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Biomedical subjects

J T Williams

Publications and source records attributed to J T Williams.

At least 109 records · Page 6Linked to original sources
PubMed1994

Papulonecrotic tuberculid secondary to disseminated Mycobacterium avium complex.

BACKGROUND: Papulonecrotic tuberculid is a rarely reported cutaneous reaction to the mycobacterium bacillus. It is most often encountered in association with tuberculosis. The clinical and histologic picture of the entity is a distinctive one, but the etiology of the disease process is uncertain. Therapy directed against the causative organism is dramatically successful. METHODS: A 35-year-old white man with AIDS was referred to the Dermatology clinic for evaluation of a widespread skin eruption. The skin lesions were biopsied for histopathology and culture. From the cutaneous cultures Mycobacterium avium complex (MAC) organisms were grown. RESULTS: We report the first case of papulonecrotic tuberculid manifestation in an AIDS patient with disseminated MAC. Unusual features seen in this case include the predominance of pruritic eschars rather than asymptomatic papules and the confirmation by special stains of mycobacterium organisms within the skin biopsy. Papulonecrotic tuberculid has not been previously associated with either MAC or AIDS. CONCLUSIONS: Papulonecrotic tuberculid should be a diagnostic consideration in immunocompromised patients with MAC whose clinical and histologic features are compatible with this rare entity.

AIDS-Related Opportunistic Infections↗
PubMed1994

Cocaine inhibits GABA release in the VTA through endogenous 5-HT.

The ventral tegmental area (VTA) is thought to be involved in the addictive properties of many drugs, including cocaine. It has been hypothesized that cocaine exerts its actions in the VTA by blocking the reuptake of dopamine released from the dendrites of the A10 dopamine neurons, thus prolonging the actions of dopamine at D2 autoreceptors. However, cocaine also blocks the reuptake of the other monoamines, including serotonin (5-HT). Using intracellular recordings from midbrain dopamine neurons in a brain slice preparation, we have found that cocaine (0.1-10 microM) inhibited the GABAB IPSP in a dose-dependent manner. This effect was observed in the presence of the D2 dopamine receptor antagonists sulpiride (1 microM) and eticlopride (0.1 microM). 5-HT mimicked this effect, as did the selective 5-HT1D receptor agonist sumatriptan and the 5-HT-releasing agent fenfluramine. The actions of both 5-HT and cocaine were attenuated by the 5-HT1C/D antagonist metergoline. Pretreatment of slices with the 5-HT-depleting agent p-chloroamphetamine (pCA; 10 microM) abolished the inhibition of the GABAB IPSP by cocaine but failed to affect the actions of sumatriptan. We conclude that cocaine acts to modulate the GABA input to A10 dopamine neurons via inhibition of the 5-HT transporter, increasing the concentration of 5-HT at presynaptic 5-HT1D receptors. These actions of cocaine were apparent at lower concentrations than those required to act via inhibition of the dopamine transporter. This reduction of inhibitory synaptic input into the VTA would be expected to attenuate the GABA-mediated feedback inhibition from the nucleus accumbens, thus leading to increased activation of dopamine neurons.

Animals↗
PubMed1994

Muscarine hyperpolarizes a subpopulation of neurons by activating an M2 muscarinic receptor in rat nucleus raphe magnus in vitro.

It has been shown previously that the muscarinic cholinergic system in the nucleus raphe magnus (NRM) is involved in the modulation of nociception. In this study, we examined the direct actions of muscarine on the NRM neurons in a slice preparation. Muscarine (1-30 microM) produced a dose-dependent hyperpolarization in a subpopulation of the NRM cells that contain 5-hydroxytryptamine (5-HT). In voltage clamp, the muscarine-induced outward current reversed polarity at the potassium equilibrium potential and was characterized by strong inward rectification. The reversal potential was dependent on external potassium concentration, suggesting that the hyperpolarization induced by muscarine was mediated through an increase in an inwardly rectifying potassium conductance. 5-HT also hyperpolarized these cells by increasing the same inwardly rectifying potassium conductance. The concentration-response curve for muscarine (EC50 = 2.7 microM) was shifted in a parallel manner to the right by increasing concentrations of pirenzepine (300 nM to 3 microM) and methoctramine (50-200 nM). Schild analysis revealed that the equilibrium dissociation constant (Kd) was 230 nM for pirenzepine and was estimated to be less than 30 nM for methoctramine. These results indicate that the muscarinic receptor mediating the muscarine activation of the potassium conductance in these cells is of the M2 subtype. The present results suggest an inhibitory cholinergic postsynaptic modulation on the activity of a subpopulation of serotonergic neurons that are involved in antinociceptive function in the NRM.

