use patterns in patients with schizophrenia.

OBJECTIVE: To describe antipsychotic medication use patterns in an inner-city, outpatient population of indigent patients with schizophrenia. METHODS: This retrospective cohort study used the Regenstrief Medical Record System to identify schizophrenic patients receiving antipsychotic medication(s). Patients were included and identified as initiating a new treatment episode if they did not receive any antipsychotic prescription for 90 days before their first antipsychotic prescription in 1995. Each patient was followed for 1 year. RESULTS: Three hundred and sixteen patients met study criteria. Typical and atypical (clozapine and risperidone) antipsychotic agents were selected as initial therapy in 88% and 12% patients, respectively. The majority of patients (71.5%) were exposed to only one antipsychotic agent during their treatment year. Approximately 25% of all patients switched from one antipsychotic to a different antipsychotic during 12 months of therapy. Nearly 90% of patients augmented their prescribed antipsychotic with a concomitant medication during the 12-month study period. Approximately 30% of the cohort received treatment with an antipsychotic for 12 continuous months and were, thus, classified as having stable antipsychotic therapy. The majority of patients (67.1%) had periods of interrupted therapy (range, 1-11 months) during the 12 month study period. CONCLUSION: As of 1995 an overwhelming majority of schizophrenic patients in this indigent, inner-city population initiated therapy with a typical antipsychotic. Patients frequently switched antipsychotics and discontinued their therapy during the 1 year study period. Reasons for switching or discontinuing may include the following: ineffective therapy; patient intolerance; change in symptoms; and improved assessment and understanding of the diagnosis or physician preference.

Adult↗
PubMed1999

Developing a computer-assisted health knowledge quiz for preschool children.

The project evaluated the reliability of a computer-assisted health education knowledge quiz, a multiple-choice picture identification assessment tool for nutrition and health-related knowledge in preschool age children. Pearson's product moment correlation coefficients were computed to assess overall and componential stability between test/retest scores of 51 children (mean age 3.6 years) enrolled in a Head Start preschool center. Cronbach alpha coefficients were calculated to determine the internal consistency of the subscales. Overall reliability for the computer-assisted quiz was high at .82 (p < .01). For individual subscales, test/retest correlations were highest for Nutrition, Safety, and Environment (r = .56 to .81) and lower but still significant for Dental, Smoking, and Fitness (r = .37 to .48). Results suggest a computer-assisted knowledge quiz can provide a reliable tool to assess health education knowledge in young children. In addition, the computer-assisted test format is highly acceptable to preschool children and enables researchers to administer a more extensive test to young children with brief attention spans in a manner that engages their full cooperation and effort. In this respect it offers several advantages over traditional paper-and-pencil formats.

Child↗
PubMed1999

Prenatal availability of choline alters the development of acetylcholinesterase in the rat hippocampus.

Choline (Ch) supplementation during embryonic days (ED) 12-17 enhances spatial and temporal memory in adult and aged rats, whereas prenatal Ch deficiency impairs attention performance and accelerates age-related declines in temporal processing. To characterize the neurochemical and neuroanatomical mechanisms that may mediate these behavioral effects in rats, we studied the development [postnatal days (PD) 1, 3, 7, 17, 27, 35, 90, and 26 months postnatally] of acetylcholinesterase (AChE) activity in hippocampus, neocortex and striatum as a function of prenatal Ch availability. We further measured the density of AChE-positive laminae (PD27 and PD90) and interneurons (PD20) in the hippocampus as a function of prenatal Ch availability. During ED11-ED17 pregnant Sprague-Dawley rats received a Ch-deficient, control or Ch-supplemented diet (average Ch intake 0, 1.3 and 4.6 mmol/kg/day, respectively). Prenatal Ch deficiency increased hippocampal AChE activity as compared to control animals in both males and females from the 2nd to 5th week postnatally. Moreover, prenatal Ch supplementation reduced hippocampal AChE activity as compared to control animals over the same developmental period. There was no effect of prenatal Ch status on either cortical or striatal AChE activity at any age measured, and by PD90 the effect of Ch on hippocampal AChE was no longer observed. In order to localize the early changes in hippocampal AChE activity anatomically, frozen coronal brain sections (PD20, PD27, PD90) were stained histochemically for AChE. Consistent with biochemical results, the AChE staining intensity was reduced in PD27 hippocampal laminae in the Ch-supplemented group and increased in the Ch-deficient group compared to control animals. There was no effect of the diet on hippocampal AChE staining intensity on PD90. In addition, the prenatal Ch availability was found to alter the size and density of AChE-positive PD20 interneurons. These results show that prenatal Ch availability has long-term consequences on the development of the hippocampal cholinergic system.

Acetylcholinesterase↗
PubMed1999

The self-mutilative nature of severe onychophagia: a comparison with self-cutting.

