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J T Williams

Publications and source records attributed to J T Williams.

At least 19 recordsLinked to original sources
PubMed1999

Presynaptic inhibition of GABA(B)-mediated synaptic potentials in the ventral tegmental area during morphine withdrawal.

Opioids increase the firing of dopamine cells in the ventral tegmental area by presynaptic inhibition of GABA release. This report describes an acute presynaptic inhibition of GABAB-mediated IPSPs by mu- and kappa-opioid receptors and the effects of withdrawal from chronic morphine treatment on the release of GABA at this synapse. In slices taken from morphine-treated guinea pigs after washing out the morphine (withdrawn slices), a low concentration of a mu receptor agonist increased, rather than decreased, the amplitude of the GABAB IPSP. In withdrawn slices, after blocking A1-adenosine receptors with 8-cyclopentyl-1, 3-dipropylxantine, mu-opioid receptor activation inhibited the IPSP at all concentrations and increased the maximal inhibition. In addition, during withdrawal, there was a tonic increase in adenosine tone that was further increased by forskolin or D1-dopamine receptor activation, suggesting that metabolism of cAMP was the source of adenosine. The results indicate that during acute morphine withdrawal, there was an upregulation of the basal level of an opioid-sensitive adenylyl cyclase. Inhibition of this basal activity by opioids had two effects. First, a decrease in the formation of cAMP that decreased adenosine tone. This effect predominated at low mu receptor occupancy and increased the amplitude of the IPSP. Higher agonist concentrations inhibited transmitter release by both kinase-dependent and -independent pathways. This study indicates that the consequences of the morphine-induced upregulation of the cAMP cascade on synaptic transmission are dependent on the makeup of receptors and second messenger pathways present on any given terminal.

Adenosine↗
PubMed1999

Comparison of variance components and sibpair-based approaches to quantitative trait linkage analysis in unselected samples.

We compared the statistical performance of sibpair-based and variance components approaches to multipoint linkage analysis of a quantitative trait in unselected samples. As a benchmark dataset, we used the simulated family data from Genetic Analysis Workshop 10 [Goldin et al., 1997], and each method was used to screen all 200 replications of the GAW10 genome for evidence of linkage to quantitative trait Q1. The sibpair and variance components methods were each applied to datasets comprising single-sibpairs and complete sibships, and for further comparison we also applied the variance components method to the nuclear family and extended pedigree datasets. For each analysis, the unbiasedness and efficiency of parameter estimation, the power to detect linkage, and the Type I error rate were estimated empirically. Sibpair and variance components methods exhibited comparable performance in terms of the unbiasedness of the estimate of QTL location and the Type I error rate. Within the single-sibpair and sibship sampling units, the variance components approach gave consistently superior power and efficiency of parameter estimation. Within each method, the statistical performance was improved by the use of the larger and more informative sampling units.

Chromosome Mapping↗
PubMed1999

Resveratrol, a polyphenolic compound found in wine, inhibits tissue factor expression in vascular cells : A possible mechanism for the cardiovascular benefits associated with moderate consumption of wine.

A number of studies suggest that moderate consumption of red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease mortality. The phytochemical resveratrol found in wine, derived from grapes, has been thought to be responsible for cardiovascular benefits associated with wine consumption because it was shown to have antioxidant and antiplatelet activities. In the present investigation, we examined the effect of resveratrol on induction of tissue factor (TF) expression in vascular cells that were exposed to pathophysiological stimuli. The data presented herein show that resveratrol, in a dose-dependent manner, inhibited the expression of TF in endothelial cells stimulated with a variety of agonists, including interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNFalpha) and lipopolysaccharide (LPS). A similar inhibition of TF induction was also seen in LPS stimulated monocytes that were pretreated with resveratrol before their stimulation with LPS. In addition, resveratrol was shown to inhibit the LPS-induced expression of TNFalpha mRNA in endothelial cells and of TNFalpha and IL-1beta mRNA in monocytes. Nuclear run-on analysis in endothelial cells showed that resveratrol inhibited TF expression at the level of transcription. However, resveratrol did not significantly alter the binding of the transcription factors c-Fos/c-Jun and c-Rel/p65, the transcription factors required for the induction of TF promoter in both endothelial cells and monocytes. Similarly, resveratrol had no significant effect on the binding of NF-kappaB in endothelial cells stimulated with IL-1beta, TNFalpha, and LPS. Overall, our data show that resveratrol could effectively suppress the aberrant expression of TF and cytokines in vascular cells, but it requires further investigation to understand how resveratrol exerts its inhibitory effect.