Action Potentials↗
PubMed1994

mu-Opioid agonists inhibit spinal trigeminal substantia gelatinosa neurons in guinea pig and rat.

The actions of opioid agonists in the substantia gelatinosa are important for their antinociceptive effects. In order to identify possible mechanisms underlying opioid actions in the substantia gelatinosa, the pre- and postsynaptic effects of opioid agonists on neurons of the substantia gelatinosa were examined using a brain slice preparation. Intracellular recordings were made from neurons of the substantia gelatinosa of the spinal trigeminal nucleus pars caudalis in guinea pig and rat. To correlate morphology and electrophysiology, neurons were filled with biocytin and visualized using HRP. The majority of neurons (86%) were hyperpolarized by [Met]5enkephalin (ME), and this was mimicked by the mu-opioid agonist (D-Ala2,N-Me-Phe4,Gly5-ol)enkephalin (DAMGO) but not the delta-opioid agonist (D-Pen2,5)enkephalin (DPDPE). Naloxone (300 nM) shifted the DAMGO dose-response 213-fold to the right, giving an estimated KD of 1.4 nM. Under voltage clamp, the ME current reversed polarity at the potassium equilibrium potential, indicating the hyperpolarization was due to an increase in potassium conductance. EPSPs mediated by glutamate were evoked by stimulating the spinal trigeminal tract, which contains the primary afferent fibers that synapse in the spinal trigeminal nucleus. The excitation produced by stimulating the spinal trigeminal tract was greatly enhanced in the presence of glycine and GABAA receptor antagonists, indicating that local inhibitory circuitry is activated by exciting the primary afferents. The EPSPs were reduced by mu- but not delta-opioid receptor activation. The degree of inhibition varied from 0 to 100%. These results indicate that opioid agonists cause inhibition in the substantia gelatinosa by both pre- and postsynaptic actions.

Animals↗
PubMed1993

kappa-Opioid receptors also increase potassium conductance.

Decrease of calcium conductance induced by opioid agonists has been reported by others for mu-, delta-, and kappa-opioid receptors. On the other hand, only mu- and delta-opioid receptors have been reported to increase potassium conductance. Intracellular recordings were made from guinea pig substantia gelatinosa neurons in a brain slice. A subset of cells (29 of 83) were hyperpolarized by the kappa-opioid receptor agonist U69593 with an EC50 of 23 nM. The kappa-opioid receptor antagonist norbinaltorphimine (10 nM) blocked the hyperpolarization by U69593 but had no effect on the mu-opioid hyperpolarization present in these cells. Naloxone (300 nM) shifted the U69593 dose-response curve to the right, giving an estimated Kd for naloxone of 7.5 and 8.1 nM measured in two cells. The hyperpolarization caused by U69593 was mediated by a potassium conductance as determined with voltage clamp experiments. This demonstrates, depending on the cell type, that all three major opioid receptors (mu, delta, and kappa) can increase potassium conductance as well as decrease calcium conductance.

Animals↗
PubMed1993

Dopamine D1 receptors facilitate transmitter release.

A physiological role for the dopamine D1 receptor has been difficult to define, particularly because of its complex pre- and postsynaptic localization in brain areas such as the striatum. In the midbrain, however, D1 receptors are selectively localized to the terminals of GABA (gamma-aminobutyric acid)-containing afferents. We have studied the actions of these D1 receptors on evoked GABA synaptic potentials recorded intracellularly from dopamine neurons in the ventral tegmental area (VTA). We report here that dopamine augmented GABAB inhibitory postsynaptic potentials (i.p.s.ps) in the presence of D2 receptor antagonists. This effect was mimicked by the D1 agonists SKF38393 and SKF82958 and blocked by the D1 antagonists SCH23390 and cis-flupenthixol. No modulation of the GABAA synaptic potential was observed. The postsynaptic actions of the GABAB agonist, baclofen, were unaffected by SKF38393, SCH23390 or cis-flupenthixol, confirming a presynaptic locus of D1 action. Additionally, D1 antagonists reduced the amplitude of the GABAB i.p.s.p. in the absence of D1 agonists. We conclude that dopamine acts tonically at presynaptic D1 receptors on the terminals of afferent GABA neurons to facilitate selectively GABAB-mediated neurotransmission in the midbrain.

