In defense of dietary fiber.
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Dietary Fiber↗
Biomedical subjects
C L Williams
Publications and source records attributed to C L Williams.
Interactions of oxytocin and vasopressin with CRF on the rat colon.
Corticotropin-releasing factor (CRF), a primary mediator of stress responses, produces changes in the gastrointestinal tract identical to those induced by stress. CRF is tenfold more potent in females than in males, but gonadectomy reverses this difference. We postulated that positive modulators of CRF, such as oxytocin (OT) and vasopressin (AVP), may act in females to potentiate effects of CRF and thus could account for the gender-related differences in colonic sensitivity to CRF and stress. Given with CRF, neither OT, peripheral AVP, nor central AVP increased colonic transit any more than CRF alone, suggesting that OT and AVP do not potentiate CRF's actions in the colon. These data indicate that endogenous OT and AVP do not directly affect colonic transit, and that OT and AVP do not account for the gender-related differences in the effects of stress and CRF on colonic transit.
Animals↗
Helicobacter pylori: bacteriology and laboratory diagnosis.
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Breath Tests↗
Cholecystokinin-induced antinociception is not blocked by CCK-A or CCK-B receptor antagonists.
To determine the relative importance of CCK-A, CCK-B, and opioid receptors in mediating the antinociceptive actions of cholecystokinin, we evaluated the actions of selective agonists and antagonists in the mouse hot plate assay. The agonists used were CCK (1-30 nmol i.c.v.), a CCK-A receptor agonist (SNF9019; 0.3-10 nmol i.c.v.), and a CCK-B receptor agonist (SNF9007; 0.3-10 nmol i.c.v.). The antagonists used were the CCK-A receptor antagonist, L364,718 (12.5 nmol i.c.v.), CCK-B receptor antagonist, L365,260 (2.5-25 nmol i.c.v.), and the nonselective opioid receptor antagonist naloxone (1 mg/kg s.c.). CCK and its receptor-selective analogues, SNF9019 and SNF9007, resulted in antinociception that was blocked by naloxone, but was not antagonized by L364,718 or L365,260. In contrast, in positive control experiments, the inhibitory effects of CCK, SNF9019, and SNF9007 on gastrointestinal propulsion in mice were antagonized by identical i.c.v. doses of L364,718 and L365,260. We conclude that centrally administered CCK produces antinociception in the mouse hot plate assay via opioid receptors, but independent of CCK-A or CCK-B receptors. It is necessary to speculate that other CCK receptors, not antagonized by currently available selective antagonists, may exist.
Analgesia↗
Nicotinic acetylcholine receptors of muscle and neuronal (alpha7) types coexpressed in a small cell lung carcinoma.
SCC-37 is a small cell lung carcinoma line that aberrantly expresses muscle-type nicotinic acetylcholine receptors (nAChRs). It was established from a patient with a paraneoplastic autoimmune neuromuscular disorder, myasthenia gravis. When grown as a xenograft tumor, SCC-37 cells express plasma membrane receptors that bind 1251-labeled alpha-bungarotoxin (125I-alpha-BTx), cosediment with 9S nAChR pentamers, and bind to a monoclonal antibody (MAb 35) specific for muscle-type (alpha1 subunit) alpha-BTx receptors. The agonist carbamylcholine (carbachol) stimulates influx of 22Na+ in SCC-37 cells; this is inhibited by alpha-BTx and by d-tubocurarine. Long-term cultured SCC-37 cells have functional and ligand-binding evidence for surface coexpression of both alpha1 and neuronal-type (alpha7 subunit) alpha-BTx receptors. A subclone of SCC-37, designated SCC-A9, expresses only the neuronal-type (alpha7 subunit) alpha-BTx receptors on its surface. Carbachol does not stimulate 22Na+ influx in SCC-A9 cells, but cytisine initiates a sustained influx of Ca2+. Activation of this response is inhibited by alpha-BTx and by the alpha7-selective antagonist methyllycaconitine. Addition of Co2+ abrogates the sustained elevation of intracellular free Ca2+ concentration, implying that the cytisine-stimulated influx of Ca2+ is sustained by secondary opening of voltage-sensitive channels in the plasma membrane. Surface receptors for 125I-alpha-BTx are blocked by methyllycaconitine and d-tubocurarine. Solubilized alpha-BTx receptors from plasma membranes of SCC-A9 cells cosediment with 10S neuronal nAChR pentamers and bind to an alpha7-specific monoclonal antibody (MAb P27) but not to the muscle nAChR-reactive MAb 35. However, MAb P27 and MAb 35 both bind to alpha-BTx receptors solubilized from the cytoplasmic compartments of SCC-A9 and the parental SCC-37 line. Reverse transcription-PCR analysis revealed RNA transcripts for alpha7 and alpha1 subunits in both SCC-A9 and SCC-37 cells. The nAChRs that are expressed in these novel human cell lines can regulate cation fluxes directly as well as indirectly by synergizing with the activity of voltage-sensitive Ca2+ channels. These activities may influence the secretion of autocrine growth factors and the transcription of growth regulatory genes and thus be pertinent to the growth and metastasis of malignant neuroendocrine neoplasms.