Alcohol Drinking↗
PubMed1999

Cells isolated from adult human skeletal muscle capable of differentiating into multiple mesodermal phenotypes.

Wound healing is the response of tissue to injury that results in scar formation. Tissue regeneration would be a more ideal response. Previously, we have isolated a population of cells from avian, rodent, and rabbit skeletal muscle capable of differentiating into multiple mesodermal phenotypes. The present experiments were designed to determine whether a similar population of cells exist in human skeletal muscle. Separate cell preparations from skeletal muscle on an amputated leg of a 75-year-old female and the pectoralis muscle of a 27-year-old male were enzymatically dissociated and cultured to confluence in Eagle's minimal essential medium with 10 per cent preselected horse serum, then trypsinized, filtered, and slowly frozen in 7.5 per cent dimethylsulfoxide to -80 degrees C. The cells were thawed and plated with the same media plus dexamethasone (a nonspecific differentiation agent) at 10(-10) - 10(-6) M concentrations for up to 6 weeks. Immunological and histochemical staining assays were performed. Phenotypes observed included stem cells with typical stellate morphology (control), skeletal myotubes (anti-myosin), smooth muscle (anti-a-actin), bone (von Kossa stain), cartilage (Alcec blue), and fat (Sudan black B). These experiments establish the existence of a population of mesenchymal stem cells in human skeletal muscle capable of differentiating into multiple mesodermal phenotypes. The possibility exists of manipulating the mesenchymal stem cells to achieve appropriate regeneration of mesenchymal tissues in the injured patient.

Adult↗
PubMed1998

Increased opioid inhibition of GABA release in nucleus accumbens during morphine withdrawal.

The nucleus accumbens is a key component of the reward pathway that plays a role in addiction to many drugs of abuse, including psychostimulants and opioids. The effects of withdrawal from chronic morphine were examined in the nucleus accumbens using brain slices from morphine-treated animals. Recordings were made from interneurons in the shell of nucleus accumbens, and the presynaptic inhibition of GABA-A IPSCs by opioids was examined. In slices from control animals, opioids caused a maximal inhibition of 50%, forskolin increased the IPSC amplitude by less than twofold, and the maximal inhibition by opioids in the presence of forskolin was not changed. During withdrawal, however, forskolin caused approximately a fourfold increase in the amplitude of the IPSC, and the maximal inhibition by opioids was increased to 80%. The results indicate that transmitter release is increased during opioid withdrawal, particularly after the activation of adenylyl cyclase. The cAMP-dependent increase in transmitter release is potently inhibited by opioids, such that the overall effect of opioids is augmented during withdrawal. The induction of an opioid-sensitive cAMP-dependent mechanism that regulates transmitter release may be a critical component of acute opioid withdrawal.

Adenylyl Cyclases↗
PubMed1998

Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons.

Rapid information transfer within the brain depends on chemical signalling between neurons that is mediated primarily by glutamate and GABA (gamma-aminobutyric acid), acting at ionotropic receptors to cause excitatory or inhibitory postsynaptic potentials (EPSPs or IPSPs), respectively. In addition, synaptically released glutamate acts on metabotropic receptors to excite neurons on a slower timescale through second-messenger cascades, including phosphoinositide hydrolysisl. We now report a unique IPSP mediated by the activation of metabotropic glutamate receptors. In ventral midbrain dopamine neurons, activation of metabotropic glutamate receptors (mGluR1) mobilized calcium from caffeine/ryanodine-sensitive stores and increased an apamin-sensitive potassium conductance. The underlying potassium conductance and dependence on calcium stores set this IPSP apart from the slow IPSPs described so far. The mGluR-induced hyperpolarization was dependent on brief exposure to agonist, because prolonged application of exogenous agonist desensitized the hyperpolarization and caused the more commonly reported depolarization. The rapid rise and brief duration of synaptically released glutamate in the extracellular space can therefore mediate a rapid excitation through activation of ionotropic receptors, followed by inhibition through the mGluR1 receptor. Thus the idea that glutamate is solely an excitatory neurotransmitter must be replaced with a more complex view of its dual function in synaptic transmission.

Action Potentials↗
PubMed1998

Genome-wide search for genes affecting the risk for alcohol dependence.

