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Biomedical subjects

G Uhl

Publications and source records attributed to G Uhl.

At least 19 recordsLinked to original sources
PubMed2002

Measurement of hypocretin/orexin content in the mouse brain using an enzyme immunoassay: the effect of circadian time, age and genetic background.

The hypocretins (1 and 2) have emerged as key regulators of sleep and wakefulness. We developed a high-throughput enzyme immunoassay (EIA) to measure total brain hypocretin levels from large numbers of mice. Hypocretin levels were not altered by circadian time or age. However, significant differences in one or both hypocretin peptides were observed between different mouse strains. We studied hypocretin levels in knockout and transgenic mouse models with obesity, circadian gene mutations or monoaminergic defects. Compared to controls, only histamine receptor knockouts had lower hypocretin levels. This was most pronounced in H1 receptor knockouts suggesting the existence of a positive feedback loop between hypocretin and histaminergic neurons.

Aging↗
PubMed2001

Genetic perspectives on the serotonin transporter.

The serotonin transporter (5-HTT) is most well known as the site of action of the serotonin reuptake inhibitors, which were initially developed as antidepressants, but now are the most widely used agents in the treatment of many additional neuropsychiatric and related disorders. The discovery that the gene that expresses the 5-HTT possesses a functional promoter-region polymorphism, which is associated with temperament and personality traits such as anxiety and negative emotionality as well as some behaviors, led to many studies examining this polymorphism in individuals with different neuropsychiatric disorders. The subsequent development of mice with a targeted disruption of the 5-HTT in our laboratory has provided an experimental model to examine the many consequences of diminished (in +/-, heterozygote mice) or absent (in -/-, homozygote knockout mice) function of the 5-HTT. The 5-HTT-deficient mice were also crossed with other knockout mice, allowing the study of multiple neurobiologic dysfunctions. As multiple genes are probably involved in the expression of complex behaviors such as anxiety, as well as neuropsychiatric disorders, these more genetically complex mice may more closely model disorders with complex etiologies. Thus, the combination of these comparative human and mouse studies may extend the opportunities to examine genetic alterations from a novel "bottom-up" approach [gene knockout or partial gene knockout in a combinational gene x gene x (yet unknown) gene approach], which is complementary to the traditional "top-down" genetic approach based upon studies of individuals with diagnosed neuropsychiatric disorders and their family members.

Animals↗
PubMed2001

Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often treated using methylphenidate, a psychostimulant that inhibits the dopamine transporter. This led E.H. Cook and colleagues to consider the dopamine transporter locus (DAT1) as a primary candidate gene for ADHD. That group reported a significant association between ADHD and the 480-base pair (bp) allele of the variable number of tandem repeats (VNTR) polymorphism located in the 3' untranslated region of the DAT1 gene. This association was later replicated in additional studies. METHODS: The DAT1 gene has additional common polymorphisms in intron 9 and exon 9. We investigated the possibility of linkage of DAT1 and ADHD using the VNTR polymorphism and two additional common polymorphisms in 102 nuclear families with an ADHD proband. Using the transmission disequilibrium test, we examined the transmission of the alleles of each of these polymorphisms, as well as the haplotypes of the polymorphisms. RESULTS: We did not observe significant evidence for the biased transmission of the alleles of either the VNTR or the additional two polymorphisms when examined individually, although there was a trend for the biased transmission of the 480-bp allele of the VNTR. When we examined the haplotypes of the three polymorphisms we found significant evidence for biased transmission of one of the haplotypes containing the 480-bp VNTR allele. We also genotyped six additional DNA sequence variants of the DAT1 gene. However, these variants were not sufficiently polymorphic in our sample to be informative. Two of the DNA variants that result in an amino acid change, Ala559Val and Glu602Gly, were not observed in our sample. CONCLUSIONS: Our results support previous findings of an association between the DAT1 gene and ADHD.

Alleles↗
PubMed2000

Enhanced delta-opioid receptor-mediated antinociception in mu-opioid receptor-deficient mice.

Inflammatory hyperalgesia was induced in wild-type, heterozygous and mu-opioid receptor knockout mice after an intraplantar injection of complete Freund's adjuvant. micro-Opioid receptor knockout mice exhibited faster recovery from hyperalgesia as compared to heterozygous (P<0.05) and wild-type (P<0.01) mice. Naloxone restored hyperalgesia in all genotypes. Naltrindole (delta-opioid receptor-selective antagonist) partially restored the hyperalgesia only in mu-opioid receptor knockout mice (P<0.001). Nor-binaltorphimine (kappa-opioid receptor-selective antagonist) had no effect. The mu-opioid receptor-selective agonist, [D-Ala(2), MePhe(4),Gly-ol(5)]enkephalin (DAMGO), reduced the hyperalgesia in heterozygous and wild-type but not in mu-opioid receptor knockout mice while U69,593 ¿(+)-(5alpha,7alpha, 8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4. 5]dec-8-yl]-benzeneacetamide, kappa-opioid receptor-selective¿ produced similar effects in all mice. The delta-opioid receptor-selective agonists, [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) and deltorphin ([D-Ala(2)]deltrophin-II), produced significantly greater antihyperalgesia in knockout mice (P<0.05). The findings suggest that mu-opioid receptors may be involved in the persistence of inflammatory hyperalgesia and that a delta-opioid receptor-mediated compensatory mechanism in the absence of the mu-opioid receptor is activated by persistent hyperalgesia.