Animals↗
PubMed1993

Modulation by serotonin of the neurons in rat nucleus raphe magnus in vitro.

Nucleus raphe magnus contains a large population of raphe-spinal serotonergic neurons that are thought to be involved in descending control of pain transmission and the modulation of opioid analgesia. Intracellular recordings were made from nucleus raphe magnus neurons in the slice preparation. Cells were divided into two groups, primary and secondary cells, based on the action potential waveform and response to opioids, as reported previously. In some experiments, cells were filled with biocytin and 5-hydroxytryptamine-containing cells were identified immunohistochemically. Of the primary cells that were filled with biocytin, 93% stained for 5-hydroxytryptamine; 90% of biocytin-filled secondary cells were unlabeled for 5-hydroxytryptamine. Previous studies have shown that primary cells are disinhibited by opioids; the finding that most primary cells are serotonergic suggests that at least some 5-hydroxytryptamine-containing neurons in the nucleus raphe magnus are excited by opioid analgesics. 5-Hydroxytryptamine hyperpolarized cells in both primary and secondary cell groups. The 5-hydroxytryptamine agonists (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide and 5-carboxamidotryptamine mimicked this action of 5-hydroxytryptamine, indicating that the 5-hydroxytryptamine 1A-subtype mediated this hyperpolarization. The hyperpolarization was mediated by an increase in potassium conductance that rectified inwardly. Local electrical stimulation of afferents evoked an inhibitory postsynaptic potential in primary cells. The inhibitory postsynaptic potential reversed polarity at the potassium equilibrium potential and was blocked by 5-hydroxytryptamine 1A receptor antagonists. It is proposed that the 5-hydroxytrypamine1A receptor on serotonergic primary cells may function as an autoreceptor to regulate the activity.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗
PubMed1993

Opioid-glutamate interactions in rat locus coeruleus neurons.

1. The effect of mu-opioids on the glutamate response was investigated in rat locus coeruleus (LC) neurons by intracellular recording in the brain slice preparation. Glutamate responses were evoked by bath application of selective glutamate agonists, glutamate iontophoresis, and stimulation of excitatory afferents. 2. The mu-opioid agonist D-Ala2-MePhe4-Gly-ol5-enkephalin (DAMGO; 1 microM) potentiated the response to bath application of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid by 91 and 142%, respectively, in slices cut in the horizontal plane. The mechanism of action of this effect was investigated under conditions that limited the DAMGO-induced hyperpolarization and improved the space clamp of the neuron through 1) addition of barium, 2) increase in extracellular potassium concentration, 3) sectioning of the LC in the coronal plane, and 4) addition of carbenoxolone. Each experimental manipulation decreased the DAMGO outward current and reduced the mu-opioid potentiation of the glutamate response. The results suggest that the mu-opioid-mediated potentiation of the glutamate response is dependent on membrane hyperpolarization. 3. Neither forskolin nor the phorbol ester 4b-phorbol 12,13-dibutyrate (PDBu) altered the glutamate-mediated inward currents. The potentiation of the glutamate response by DAMGO was not affected by PDBu. 4. The mu-opioids DAMGO and [met]5enkephalin (10 microM) did not significantly affect the NMDA receptor-mediated depolarization (mean 14%) evoked by local application of glutamate but inhibited the NMDA receptor-mediated synaptic potential (mean 25%).(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1993

Origin and population structure of the Icelanders.

The Norse and Celtic contributions to the founding population of Iceland have been estimated previously on a pan-Icelandic basis using gene frequency data for the entire island. Accounts of the settlement of Iceland, however, suggest that different regions received different proportions of Norse and Celtic settlers, indicating the need to incorporate geographic variation into Icelandic admixture studies. A formal likelihood ratio test rejects the null hypothesis of regional homogeneity in admixture proportions. Here, regional admixture estimates for Iceland are reported; they are in agreement with the settlement pattern inferred from historical accounts. The western, northern, and southern regions of Iceland exhibit a moderate Celtic component, consistent with historical indications that these regions were settled by Norse Vikings from the British Isles, accompanied by Celtic wives and slaves. Eastern Iceland, believed to have been settled chiefly by Vikings from Scandinavia, is characterized by a large Norse component of admixture. The northwestern peninsula is also found to be predominantly Norse. Regional genetic data are used to elucidate the contemporary population structure of Iceland. The observed structure correlates well with patterns of Icelandic geography, history, economy, marriage, urbanization, and internal migration. The northeastern region is strongly isolated, the urbanized areas of the north and southwest are representative of the overall population, and the remaining regions exhibit small-scale variation about the genetic central tendency. A high level of genetic homogeneity is indicated (RST = 0.0005), consistent with the high internal migration rate of the Icelanders. A regression of mean per-locus heterozygosity on distance from the gene frequency centroid reveals a greater than average external gene flow into the eastern region, whereas the northwestern peninsula has received less than average external gene flow. Iceland is compared with possible founding populations and was found to have diverged markedly from other northern European countries.