Antigens↗
School and community influences on adolescent alcohol and drug use.
Social environment risk factors present in schools and communities have not been thoroughly investigated. This study cross-sectionally examined the social environments of schools and communities, and their influence on adolescent alcohol and drug use. Survey responses of eighth grade students (N = 2309), a random half of their parents (n = 943), community leaders (n = 118), school principals (n = 30), school counselors (n = 30) and chemical health providers (n = 14) were pooled to create indices of social environmental norms, role models, social support and opportunities for non-use of alcohol. Each index was examined for its association with prevalences from 30 schools of alcohol use onset, last-month alcohol use, heavy alcohol use and last-year marijuana use in univariate and stepwise regression analyses. Increases in the levels of norms, role models and opportunities for non-use predicted decreases in alcohol use prevalences. The explanatory power of the examined constructs in multivariate analyses was acceptably high (R2: 38-53%). These findings further support the notion that community-wide efforts need to be launched to affect changes in the normative, role model and opportunity structures of adolescents' social environments in order to curb adolescent alcohol and drug use.
Adolescent↗
Basic science of small cell lung cancer.
The unique phenotype expressed by small cell lung cancer (SCLC) cells is responsible for the distinct clinical behavior of SCLC. Basic research of SCLC is aimed at identifying and characterizing the unique attributes of SCLC cells that distinguish SCLC from other forms of lung cancer and contribute to the malignant behavior of SCLC. This article summarizes recent scientific advances in this area. Specific issues which are addressed include our current understanding of how SCLC arises, the origin and consequences of the neuroendocrine phenotype expressed by SCLC cells, and the role of SCLC adhesion molecules in SCLC metastasis.
Carcinoma, Small Cell↗
Morphine tolerance and dependence in the rat intestine in vivo.
There has been no previous demonstration of opioid tolerance and dependence with respect to the propulsive and contractile activities of the gut in vivo. In the experiments described herein, morphine was administered continuously (1 mg/kg/hr s.c., 72 hr) and/or by bolus injection (2 mg/kg) and intestinal motility and transit were evaluated in unanesthetized rats. Tolerance in intestinal motility (contractions) and propulsion (transit) was measured in two ways, i.e., by measuring the time required for motility and propulsion to return to control values and by measuring the loss of effectiveness of bolus morphine administered to animals receiving continuous infusion of the opiate. The dose of morphine chosen for continuous administration (1 mg/kg/hr s.c. via Alzet minipumps) was based on the dose at which morphine inhibited intestinal propulsion by 50%. Morphine (1 mg/kg/hr) decreased the frequency of contractions in, and propulsion along, the small bowel and colon and produced mild antinociception. The frequency of duodenal and colonic contractions returned to normal within 13 to 16 hr. After 24 hr of morphine treatment, the inhibitory effects of bolus doses of morphine on motility and transit were diminished; the effects were eventually lost (48 hr). Similarly, the antinociceptive effects of bolus doses of morphine were diminished by 18 hr and lost by 24 hr. Naloxone (0.1 mg/kg s.c.) given to morphine-tolerant animals (72 hr) resulted in an increase in the frequency and amplitude of contractions in the colon, an increase in the propulsive activity of the small intestine and colon and diarrhea. These results provide direct demonstration of opioid tolerance and dependence of contractile and propulsive activity in the rat intestine in vivo.
Animals↗
Quantitation of cocaine and cocaethylene in canine serum by high-performance liquid chromatography.
A reversed-phase high-performance liquid chromatographic procedure for the determination of cocaine and cocaethylene in canine serum has been developed. The compounds were extracted from 1 ml of alkalinized canine serum with hexane. Chromatographic separation was achieved with a cyanopropyl column (250 x 4.6 mm I.D., 5 microns) using a mobile phase of acetonitrile and phosphate buffer, pH 7.40 (38:62, v/v) flowing at 1 ml/min. Eluate was monitored by a variable-wavelength UV detector set to 230 nm. The extraction procedure yields an average recovery of 99 and 96% for cocaine and cocaethylene, respectively. The between-day coefficients of variation, at 2400 ng/ml, for cocaine and cocaethylene were both 8.6% and the within-day coefficients of variation, at 400 ng/ml, for cocaine and cocaethylene were 7.3 and 8.0%, respectively. A concentration-time profile resulting from administration of 3 mg/kg cocaine and cocaethylene to the dog revealed a similar disposition between cocaine and cocaethylene, with a clearance and volume of distribution at steady-state values of 72.8 and 61.0 ml/min/kg and 2.6 and 2.7 1/kg, respectively.