Analgesia↗
PubMed1999

Characterization of mechanical withdrawal responses and effects of mu-, delta- and kappa-opioid agonists in normal and mu-opioid receptor knockout mice.

Clinical and experimental observations suggest that opiates can exert different influences on the perception of stimuli from distinct sensory modalities. Thermally-induced nociception is classically responsive to opiate agonists. mu-Opioid receptor-deficient transgenic mice are more sensitive to thermal nociceptive stimuli and morphine fails to attenuate the nociceptive responses to thermal stimuli in these animals. To enhance our understanding of opiate influences on mechanical sensitivity, we have examined withdrawal responses to a sequence of ascending forces of mechanical stimuli in mice with normal (wild type), half-normal (heterozygous) and absent (homozygous) mu-opioid receptor levels. We report data from mice examined without drug pretreatment or following pretreatment with morphine, the selective kappa-opioid agonist, U50488H, and the selective delta-opioid agonist, DPDPE. Saline-pretreated mice of each genotype displayed similar, monotonically increasing frequency of withdrawal responses to the graded stimuli. Subcutaneously administered morphine produced a dose-dependent reduction in withdrawal responses in wild type and heterozygous mice, but had no significant effect in homozygous mice. Intraventricular administration of DPDPE also reduced the frequency of paw withdrawal (FPW) in wild type mice, but not in homozygous mice. In contrast, systemic U50488H produced a dose-dependent attenuation of paw withdrawal in both wild type and homozygous mice. These findings suggest that (1) interactions of endogenous peptides with mu-opioid receptors may not play a significant role in the response to mechanical stimuli in drug-free animals, and (2) deficiency of mu-opioid receptors has no functional consequence on the response to the prototypical kappa-opioid receptor agonist, but decreases responses to the prototypical mu- and delta-opioid receptor agonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Follow-up of hepatitis C virus RNA in peripheral blood mononuclear cells during interferon therapy.

Mononuclear cells can be infected in vitro by hepatitis C virus and the viral RNA can be detected in mononuclear cells of chronically infected patients. It was suggested that the virus could persist in the mononuclear cells of some patients treated by interferon. The aim of this study was to follow the presence of viral RNA in the plasma and peripheral blood mononuclear cells of 16 chronically infected patients treated by alpha 2b interferon for 1 year. The RNA was detected by reverse transcription followed by nested PCR and quantified using the branched DNA method at regular intervals for at least one year. Before PCR, the mononuclear cells were treated by RNase and trypsin in order to eliminate the viral particles that could be stuck at the cell surface. Six patients were non responders and had persistent plasmatic viral RNA during the treatment. Two patients were good responders and had persistently negative PCR in both plasma and mononuclear cells. Eight patients had initial negativation of plasmatic hepatitis C virus RNA but showed a relapse characterized by positive plasmatic PCR. Positive PCR in mononuclear cells despite negativity of plasmatic PCR was noted 18 times in 8 patients. Persistently positive PCR in mononuclear cells in absence of detectable viraemia was followed by a virological relapse in 5 of these patients. This study confirms that hepatitis C virus RNA can be detected in mononuclear cells despite negative plasmatic PCR in patients treated by interferon. Moreover, the persistence of viral RNA in peripheral mononuclear cells could be a predictive factor of treatment failure. Our data also suggest that detection of viral RNA in mononuclear cells is probably not only due to passive virus adsorption from plasma.

Adult↗
PubMed1998

Mating behaviour in the cellar spider, Pholcus phalangioides, indicates sperm mixing.

In insects and spiders, the pattern of sperm priority is often attributed to the shape of the spermathecae and should entail marked consequences for mating behaviour. Since last-male priority is assumed to occur in haplogyne spiders such as the cellar spider, females of this species are predicted to be more attractive to males shortly before, than shortly after, egg laying and males may guard females after copulation until oviposition. To test these predictions, I individually marked spiders of a natural population and recorded their position and the distance between potential mating partners twice a day over 100 days. The distance between female and male was taken as a measure of the female's attractiveness. The behaviour of cellar spider males was not in accordance with the predictions; females were visited throughout the observation period with no significant increase in attractiveness before egg laying and there was no evidence for mate guarding. However, female attractiveness was correlated with female size, which was correlated with the number of eggs laid. Behaviour and genital morphology suggest sperm mixing occurs in this species. This is discussed in the light of conflicting data on sperm priority. Copyright 1998 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed1997

Murine vesicular monoamine transporter 2: molecular cloning and genomic structure.