Alcohol dependence is a leading cause of morbidity and premature death. Several lines of evidence suggest a substantial genetic component to the risk for alcoholism: sibs of alcoholic probands have a 3-8 fold increased risk of also developing alcoholism, and twin heritability estimates of 50-60% are reported by contemporary studies of twins. We report on the results of a six-center collaborative study to identify susceptibility loci for alcohol dependence. A genome-wide screen examined 291 markers in 987 individuals from 105 families. Two-point and multipoint nonparametric linkage analyses were performed to detect susceptibility loci for alcohol dependence. Multipoint methods provided the strongest suggestions of linkage with susceptibility loci for alcohol dependence on chromosomes 1 and 7, and more modest evidence for a locus on chromosome 2. In addition, there was suggestive evidence for a protective locus on chromosome 4 near the alcohol dehydrogenase genes, for which protective effects have been reported in Asian populations.

Adolescent↗
PubMed1998

Effect of conductivity uncertainties and modeling errors on EEG source localization using a 2-D model.

This paper presents a sensitivity study of electroencephalography-based source localization due to errors in the head-tissue conductivities and to errors in modeling the conductivity variation inside the brain and scalp. The study is conducted using a two-dimensional (2-D) finite element model obtained from a magnetic resonance imaging (MRI) scan of a head cross section. The effect of uncertainty in the following tissues is studied: white matter, gray matter, cerebrospinal fluid (CSF), skull, and fat. The distribution of source location errors, assuming a single-dipole source model, is examined in detail for different dipole locations over the entire brain region. We also present a detailed analysis of the effect of conductivity on source localization for a four-layer cylinder model and a four-layer sphere model. These two simple models provide insight into how the effect of conductivity on boundary potential translates into source location errors, and also how errors in a 2-D model compare to errors in a three-dimensional model. Results presented in this paper clearly point to the following conclusion: unless the conductivities of the head tissues and the distribution of these tissues throughout the head are modeled accurately, the goal of achieving localization accuracy to within a few millimeters is unattainable.

Brain↗
PubMed1998

Axillary staging utilizing selective sentinel lymphadenectomy for patients with invasive breast carcinoma.

The clinical staging of the regional lymphatics in patients with breast carcinoma is currently receiving much attention in the medical literature. However, controversy still exists regarding surgical staging of the axilla. Most recently, the technique of selective sentinel lymphadenectomy has been applied to staging of breast carcinoma. Our experience with this technique is presented. From July 1, 1995 through December 31, 1996, 20 patients underwent 21 selective sentinel lymphadenectomies prior to level I, level II, and partial level III axillary dissections. There were 13 modified radical mastectomies and 8 segmental mastectomies. The median number of lymph nodes per specimen was 9 (range, 1-31). The sentinel node was identified in 14 patients (66%). Dual sentinel nodes were identified during 3 procedures. The sentinel nodes were negative in 9 procedures, of which all axillary nodes dissected were negative. The sentinel node was positive in 5 procedures for a 100 per cent predictive value. The sentinel node was the only positive node in 3 of the 5 patients, and 2 of these were microscopic (less than 2 mm). There were no associated complications due to the sentinel node biopsy. These results add to the growing literature supporting the feasibility of the sentinel node technique for accurately staging breast carcinoma. This technique is sensitive and specific and can be performed with minimal morbidity.

Adenocarcinoma↗
PubMed1997

Nicotine activates and desensitizes midbrain dopamine neurons.

Tobacco use in developed countries is estimated to be the single largest cause of premature death. Nicotine is the primary component of tobacco that drives use, and like other addictive drugs, nicotine reinforces self-administration and place preference in animal studies. Midbrain dopamine neurons normally help to shape behaviour by reinforcing biologically rewarding events, but addictive drugs such as cocaine can inappropriately exert a reinforcing influence by acting upon the mesolimbic dopamine system. Here we show that the same concentration of nicotine achieved by smokers activates and desensitizes multiple nicotinic receptors thereby regulating the activity of mesolimbic dopamine neurons. Initial application of nicotine can increase the activity of the dopamine neurons, which could mediate the rewarding aspects of tobacco use. Prolonged exposure to even these low concentrations of nicotine, however, can cause desensitization of the nicotinic receptors, which helps to explain acute tolerance to nicotine's effects. The effects suggest a cellular basis for reports that the first cigarette of the day is the most pleasurable, whereas the effect of subsequent cigarettes may depend on the interplay between activation and desensitization of multiple nicotinic receptors.