Acetonitriles↗
Expression of Ca2+/calmodulin-dependent protein kinase types II and IV, and reduced DNA synthesis due to the Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 (1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenyl piperazine) in small cell lung carcinoma.
Because changes in intracellular Ca2+ affect progression through the mitotic cell cycle, we investigated the role of Ca2+-binding proteins in regulating cell cycle progression. Evidence was found demonstrating that the activation of Ca2+/calmodulin-dependent protein kinase (CaM kinase) inhibits cell cycle progression in small cell lung carcinoma (SCLC) cells. We also demonstrated that SCLC cells express both CaM kinase type II (CaMKII) and CaM kinase type IV (CaMKIV). Five independent SCLC cell lines expressed proteins reactive with antibody to the CaMKII beta subunit, but none expressed detectable proteins reactive with antibody to the CaMKII alpha subunit. All SCLC cell lines tested expressed both the alpha and beta isoforms of CaMKIV. Immunoprecipitation of CaMKII from SCLC cells yielded multiple proteins that autophosphorylated in the presence of Ca2+ / calmodulin. Autophosphorylation was inhibited by the CaMKII(281-302) peptide, which corresponds to the CaMKII autoinhibitory domain, and by 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine (KN-62), a specific CaM kinase antagonist. Influx of Ca2+ through voltage-gated Ca2+ channels stimulated phosphorylation of CaMKII in SCLC cells, and this was inhibited by KN-62. Incubation of SCLC cells of KN-62 potently inhibited DNA synthesis, and slowed progression through S phase. Similar anti-proliferative effects of KN-62 occurred in SK-N-SH human neuroblastoma cells, which express both CaMKII and CaMKIV, and in K562 human chronic myelogenous leukemia cells, which express CaMKII but not CaMKIV. The expression of both CaMKII and CaMKIV by SCLC cells, and the sensitivity of these cells to the anti-proliferative effects of KN-62, suggest a role for CaM kinase in regulating SCLC proliferation.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Inhibition of adenylyl cyclase activity by the cholecystokinin analog SNF 9007 in neuroblastoma x glioma NG108-15 hybrid cells.
The effect of the cholecystokininB (CCKB) receptor-selective cholecystokinin octapeptide (CCK-8) analog SNF 9007 on forskolin-stimulated adenylyl cyclase activity in NG108-15 hybrid cells was measured. The activity of SNF 9007 was compared to the delta opioid agonists D-Pen2-D-Pen5-enkephalin (DPDPE, delta 1 receptor-selective) and Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2, (D-Ala2-deltorphin II, delta 2-receptor-selective) because SNF 9007 binds with moderate affinity to delta opioid receptors. SNF 9007 inhibited forskolin-stimulated adenylyl cyclase activity with efficacy similar to DPDPE. IC50 determinations showed that D-Ala2-deltorphin II was the most potent, followed by DPDPE, then SNF 9007 (IC50 values = 0.013, 0.21 and 4.8 microM, respectively). CCK-8 had no effect on adenylyl cyclase activity. The delta 1 receptor-selective antagonist 7-benzylidenenaltrexone hydrochloride (BNTX, 10 nM) had no effect on the activity of any of these agonists, but the delta 2 receptor-selective antagonist naltriben methanesulfonate (NTB, 10 nM) increased IC50 values of all the agonists. Combinations of BNTX and NTB (10 nM each) increased the D-Ala2-deltorphin II IC50 value 12-fold, the DPDPE IC50 value 18-fold and the SNF 9007 IC50 value 26-fold. The effect of the combined delta antagonists on SNF 9007 activity was different from the effect on DPDPE or D-Ala2-deltorphin II activity. These data suggest that the interaction of the CCK-8 analog SNF 9007 with opioid receptors in NG108-15 hybrid cells is different from the interaction of opioid peptides with these receptors.
Adenylyl Cyclase Inhibitors↗
Peripheral post-training administration of 4-OH amphetamine enhances retention of a reduction in reward magnitude.