Emigration and Immigration↗
PubMed1992

Comparison of glutamine synthetases from brains of genetically epilepsy prone and genetically epilepsy resistant rats.

Since glutamine synthetase (GS) has been proposed as the primary enzyme in the regulation of glutamate metabolism in the central nervous system and since inhibition of the activity of this enzyme in vivo leads to seizures, it has been proposed that an abnormality in the structure or function of this enzyme could be responsible for the induction of seizures in epilepsy prone rats. To test this hypothesis the glutamine synthetases were purified from the brains of both genetically epilepsy prone rats (GEPR) and their progenitors, genetically epilepsy resistant rats (GERR). The enzymes were compared using both SDS-PAGE and isoelectric focusing. The immunoreactivities of equal amounts of protein were determined using the ELISA technique, and the regulation of the glutamine synthetase activities by Mn2+/Mg2+ ratios were compared. The only difference found between the glutamine synthetases from the two strains was a slightly lower specific activity of the enzyme from the epilepsy prone animals.

Animals↗
PubMed1992

Cocaine induced synchronous oscillations in central noradrenergic neurons in vitro.

Through inhibition of reuptake, cocaine increases monoaminergic tone in the central nervous system. The activities of the neurons within the locus coeruleus play a pivotal role in central noradrenergic transmission and regulate overall levels of arousal and attention. We have found that cocaine in low concentrations (0.3-1.0 microM) induced slow oscillations (0.8 Hz) in membrane potential (2-6 mV). These oscillations were synchronized in neurons throughout the nucleus and were blocked by alpha 2-adrenergic receptor antagonists. The synchrony of these events was thought to arise from within the nucleus, through a combination of spontaneous activity (intrinsic properties) and noradrenergic mediated inhibitory postsynaptic potentials augmented by cocaine. The synchronous firing of noradrenergic neurons may facilitate transmitter release in the widespread projection areas and thus be important for the action of cocaine to increase levels of arousal.

Adrenergic alpha-Antagonists↗
PubMed1992

Sensitization of locus ceruleus neurons during withdrawal from chronic stimulants and antidepressants.

The effects of chronic exposure to cocaine, amphetamine and desipramine on noradrenergic neurons in the locus ceruleus were examined using intracellular recordings in rat brain slices. Animals were treated for 2 weeks with either cocaine, amphetamine or desipramine, and all recordings were made after a 1-week withdrawal period. Cells from all three drug-treated groups showed a significant increase in sensitivity to the acute effects of cocaine and amphetamine in prolonging the time course of the noradrenaline-mediated inhibitory postsynaptic potential. At the highest cocaine and amphetamine doses tested (10 and 3 microM, respectively), the inhibitory postsynaptic potential duration was increased approximately 233% in the drug-treated groups relative to saline controls. In addition, locus ceruleus neurons from the cocaine-, amphetamine- and desipramine-treated groups showed a significant 10, 12 and 17% increase, respectively, in the maximum outward current produced by clonidine. There was also a significant increase in the behavioral sensitivity of the drug-treated animals to the sedative effects of clonidine. The mechanisms responsible for the increased sensitivity to the acute effects of cocaine, amphetamine and alpha-2 agonists may play a role in the withdrawal response to psychostimulants.

Amphetamine↗
PubMed1991

Synaptic potentials in locus coeruleus neurons in brain slices.

Neurons of the locus coeruleus (LC) fire action potentials spontaneously in vitro in the absence of any stimulation. This spontaneous activity is thought to arise from intrinsic membrane properties that include a balance between at least two ion conductances. One is a persistent inward sodium current that is active near the threshold for action potential generation. The second is a calcium-dependent potassium current that is activated following the entry of calcium during the action potential, is responsible for the after-hyperpolarization following the action potential, and decays over a period of 1-2 sec following the action potential. The spontaneous activity of LC neurons can be altered by both excitatory and inhibitory synaptic inputs. One excitatory input has been described that is mediated by glutamate receptors of both the non-NMDA and NMDA subtypes. Inhibitory synaptic potentials include those mediated by GABA (acting on GABAA-receptors), glycine (acting on a strychnine-sensitive receptor) and noradrenaline (acting on alpha 2-adrenoceptors). The presence of synaptic potentials mediated by these transmitters, studied in vitro, correlate with studies made in vivo and with histochemical identification of synaptic inputs to the locus coeruleus.