OBJECTIVE: To investigate the psychophysiological pattern associated with severe and mild onychophagia, and to compare this pattern with that demonstrated by previous research on self-cutting. METHOD: Comparisons between the psychophysiological responses accompanying 3 behaviours were made using a guided imagery methodology. Imagery of nail-related, skin-cutting, and neutral events were presented in 4 stages. RESULTS: Experiment I distinguished participants exhibiting severe and mild onychophagia by the severity and frequency of nail-biting and by the pattern of psychophysiological response across the stages. Experiment II indicated that the change in psychophysiological arousal accompanying severe onychophagia was not as dramatic as that demonstrated for skin-cutting. The behaviour seems to be less effective in reducing tension. CONCLUSION: Severe onychophagia appears to manage the level of tension experienced by an individual, instead of dramatically reducing it in times of crisis. Such a process is consistent with that demonstrated in individuals with obsessive-compulsive disorder.

Adult↗
PubMed1999

Project Northland: comprehensive alcohol use prevention for young adolescents, their parents, schools, peers and communities.

OBJECTIVE: Project Northland is an ongoing prevention trial with the objective of reducing underage drinking and related problems. Phase I focused on early adolescence and this study describes the multiple interventions, highlighting its parent components. METHOD: A cohort design was used with sixth graders from 24 school districts (N = 2,35 1: 97% of the eligible population: 51.3% boys), randomly assigned to intervention or reference condition. Phase I ended in eighth grade (N = 1,901: 81% retention rate). Both demand and supply reduction guided the interventions. This study examined Project Northland's impact using MMPI-A scales assessing clinical problems related to adolescents' alcohol and other drug use (Alcohol/Drug Problems Proneness scale; Alcohol/Drug Problems Acknowledgement scale), as well as MMPI-A scales related to school functioning (Adolescent-School Problems Content scale: Adolescent-Low Aspirations Content scale) and family functioning (Adolescent-Family Problems Content scale). RESULTS: Results showed significant reductions on the MMPI-A Proneness scale for those exposed to the interventions. The greatest program effects were among baseline nonusers of alcohol. CONCLUSIONS: Results suggest that the impact of Project Northland is not only on specifically targeted alcohol and drug use behaviors and their predictive factors, but also on intra-individual and familial factors generally considered precursors of more extensive problem behaviors and more resistant to change. Furthermore, the engaging home-based sixth-grade intervention, the Slick Tracy Home Team Program, is a promising population-based prevention approach that may generalize to other serious problems within a young person's family.

Adolescent↗
PubMed1999

Overexpression of protein kinase C-alpha in MCF-7 breast cancer cells results in differential regulation and expression of alphavbeta3 and alphavbeta5.

MCF-7 breast cancer cells stably transfected with protein kinase C-alpha (MCF-7-PKC-alpha cells) show anchorage-independent growth and exhibit increased tumorigenicity in nude mice. Since integrins are involved in tumor growth and metastatic spread, we investigated whether integrin expression is differentially regulated in MCF-7-PKC-alpha cells. Fluorescence-activated cell sorting revealed that alphavbeta3 is highly expressed on MCF-7-PKC-alpha cells, but is undetectable on MCF-7V cells (MCF-7 cells transfected with vector only). In contrast, MCF-7-PKC-alpha cells have reduced expression of alphavbeta5. Blocking experiments with antibodies to alphavbeta3 and alphavbeta5 revealed that these receptors are used by MCF-7-PKC-alpha cells to adhere primarily to vitronectin and osteopontin. Consistent with heterodimer expression, MCF-7-PKC-alpha cells express increased beta3 and decreased beta5 on their surface. Surface expression of alphav on MCF-7-PKC-alpha cells is unchanged. Western blotting, Northern analysis, and nuclear run-on assays indicated that post-translational mechanisms increase the surface expression of beta3 on MCF-7-PKC-alpha cells. In contrast, reduced beta5 transcription diminishes beta5 surface expression on MCF-7-PKC-alpha cells. These results indicate that overexpression of PKC-alpha in MCF-7 cells alters beta5 and beta3 expression by transcriptional and post-translational mechanisms, respectively, resulting in altered heterodimer expression. These findings suggest that the increased metastatic capacity of tumor cells with elevated protein kinase C levels may result, in part, from modulation of integrin expression.

Animals↗
PubMed1999

Can we create a therapeutic relationship with nursing home residents in the later stages of Alzheimer's disease?

1. Despite their entrance into advanced illness, the majority (83%) of participants in the study displayed evidence of having begun a therapeutic relationship with their assigned advanced practice nurse. 2. With one exception, those participants who did not evidence development of the relationship had severely limited speech, perseverative speech, or did not speak at all. 3. It is time to challenge the assumption that individuals in the middle and later stages of Alzheimer's disease are not good candidates for developing a therapeutic relationship.

Aged↗
PubMed1998

Reduced DNA synthesis and cell viability in small cell lung carcinoma by treatment with cyclic AMP phosphodiesterase inhibitors.

