[Autoimmune hepatitis. New pathophysiological and clinical aspects].
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Autoimmune Diseases↗
Biomedical subjects
G Uhl
Publications and source records attributed to G Uhl.
Substance abuse vulnerability and D2 receptor genes.
Dopamine systems are key to the actions of several substances. Inter-individual differences in genes encoding proteins involved in dopaminergic neurotransmission could plausibly explain some of the genetic bases for inter-individual differences in vulnerability to substance abuse. The restriction fragment length polymorphism (RFLP) markers TaqIA1 and B1 at the dopamine D2 receptor (DRD2) gene locus in Caucasians are associated with substance abuse behaviors. In most, but not all, studies of alcoholics and polysubstance abusers, these TaqIA1 and B1 gene markers are present more often in substance abusers than in control individuals. No study has identified substance abusers or controls by sampling randomly from the general population; allelic association findings could thus conceivably be confounded by RFLP differences based on ethnicity or other factors. However, meta-analyses of the data from controlled studies available to date are consistent with the proposal that DRD2 gene variants contribute to inter-individual differences in vulnerability to alcoholism and polysubstance abuse.
Animals↗
Fos family member changes in nucleus caudalis neurons after primary afferent stimulation: enhancement of fos B and c-fos.
In situ hybridization using cDNAs complementary to specific regions of the mRNAs encoding four members of the FOS transcription factor gene family reveals modest levels of hybridization over superficial lamina of the nucleus caudalis of the spinal tract of the trigeminal in sections taken from unstimulated brains. Fos B expression is markedly and rapidly enhanced ipsilateral to electrical stimulation of the trigeminal ganglia. c-fos mRNA also changes; these differences contrast with the lack of significant changes in the low basal levels of expression of fra-1 and fra-2 mRNAs. The prominent change in fos B mRNA is mediated largely by an increase in the number of neurons that express hybridization densities above background after stimulation. This result, taken together with data on stimulation-induced changes in expression of preproenkephalin and other AP-1 transcription factors in wild-type animals and stimulation-induced changes in CAT activity in transgenic mice expressing portions of the proenkephalin promoter, is consistent with a role for the enhanced fos B expression in upregulation of expression of preproenkephalin in these neurons.
Afferent Pathways↗
Species differences in dopamine transporters: postmortem changes and glycosylation differences.
The apparent molecular masses of photoaffinity-labeled dopamine transporters (DATs) from rat, human, dog, and primate kidney COS cells expressing the rat DAT1 cDNA differ. Sequences predicted from cDNA cloning reveal only one amino acid difference between the length of the rat and human DAT but one less site for potential N-linked glycosylation in the human DAT. Possible posttranslational and postmortem bases for species differences in DAT molecular mass were explored. Rat DAT proteins from striata subjected to approximately 5 h of postmortem delay modeled after the human postmortem delay process revealed small but consistent losses in apparent molecular mass and in cocaine analogue binding; the DAT molecular mass displayed no further losses for up to 30 h of model postmortem treatment. Degradative postmortem changes could thus contribute to molecular mass differences between rat and human DATs. Neuraminidase treatment reduced the apparent molecular mass of native rat DAT but not that of the rat DAT expressed in COS cells, suggesting that the sugars added to the DAT expressed in COS cells were different than those added to the rat brain striatal transporter. These differences could account for the somewhat higher Km values for expressed DAT cDNA in COS cells when compared with the wild-type striatal transporter. These results are in accord with the differences in number of predicted N-linked glycosylation sites between rat and human DATs and with cell-type specificity in transporter posttranslational processing.
Affinity Labels↗
Dopamine transporter mRNA: dense expression in ventral midbrain neurons.
Oligonucleotides and a full-length cDNA encoding a functional dopamine transporter (DAT1) hybridize to a 3.7 kb mRNA that is concentrated in mRNA prepared from midbrain and absent in specimens from cerebellum or cerebral cortex. In situ hybridization reveals substantial hybridization densities overlying neurons of the substantia nigra, pars compacta, and the parabrachialis pigmentosus region of the ventral tegmental area (VTA). Neurons in the linear and paranigral VTA regions display lower levels of expression. Preliminary studies in arcuate neurons suggest modest hybridization. Different dopaminergic cell groups display different levels of DAT1 dopamine transporter expression.
Animals↗
Expression of a single dopamine transporter cDNA can confer two cocaine binding sites.
Radiolabeled cocaine analogs can bind to low and high affinity sites on striatal dopamine transporters (DAT). Recently, a cDNA encoding a rat brain dopamine transporter pDAT1 has been cloned. COS cells transfected with the pDAT1 in a eukaryotic expression vector express both a high (KD = 3.4 nM) and low affinity (KD = 163.6 nM) cocaine binding sites, suggesting that both sites are provided by a single gene product.
Animals↗
Cloning and expression of a cocaine-sensitive dopamine transporter complementary DNA.
