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Biomedical subjects

J T Williams

Publications and source records attributed to J T Williams.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1997

Where is the locus in opioid withdrawal?

Identification of neuroadaptations in specific brain regions that generate withdrawal is crucial for understanding and perhaps treating opioid dependence. It has been widely proposed that the locus coeruleus (LC) is the nucleus that plays the primary causal role in the expression of the opioid withdrawal syndrome. MacDonald Christie, John Williams, Peregrine Osborne and Clare Bellchambers believe that this view and the interpretation of the literature on which it is based are at best controversial. Here, they suggest an alternative view in which regions close to the LC such as the periaqueductal grey, as well as other brain structures which are independent of the LC noradrenergic system, play a more important role in the expression of the opioid withdrawal syndrome.

Animals↗
PubMed1997

A subset of ventral tegmental area neurons is inhibited by dopamine, 5-hydroxytryptamine and opioids.

Neurons originating in the ventral tegmental area are thought to play a key role in the formation of addictive behaviors, particularly in response to drugs such as cocaine and opioids. In this study we identified different populations of ventral tegmental area neurons by the pharmacology of their evoked synaptic potentials and their response to dopamine, 5-hydroxytryptamine and opioids. Intracellular recordings were made from ventral tegmental area neurons in horizontal slices of guinea-pig brain and electrical stimulation was used to evoke synaptic potentials. The majority of cells (61.3%) hyperpolarized in response to dopamine, depolarized to 5-hydroxytryptamine, failed to respond to [Met]5enkephalin and exhibited a slow GABAB-mediated inhibitory postsynaptic potential. A smaller proportion of cells (11.3%) hyperpolarized in response to [Met]5enkephalin, depolarized to 5-hydroxytryptamine, failed to respond to dopamine and did not exhibit a slow inhibitory postsynaptic potential. These two groups of cells corresponded to previously described "principal" and "secondary" cells, respectively. A further group of cells (27.4%) was identified that like the principal cells, hyperpolarized to dopamine. However, these "tertiary cells" also hyperpolarized to both 5-hydroxytryptamine and [Met]5enkephalin and exhibited a slow, cocaine-sensitive 5-hydroxytryptamine(1A)-mediated inhibitory postsynaptic potential. When principal and tertiary cells were investigated immunohistochemically, 82% of the principal cells were positive for tyrosine hydroxylase compared with only 29% of the tertiary cells. The 5-hydroxytryptamine innervation of both these cell types was investigated and a similar density of putative contacts was observed near the somata and dendrites in both groups. This latter finding suggests that the existence of a 5-hydroxytryptamine-mediated inhibitory postsynaptic potential in the tertiary cells may be determined by the selective expression of 5-hydroxytryptamine receptors, rather than the distribution or density of the 5-hydroxytryptamine innervation. We conclude that tertiary cells are a distinct subset of ventral tegmental area neurons where cocaine and mu-opioids both mediate inhibition.

Animals↗
PubMed1997

Computational aspects of finite element modeling in EEG source localization.

A comparison is made of two different implementations of the finite element method (FEM) for calculating the potential due to dipole sources in electroencephalography (EEG). In one formulation (the direct method) the total potential is the unknown that is solved for and the dipole source is directly incorporated into the model. In the second formulation (the subtraction method) the unknown is the difference between the total potential and the potential due to the same dipole in an infinite region of homogeneous conductivity, corresponding to the region where the dipole is located. Both methods have the same FEM system matrix. However, the subtraction method requires an additional calculation of flux integrations along the edges of the elements in the computation of the right-hand side (RHS) vector. It is shown that the subtraction method is usually more accurate in the forward modeling, provided the flux integrations are computed accurately. Errors in calculating the flux integrations may result in large errors in the forward solution due to the ill-conditioned nature of the FEM system matrix caused by the Neumann boundary condition. To minimize the errors, closed-form expressions for the flux integrations are used for both linear and quadratic triangular elements. It is also found that FEM forward modeling errors may cause false extrema in the least-square objective function obtained from the boundary potential, near boundaries between media of differing conductivity. Multiple initial guesses help eliminate the possibility of the solution getting trapped in these false extrema.

Brain↗
PubMed1997

Efficacy and kinetics of opioid action on acutely dissociated neurons.

Opioids have been shown to cause a potent inhibition of neurons in the locus ceruleus (LC) in vivo in brain slices and isolated neurons; however, the kinetics of opioid action have not been described. In this study, we used acutely isolated LC neurons to examine opioid and alpha2-adrenoceptor action on potassium and calcium currents. [Met]Enkephalin (ME), [D-Ser2,Leu5,Thr6]-enkephalin, etorphine, and [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin increased potassium conductance, whereas morphine and naloxone were antagonists. The time constant of potassium channel activation was approximately 0.7 sec and was the same for each agonist. The amplitude of the current and the time constant of decay were dependent on the agonist, suggesting that agonist efficacy and affinity, respectively, determined these parameters. The amplitude of potassium current induced by the alpha2-adrenoceptor agonist UK14304 was not significantly different from that induced by ME, but the time constant of current activation was half that of ME, and the decline was more rapid. When potassium conductances were blocked with the combination of internal cesium and external barium, opioid and alpha2 agonists had no effect at potentials more negative than -50 mV and decreased barium currents at potentials between -40 and +20 mV. Both morphine and clonidine caused a small inhibition of barium current. In dorsal root ganglion cells, morphine alone had small and inconsistent effects on the calcium current, but it always competitively antagonized the inhibition caused by [D-Ala2,N-Me-Phe4,Gly-ol5]enkephalin. The results in isolated LC neurons suggest 1) the amplitude and time course of the opioid-induced potassium current depend on agonist efficacy and affinity and 2) the coupling of both mu-opioid and alpha2-adrenoceptors to calcium channels seems to be more efficient than that to potassium channels.