This study investigated the effects of the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitors caffeine, theophylline, and 3-isobutyl-1-methyl-xanthine (IBMX) on the proliferation and viability of the small cell lung carcinoma (SCLC) cell lines NCI-H345, NCI-H128, and SCC-9. These effects were correlated with the ability of the drugs to induce intracellular Ca2+ mobilization. Treatment of NCI-H345 cells with caffeine resulted in rapid mobilization of Ca2+, as indicated by Fura-2 fluorescence. Incubation of NCI-H345 cells with 6.25 mM caffeine resulted in a 62% inhibition of [3H]thymidine uptake after 2 hr, indicating reduced DNA synthesis. Incubation with 25 mM caffeine resulted in almost total inhibition of [3H]thymidine uptake after 2 hr. Similar effects on [3H]thymidine uptake were seen upon treatment of NCI-H128 and SCC-9 cells with caffeine; however, these cells did not exhibit caffeine-induced Ca2+ mobilization. Inhibition of DNA synthesis (66-93%) also occurred upon incubation of all cell lines with theophylline and IBMX, which did not mobilize Ca2+. Treatment of NCI-H345, NCI-H128, and SCC-9 cells with caffeine, theophylline, or IBMX markedly reduced cell viability. Levels of cAMP increased in the cells following treatment with caffeine, theophylline, or IBMX, reflecting the ability of these drugs to inhibit cAMP phosphodiesterase. These results suggest that the decrease in DNA synthesis and the subsequent cell death induced by these drugs are due to reduced cAMP phosphodiesterase activity, rather than to changes in intracellular Ca2+. These findings indicate that drugs that alter cAMP signaling pathways are potentially valuable agents to inhibit SCLC survival.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Hypertrophy of basal forebrain neurons and enhanced visuospatial memory in perinatally choline-supplemented rats.

The effects of choline supplementation during two time-frames of early development on radial-arm maze performance and the morphology of basal forebrain neurons immunoreactive for the P75 neurotrophin receptor (NTR) in male and female Sprague-Dawley rats were examined. In the first experiment, rats were supplemented with choline chloride from conception until weaning. At 80 days of age, subjects were trained once a day on a 12-arm radial maze for 30 days. Compared to control littermates, supplemented rats made fewer working and reference memory errors; however, the memory enhancing effects of choline supplementation were greater in males than females. A morphometric analysis of NTR-immunoreactive cell bodies at three levels through the medial septum/diagonal band (MS/DBv) of these rats revealed that perinatal choline supplementation caused the somata of cells in the MS/DBv to be larger by 8-15%. In a second experiment, choline supplementation was restricted to embryonic days 12-17. A developmental profile of NTR immunoreactive cell bodies in the MS/DBv of 0-, 8-, 16-, 30- and 90-day old male and female rats again revealed that cell bodies were larger in choline-supplemented rats than controls. As in the behavioral studies, the effect of choline supplementation was greater in male than female rats. These data are consistent with the hypothesis that supplementation with choline chloride during early development leads to an increase in the size of cell bodies of NTR-immunoreactive cells in the basal forebrain and that this change may contribute to long-term improvement in spatial memory.

Animals↗
PubMed1998

Evaluation of dose-dependent pharmacokinetics of cocaethylene and cocaine in conscious dogs.

Cocaine use continues to be widespread in the United States. Most cocaine users co-ingest ethanol resulting in decreased elimination of cocaine and formation of the active cocaine metabolite, cocaethylene, by hepatic carboxylesterases. In a recent study from our laboratory in dogs to evaluate the cocaine-ethanol interaction, we demonstrated a similar ethanol-induced reduction in cocaine metabolism, although we were unable to detect cocaethylene when the two drugs were given together. This unexpected finding could be explained by ethanol-induced inhibition of cocaine metabolism via a pathway that does not involve hepatic carboxylesterases or formation of cocaethylene that inhibits cocaine metabolism and is then rapidly cleared. The purpose of the present study is to determine which of these mechanisms best explain our data by characterizing the pharmacokinetics of cocaine and cocaethylene over a range of doses in conscious dogs. Seven adult mongrel dogs received 1, 3, and 5 mg/kg cocaine and cocaethylene HCl base with each drug dose administered i.v. on a separate study day. Arterial blood samples were collected at various times after each dose and analyzed for cocaine and cocaethylene by HPLC. Cocaine clearance was dose-dependent with clearance decreasing from 1.53 +/- 0.31 to 1.09 +/- 0.11 l/min as the dose was increased from 1 to 5 mg/kg (p<0.05). Vmax x Vss and Km for cocaine were 0.95 +/- 0.40 l/min/kg and 11.2 +/- 6.2 mg/kg, respectively. Cocaethylene pharmacokinetics were similar to those of cocaine, but were not dose-dependent over the dose range of 1-5 mg/kg. These results suggest that cocaethylene is not formed and rapidly cleared after co-administration of cocaine and ethanol to the dog, but rather suggests that cocaethylene is not formed in appreciable quantities in the dog. Therefore, we conclude that the decrease in cocaine elimination in the dog associated with ethanol administration is due to ethanol-mediated inhibition cocaine metabolism, rather than inhibition by cocaethylene.

Animals↗