This experiment examined the effect of post-training systemic (sc) injections of 4-OH amphetamine on memory for a reduction in reward. Rats were trained to run in a straight alley (six trials per day, 30-s intertrial interval) and received either 1 or 10 45-mg sucrose pellets on each trial. On Day 8, rats receiving 10 pellets were shifted to the 1-pellet reward. Shifted rats displayed a characteristic increase in response latencies typically attributed to an aversive emotional response to reward reduction. Immediately after the reward shift, all rats received an injection of either 2 mg/kg of 4-OH amphetamine or the equivalent volume of physiological saline. The rats were then returned to their home cages for 6 days without further training. On Day 15 the rats were returned to training, all with 1 sucrose pellet as reward. The performance of unshifted rats was comparable to that on Day 8 and the first trial performance of shifted rats given post-training saline was not significantly different from that of unshifted rats. Further, the shifted saline group's mean latencies for the entire training block on Day 15 were comparable to their mean latencies on Day 8. These findings suggest that the shifted saline rats did not remember the prior reward reduction on Day 8. In contrast, the shifted rats given post-training 4-OH amphetamine displayed first trial latencies that were longer than those of all other groups on Day 15. Additionally, on the entire training block on Day 15 the latencies of the shifted 4-OH amphetamine group were longer than those recorded on Day 8, indicating that shifted 4-OH amphetamine rates retained memory of the prior reward reduction. These findings suggest that post-training activation of peripheral adrenergic systems by 4-OH amphetamine enhances the retention for aversive emotional consequences elicited by reward reduction.
Amphetamine↗
Fear of AIDS and homophobia: implications for direct practice and advocacy.
Studies of health care trainees and professionals have demonstrated that their level of empathy and caring is negatively affected by the knowledge that the person being treated is homosexual, in part because of stigma associated with HIV infection and AIDS. The survey discussed in this article examined the relationship between homophobia and the fear of AIDS within the context of several categorical questions. Gender differences in attitudes were also examined. Respondents who more liberally endorsed rights for gay men and lesbians were less homophobic and had less fear of AIDS. Suggestions are made for sensitizing social workers to the inhibitory effects of homophobia and fear of AIDS when working with HIV-infected clients or people in the gay community.
Acquired Immunodeficiency Syndrome↗
Helicobacter pylori utilises urea for amino acid synthesis.
Helicobacter pylori has one of the highest urease activities of all known bacteria. Its enzymatic production of ammonia protects the organism from acid damage by gastric juice. The possibility that the urease activity allows the bacterium to utilise urea as a nitrogen source for the synthesis of amino acids was investigated. H. pylori (NCTC 11638) was incubated with 50 mM urea, enriched to 5 atom% excess 15N, that is the excess enrichment of 15N above the normal background, in the presence of either NaCl pH 6.0, or 0.2M citrate pH 6.0. E. coli (NCTC 9001) was used as a urease-negative control. 15N enrichment was detected by isotope ratio mass spectrometry. H. pylori showed intracellular incorporation of 15N in the presence of citrate buffer pH 6.0 but there was no significant incorporation of 15N in unbuffered saline or by E. coli in either pH 6.0 citrate buffer or unbuffered saline. The intracellular fate of the urea-nitrogen was determined by means of gas chromatography/mass spectrometry following incubation with 15N enriched 5 mM urea in the presence of either 0.2 M citrate buffer pH 6.0 or 0.2 M acetate buffer pH 6.0. After 5 min incubation in either buffer the 15N label appeared in glutamate, glutamine, phenylalanine, aspartate and alanine. It appears, therefore, that at pH and urea concentrations typical of the gastric mucosal surface, H. pylori utilises exogenous urea as a nitrogen source for amino acid synthesis. The ammonia produced by H. pylori urease activity thus facilitates the organism's nitrogen metabolism at neutral pH as well as protecting it from acid damage at low pH.
Amino Acids↗
Peer-planned social activities for preventing alcohol use among young adolescents.
The Project Northland peer participation program tested the feasibility of involving students in the planning and promotion of alcohol-free social activities for their peers and to determine whether such participation was associated with reduced alcohol use. The peer program was offered in 20 northeastern Minnesota schools when the study cohort was in seventh grade; students completed a survey in the beginning of sixth grade and at the end of sixth grade and seventh grade. Nearly 50% of the study cohort participated in the program. At the end of seventh grade, after controlling for confounders, an association was observed between student involvement with planning activities and a lower rate of alcohol use. This association was strongest among students who had reported alcohol use at the beginning of sixth grade. This cohort study suggests adolescent involvement in planning their own alcohol-free activities may be an efficacious strategy to prevent or reduce the prevalence of alcohol use among youth. Future studies are warranted to evaluate this association using experimental research designs.