A rat dopamine (DA) transporter complementary DNA has been isolated with combined complementary DNA homology and expression approaches. The DA transporter is a 619-amino acid protein with 12 hydrophobic putative membrane-spanning domains and homology to the norepinephrine and gamma-aminobutyric acid transporters. The expressed complementary DNA confers transport of [3H]DA in Xenopus oocytes and in COS cells. Binding of the cocaine analog [3H]CFT ([3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane) to transfected COS cell membranes yields a pharmacological profile similar to that in striatal membranes.
Amino Acid Sequence↗
Endothelin receptor: a profoundly desensitizing receptor expressed in Xenopus oocytes.
Xenopus oocyte expression studies can help to define the physiological properties of a receptor and can aid in receptor cloning. Expression of an endothelin receptor in oocytes injected with brain mRNA is inferred from depolarizations induced by several endothelin-related peptides. The response is abolished by intracellular EGTA injection but not in the absence of extracellular Ca2+. It is not present in non-injected oocytes, and reverses at a potential indicating that it is mediated by an increased Cl-1 conductance. Responses display striking, long-lasting desensitization. The expressed endothelin receptor thus displays properties characteristic of several receptors coupled to changes in phosphoinositide turnover, several of which have been successfully cloned using this response as a reporter.
Animals↗
Somatostatin: alterations in the central nervous system in neurological diseases.
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Adenylyl Cyclase Inhibitors↗
Variations in normal electrocardiographic response to treadmill testing.
Forty healthy young men at low risk for coronary artery disease underwent progressive maximal treadmill testing. Four bipolar electrocardiographic leads including CM5, CC5, inferior-superior Y, anterior-posterior Z, and a standard V5 were recorded and later computer-processed. Measurements included amplitudes of the Q, R, S, J junction and T wave, R-T and Q-S intervals and S-T segment slope. These variables are presented as the 10th, 50th (median) and 90th percentiles throughout the testing procedure to define reference values for the electrocardiographic response to maximal treadmill testing. The medians are presented graphically so that the exercise-induced changes can be visualized. In addition, the percent change of R wave amplitude in V5 compared with the supine pretest value is displayed for each subject during and after testing.
Adult↗
Febrile reactions to pneumococcal vaccine.
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Aged↗
Quantification of hepatitis C virus RNA in peripheral blood mononuclear cells: a comparison between patients chronically infected by HCV and patients coinfected by HIV.
In patients chronically infected by hepatitis C virus (HCV), peripheral blood mononuclear cells (PBMCs) were shown to be targets for virus replication and in those coinfected with HIV, HCV viraemia was considerably increased. The purpose of this study was to quantify HCV RNA in PBMCs from 25 patients infected by HCV and from 25 patients coinfected by HCV and HIV. We used the branched DNA assay after extraction of total RNA on 5 x 10(6) cells to quantify HCV RNA, and the Inno LiPA assay to determine the HCV genotype. HCV RNA in PBMCs could be quantified in 8/25 patients in each group, but the HCV RNA concentration was very low in comparison with viraemia, since the highest result was 8.1 x 10(4) Eq genome/10(6) cells. In 10 ml of total blood, there was approximately 100 to 5,000 times less HCV RNA in PBMCs than in the plasma. It is therefore likely that PBMCs play only a minor part in the viral load present in the plasma. There was no preferential genotype associated with quantifiable HCV RNA in the PBMCs. In the case of HIV coinfection, there was no increase in the HCV-RNA concentration in PBMCs that could explain the increased viraemia observed in these patients. On the contrary, HCV RNA could not even be detected by RT-PCR in some of our coinfected patients.
Adult↗
HIV increases hepatitis C viraemia irrespective of the hepatitis C virus genotype.
In case of coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV), HCV viraemia is increased. Because the HCV genotype 1 is associated with elevated viraemia, the increase in HCV viraemia observed and described in HIV+ patients could be attributed to the predominance of HCV genotype 1 in these patients. Therefore, the purpose of this study was to quantify HCV RNA in patients coinfected with HIV and HCV, according to the HCV genotype. The HCV genotype was thus determined in serum samples of 59 HIV+HCV+ patients and 51 HIV-HCV+ patients. HCV RNA was quantified using a branched DNA assay and the HCV genotype was determined using the "InnoLiPA" technique. The distribution of the HCV genotype was not significantly different in the two groups of patients, and there were even more patients infected by genotype 1 in the HIV-HCV+ group. The mean HCV viraemia of patients infected by HCV genotype 1 and by HCV genotype 3 was higher in patients coinfected by HIV than in HIV- patients (p < 10(-7) and p = 0.05, respectively). The increase in HCV viraemia observed in HIV+ patients was not the result of a specific distribution of HCV genotype in these patients. HIV infection was responsible for an increase in HCV viraemia irrespective of the HCV genotype.
Adult↗