Acetylcholine↗
PubMed1997

Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12.

A report on an initial genome screen on 540 individuals in 97 families was collected as part of the NIMH Genetics Initiative on Bipolar Disorder. Families were ascertained to be informative for genetic linkage and underwent a common ascertainment and assessment protocol at four clinical sites. The sample was genotyped for 65 highly polymorphic markers from chromosomes 1, 6, 8, 10, and 12. The average intermarker interval was 16 cM. Genotypic data was analyzed using affected sib pair, multipoint affected sib pair, and pedigree analysis methods. Multipoint methods gave lod scores of approximately two on chromosomes 1, 6, and 10. The peak lod score on chromosome 6 occurred at the end of the q-arm, at some distance from the 6p24-22 area previously implicated for schizophrenia. We are currently genotyping additional markers to reduce the intermarker interval around the signals. The interpretation of results from a genome screen of a complex disorder and the problem of achieving a balance between detecting false positive results and the ability to detect genes of modest effect are discussed.

Bipolar Disorder↗
PubMed1997

Increased probability of GABA release during withdrawal from morphine.

Opioid receptors located on interneurons in the ventral tegmental area (VTA) inhibit GABA(A)-mediated synaptic transmission to dopamine projection neurons. The resulting disinhibition of dopamine cells in the VTA is thought to play a pivotal role in drug abuse; however, little is known about how this GABAA synapse is affected after chronic morphine treatment. The regulation of GABA release during acute withdrawal from morphine was studied in slices from animals treated for 6-7 d with morphine. Slices containing the VTA were prepared and maintained in morphine-free solutions, and GABAA IPSCs were recorded from dopamine cells. The amplitude of evoked IPSCs and the frequency of spontaneous miniature IPSCs measured in slices from morphine-treated guinea pigs were greater than placebo-treated controls. In addition, activation of adenylyl cyclase, with forskolin, and cAMP-dependent protein kinase, with Sp-cAMPS, caused a larger increase in IPSCs in slices from morphine-treated animals. Conversely, the kinase inhibitors staurosporine and Rp-CPT-cAMPS decreased GABA IPSCs to a greater extent after drug treatment. The results indicate that the probability of GABA release was increased during withdrawal from chronic morphine treatment and that this effect resulted from an upregulation of the cAMP-dependent cascade. Increased transmitter release from opioid-sensitive synapses during acute withdrawal may be one adaptive mechanism that results from prolonged morphine treatment.

2-Amino-5-phosphonovalerate↗
PubMed1997

Genetic structure of the indigenous populations of Siberia.

This study explores the genetic structure of Siberian indigenous populations on the basis of standard blood group and protein markers and DNA variable number of tandem repeats (VNTR) variation. Four analytical methods were utilized in this study: Harpending and Jenkin's R-matrix; Harpending and Ward's method of correlating genetic heterozygosity (H) to the distance from the centroid of the gene frequency array (rii); spatial autocorrelation, and Mantel tests. Because of the underlying assumptions of the various methods, the numbers of populations used in the analyses varied from 15 to 62. Since spatial autocorrelation is based upon separate correlations between alleles, a larger number of standard blood markers and populations were used. Fewest Siberian populations have been sampled for VNTRs, thus, only a limited comparison was possible. The four analytical procedures employed in this study yielded complementary results suggestive of the effects of unique historical events, evolutionary forces, and geography on the distribution of alleles in Siberian indigenous populations. The principal components analysis of the R-matrix demonstrated the presence of populational clusters that reflect their phylogenetic relationship. Mantel comparisons of matrices indicate that an intimate relationship exists between geography, languages, and genetics of Siberian populations. Spatial autocorrelation patterns reflect the isolation-by-distance model of Malecot and the possible effects of long-distance migration.

ABO Blood-Group System↗
PubMed1997

A variance component approach to dichotomous trait linkage analysis using a threshold model.

We developed and utilized a multipoint variance components method to test for linkage between a disease trait and markers on chromosome 5 in the simulated data provided in GAW10 Problem 2. We demonstrated that the discrete trait variance components method recovers unbiased estimates of quantitative trait locus (QTL) location and reasonable estimates of effect size. We also showed that dichotomization of (a continuous trait such as) Q1 diminished the power to detect linkage compared to direct analysis of Q1, and that extended pedigree analyses provided superior power to detect linkage compared to those in nuclear families.

Analysis of Variance↗