Action Potentials↗
PubMed1991

Developmental aspects of the locus coeruleus-noradrenaline system.

The locus coeruleus-noradrenaline (LC-NA) system exhibits an early developmental pattern, so that its nerve terminals are present in target areas before formation of most synapses. Several properties of the source neurons in the LC change substantially during early postnatal periods: spontaneous activity patterns, responsiveness to sensory stimulation, and responsiveness to NA. The effect may be to confer enhanced responsiveness of LC neurons, and an enhanced release of NA in target areas, during early postnatal development. Developmental changes in density of adrenoceptors or adrenergic responsiveness in target areas have also been documented. The usual pattern is a progressive increase in adrenergic ligand binding, with some reduction during later phases of development. However, there are a number of examples of receptor subtypes and region-specific transient binding during the first few weeks of postnatal life, followed by reductions to very low levels. These observations may reflect developmentally transient adrenergic responsiveness in certain target areas. NA and the LC-NA system have been implicated in the control of morphological and functional properties of neurons in target areas, and in the control of developmentally important biochemical systems (ornithine decarboxylase). NA, as well as other neurotransmitters, may individually, or in cooperation, exert important trophic influences during a restricted developmental period.

Action Potentials↗
PubMed1991

Transient homologous mu-opioid receptor desensitization in rat locus coeruleus neurons.

Opioid agonists hyperpolarize neurons of the locus coeruleus (LC) in the slice preparation. When opioids were applied at concentrations that caused a maximum hyperpolarization, the membrane potential hyperpolarized to a peak (about 30 mV) in the first minute and then declined over a period of 5 min. In addition, following the washout, the amplitude of the hyperpolarization induced by a lower concentration of opioid was significantly reduced as compared to control. The original response to both the low and the high concentrations of opioid recovered after removal of opioids for about 20 min. The decline in response, termed "acute desensitization," was observed only with concentrations of opioids that caused a maximum hyperpolarization and was dependent on the concentration of opioid applied (EC50 for [Met5]-enkephalin (ME), between 3 and 5 microM). The response to ME (300 nM) was reduced to 6% of control following washout of a 5-min application of ME (30 microM), whereas the response to noradrenaline (300 nM) was reduced to 75% of control. The acute desensitization therefore was selective for the opioid receptor with marginal cross-desensitization to the alpha 2-adrenoceptor-mediated hyperpolarization. The desensitization still occurred following treatment with beta-chlornaltrexamine (beta-CNA), to decrease receptor reserve, as well as in cells taken from animals treated chronically with morphine. The mechanism for the acute desensitization was investigated using agents thought to alter kinase activity. This acute desensitization may represent an initial stage in the development of tolerance produced by chronic administration of opioids.

Animals↗
PubMed1991

Cocaine and amphetamine interact at 5-HT synapses through distinct mechanisms in guinea-pig prepositus hypoglossi.

Intracellular recordings were made from guinea-pig prepositus hypoglossi (PH) neurons in vitro. Neurons within this nucleus are innervated by terminals that release 5-HT (serotonin) to mediate an IPSP. Cocaine caused a concentration-dependent prolongation of that IPSP, while having no effect on either membrane potential or firing rate. Cocaine also caused an increase in the IPSP amplitude at lower concentrations (less than or equal to 1 microM) and a decrease at higher concentrations. The selective 5-HT uptake inhibitor fluoxetine also prolonged the IPSP duration but depressed the amplitude at all concentrations tested. The effects of cocaine on IPSP duration can be completely accounted for by inhibition of 5-HT uptake. The depression of the IPSP is most likely due to a presynaptic effect, because cocaine augmented the response to applied 5-HT. Amphetamine (3-300 microM), unlike cocaine, changed the membrane potential. At lower concentrations, it caused a ketanserin-sensitive depolarization, while higher concentrations resulted in a spiperone-sensitive hyperpolarization. The hyperpolarization was most likely caused by the evoked release of 5-HT, while the depolarization may have been due to a direct effect of amphetamine on 5-HT2 receptors. Amphetamine also acted as a weak uptake inhibitor. The effects of cocaine, but not those of amphetamine, were observed at concentrations that are attained during self-administration.

Amphetamine↗