Animals↗
PubMed1997

Inhibition of tissue factor gene activation in cultured endothelial cells by curcumin. Suppression of activation of transcription factors Egr-1, AP-1, and NF-kappa B.

Binding of plasma factor VII(a) to tissue factor (TF) initiates the coagulation cascade. In health, TF is not expressed in endothelial cells. However, endothelial cells express TF in response to lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF alpha), and other biological stimuli. TF expression by endothelial cells is implicated in thrombotic disorders in patients with a variety of clinical disorders. In the present study, we demonstrate that curcumin (diferulolylmethane), a known anticarcinogenic and anti-inflammatory agent, inhibited phorbol 12-myristate 13-acetate (PMA), LPS, TNF alpha, and thrombin-induced TF activity and TF gene transcription in human endothelial cells. The present data show that curcumin prevented the activation of c-Rel/p65, which is essential for TF gene activation in endothelial cells, by impairing the proteolytic degradation inhibitor protein, I kappa B alpha. The data also show that curcumin downregulated AP-1 binding activity. The present studies are the first to demonstrate that PMA, but not LPS, TNF alpha, and thrombin, induced Egr-1 binding to the second serum-responsive region (SRR-2) of TF promoter and that curcumin inhibited the PMA-induced Egr-1 binding to SRR-2. Overall, the data suggest that the anticarcinogenic and anti-inflammatory properties of curcumin may be related to its ability to inhibit cellular gene expression regulated by transcription factors NF-kappa B, AP-1, and Egr-1.

Cells, Cultured↗
PubMed1997

Acidic and basic fibroblast growth factors suppress transcriptional activation of tissue factor and other inflammatory genes in endothelial cells.

Tissue factor (TF) is a transmembrane receptor that serves as a cofactor for factor VIIa and initiates the extrinsic pathway of blood coagulation. Under normal physiological conditions, TF is expressed in extravascular and perivascular cells but not in vascular endothelial cells and monocytes. TF can be induced in these cells by inflammatory regulators and other stimulators, such as LPS, thrombin, oxidized lipoproteins, and certain growth factors. An earlier study showed that growing primary cultures of human umbilical vein endothelial cells (HUVECs) with endothelial cell growth supplement (ECGS) and heparin had impaired the ability of monolayers to express surface membrane TF activity after perturbation. The mechanism by which ECGS suppressed TF activity was not known. In the present study, we investigated the effect of recombinant acidic and basic fibroblast growth factors (aFGF and bFGF) on the induction of TF in a HUVEC cell line and a fibroblast cell line. Both aFGF and bFGF suppressed the phorbol myristate acetate-induced expression of TF in endothelial cells but not the serum-induced expression of TF in fibroblast cells. Diminished expression of the cell surface TF activity observed in endothelial cells grown with aFGF or bFGF was due to the accumulation of a lower number of TF mRNA transcripts. TF mRNA stability was not altered in HUVECs grown with aFGF or bFGF. Nuclear run-on experiments revealed that the transcription of TF and several other genes that play an important role in inflammation and angiogenesis was reduced in the endothelial cells that were cultured with aFGF or bFGF. The diminished expression of TF may be part of a generalized response of endothelial cells to FGF that facilitates migration of endothelial cells during angiogenesis.

Cells, Cultured↗
PubMed1996

Synchronous activity in locus coeruleus results from dendritic interactions in pericoerulear regions.

Locus coeruleus (LC) neurons in brain slices from adult rats were studied using intracellular and extracellular recording to investigate synchronous activity. Spontaneous field potentials were recorded with extracellular electrodes in solutions containing tetraethylammonium chloride (10 mM) and BaCl2, (1 mM). These field potentials were found throughout but not outside the LC cell body region. No field potentials were observed in control solutions. Paired recordings showed that field potentials were synchronous in all areas of the LC. The synchronous activity was resistant to tetrodotoxin (1 microM) and to the neurotransmitter receptor blockers D-2-amino-5-phosphonopentanoic acid, bicuculline, 6-cyano-7-nitroquinoxaline-2,3-dione, idazoxan, and strychnine, suggesting that this activity was not synaptically driven. Field potentials were also synchronous with oscillations in membrane potential recorded with intracellular electrodes. The oscillations in membrane potential were 5-30 mV in amplitude and had a biphasic wave-form. Neither the frequency nor the waveform of the oscillations was dependent on the membrane potential. The glycynhetinic acid derivative carbenoxolone and intracellular acidification with CO2 disrupted synchronous activity, suggesting a role of electrotonic coupling. When the cell body region of the LC was isolated from the pericoerulear dendritic regions by sectioning the size rostral and caudal to the cell body region, synchronous activity was reduced or abolished. Dendritic interaction in the pericoerulear region was also indicated by improved voltage control of the opioid-induced potassium current, as indicated by a shift in the reversal potential to the potassium equilibrium potential. The results suggest that electrical interactions between dendrites outside the cell body region can account for synchronous activity within the nucleus.

Animals↗