Adolescent↗
Project Northland: outcomes of a communitywide alcohol use prevention program during early adolescence.
OBJECTIVES: Project Northland is an efficacy trial with the goal of preventing or reducing alcohol use among young adolescents by using a multilevel, communitywide approach. METHODS: Conducted in 24 school districts and adjacent communities in northeastern Minnesota since 1991, the intervention targets the class of 1998 (sixth-grade students in 1991) and has been implemented for 3 school years (1991 to 1994). The intervention consists of social-behavioral curricula in schools, peer leadership, parental involvement/education, and communitywide task force activities. Annual surveys of the class of 1998 measure alcohol use, tobacco use, and psychosocial factors. RESULTS: At the end of 3 years, students in the intervention school districts report less onset and prevalence of alcohol use than students in the reference districts. The differences were particularly notable among those who were nonusers at baseline. CONCLUSIONS: The results of Project Northland suggest that multilevel, targeted prevention programs for young adolescents are effective in reducing alcohol use.
Adolescent↗
Effects of ethanol and cocaethylene on cocaine pharmacokinetics in conscious dogs.
Coingestion of cocaine and ethanol is common among cocaine users, and this combination is reported to enhance the euphoric effects of cocaine. The cardiovascular effects of cocaine are increased in the presence of ethanol, although the mechanism(s) involved in this interaction are poorly understood. Recent studies suggest the enhanced cardiac effects may be caused by ethanol-mediated inhibition of cocaine metabolism leading to higher cocaine plasma concentrations. However, these studies were all performed in animals or humans that form cocaethylene when ethanol and cocaine are coadministered. Thus, it is also possible that cocaethylene could inhibit cocaine's metabolism. Preliminary studies in our laboratory indicate the dog does not form detectable quantities of cocaethylene after coadministration of cocaine and intravenous ethanol. Thus, the dog may be a useful model for isolating the individual contributions of ethanol and cocaethylene to this interaction. The purpose of the present study was to confirm this observation, and to determine the effects of ethanol and cocaethylene on cocaine pharmacokinetics in the conscious dog. Six dogs received cocaine (3 mg/kg i.v.) alone, ethanol (1 g/kg i.v.) followed by cocaine (3 mg/kg i.v.), and cocaine (3 mg/kg i.v.) + cocaethylene (3 mg/kg i.v.). Cocaethylene was not detected in any of the plasma samples from the six dogs after administration of cocaine and ethanol. Ethanol and cocaethylene reduced mean cocaine clearance by 47% and 26%, respectively. Inhibition of cocaine's metabolism by both ethanol and cocaethylene may play an important role in mediating the enhanced effects of cocaine in the presence of ethanol.
Animals↗
Inhibition of voltage-gated Ca2+ channel activity in small cell lung carcinoma by the Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 (1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperaz ine) .
Although small cell lung carcinoma (SCLC) cells express both voltage-gated Ca2+ channels (VGCC) and second messenger-operated Ca2+ channels (SMOCC), little is known about the factors that regulate the activity of these channels in SCLC cells. Ca2+/calmodulin-dependent protein kinase (CaM kinase) type II has been implicated recently in regulating Ca2+ channel activity in other cell types. Because of this, we investigated the effects of the specific CaM kinase antagonist 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tryosyl] -4-phenylpiperazine [sequence: see text] (KN-62) on Ca2+ channel activity in SCLC cells. Incubation with 10 microM KN-62 for 20 min inhibited depolarization-dependent 45Ca2+ influx by 96.1 +/- 2.1% in four independent SCLC cell lines, and by 42.2 +/- 6.8% in the NCI-H146 SCLC cell line. Similar inhibitory effects of KN-62 were observed when Fura-2 was used to measure depolarization-dependent Ca2+ influx. These results indicate that KN-62 potently inhibits VGCC activity in SCLC cells. In contrast, KN-62 (10 microM, 20 min) did not inhibit significantly Ca2+ mobilization induced by muscarinic acetylcholine receptor (mAChR) activation in SCLC cells. This indicates that SMOCC are less susceptible than VGCC to inhibition by KN-62 in SCLC cells. Because mAChR activation also inhibits VGCC activity in SCLC cells, we examined the effects of KN-62 on the mAChR-mediated inhibition of VGCC activity. To do this, we measured depolarization-dependent 45Ca2+ influx in SCLC cells incubated with submaximal concentrations of KN-62 and the mAChR agonist carbachol. Treatment of cells with both drugs resulted in almost twice as much inhibition of VGCC activity as in cells treated with only one of the drugs. This indicates that inactivation of CaM kinase with KN-62 does not suppress the ability of mAChR agonists to inhibit VGCC activity.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