The principal brain vesicular monoamine transporter (VMAT2) pumps monoamines including dopamine, norepinephrine, serotonin and histamine from neuronal cytoplasm into synaptic vesicles and is implicated in actions of certain psychostimulants and selective neurotoxins. To improve understanding of this gene and its regulation, and to facilitate study of the roles played by this important molecule in mouse genetic models, we have cloned murine VMAT2 cDNA and genomic sequences. A 4.2-kb mouse VMAT2 cDNA hybridized to a 4.3-kb mRNA expressed chiefly in brainstem. Murine cDNA and genomic DNA analyses reveal an open reading frame of 1551 bp encoding 517 amino acids that display 92, 96 and 60% amino-acid identity with human and rat VMAT2, and rat vesicular acetylcholine transporter sequences, respectively. This open reading frame is distributed over 15 of 16 identified exons, and spans > 35 kb of genomic DNA. A major transcriptional initiation site is identified 107 bp 5' to the translational initiation ATG codon using primer extension/5' rapid amplification of cDNA ends. Sequences immediately 5' of this putative transcription start site lack 'TATA' or 'CATT' boxes, but contain consensus sequences that may bind cAMP response element, Sp1, AP2 and other transcription factors. Identification of these genomic sequences facilitates construction of homologous recombinant mice, provides a template for gene structures in the vesicular transporter family, and identifies sequences elements that could contribute to the specific patterns of regulated VMAT2 expression in monoaminergic neurons.

Amino Acid Sequence↗
PubMed1997

Lymphocyte reactivity to hepatitis C virus (HCV) antigens shows evidence for exposure to HCV in HCV-seronegative spouses of HCV-infected patients.

Lymphocyte reactivity against hepatitis C virus (HCV) antigens was studied in 20 couples in which 1 member had chronic hepatitis C. This was done to investigate the possibility of HCV transmission between spouses that was not followed by seroconversion. Twenty healthy subjects without any risk factors for HCV transmission served as negative controls. All the patients' spouses and the healthy controls were negative for HCV RNA and for anti-HCV antibody. Lymphocytes were cultured with recombinant HCV core and nonstructural antigens (c22, c33, c100, c200, and NS5) and with control antigens (sperm whale myoglobin, chicken lysozyme, and superoxide dismutase). Lymphocytes from 10 patients and 4 seronegative spouses proliferated in the presence of at least one HCV antigen. No proliferation was shown with nonspecific antigens or in the control group. This study gives evidence for possible in vivo priming with HCV antigens that did not lead to seroconversion in spouses of HCV-positive patients.

Adult↗
PubMed1996

Comparison of resection, liver transplantation and transcatheter oily chemoembolization in the treatment of hepatocellular carcinoma.

BACKGROUND/AIMS: Resection and liver transplantation are currently considered as the most useful treatments for hepatocellular carcinoma. However, transcatheter oily chemoembolization may be favourably compared with these two surgical treatments in patients with anatomically operable tumors. METHODS: Between 1985 and 1991, 122 patients with an Okuda stage I tumor were hospitalized in two French hospitals. Among these patients, 33 remained untreated, 42 were treated by transcatheter oily chemoembolization, 30 by resection and 17 by liver transplantation. The four groups were closely comparable except for age, the patients in the two surgical groups being significantly younger. Moreover, the frequency of pTNM II tumor was significantly higher in the resection group. RESULTS: The 5-year probability of survival was close to 45% in each of the three treated groups and was significantly higher than in the untreated group (0% at 4 years, p < 0.0001). The probability of cancer recurrence and/or metastatic dissemination was lower after transcatheter oily chemoembolization than after surgery. CONCLUSION: Thus, transcatheter oily chemoembolization seems comparable at 5 years with resection or transplantation for the treatment of resectable hepatocellular carcinoma.

Aged↗
PubMed1996

Abnormal urinary coproporphyrin levels in patients infected by hepatitis C virus with or without human immunodeficiency virus. A study of 177 patients.

OBJECTIVE: Many cases of porphyria cutanea tarda have been described in association with human immunodeficiency virus (HIV) infection in young individuals. The link between hepatitis C virus (HCV) and porphyria cutanea tarda is even stronger as more than 50% of patients who have this diagnosis in Italy, France, or Spain are also infected by HCV. To study the role of viral infections on the metabolism of porphyrins, we measured the urinary porphyrin levels in patients with HIV and HCV infections. DESIGN: Survey; prospective study. SETTING: University Hospital of Strasbourg, France. PATIENTS: Sixty-one HIV-positive patients, 56 HCV-positive patients, 60 HIV- and HCV-positive patients, and 51 HIV- and HCV-negative control subjects were randomly selected. None had clinical signs of porphyria or a familial history of porphyria. MAIN OUTCOME MEASURES: The porphyrin-excretion profile was determined by high-performance liquid chromatography on fresh urine samples. The HIV and HCV viremias were quantified in the serum by the branched DNA assay. Measures were planned before data collection began. RESULTS: The porphyrin-excretion profile typical of porphyria cutanea tarda was found in only 1 of 177 patients. In the remaining 176 patients, the mean coproporphyrin level was significantly raised in HCV-positive patients and even higher in patients who were HIV- and HCV-positive. The coproporphyrin level was not correlated to the alanine aminotransferase level, the CD4+ cell count, or the HCV and HIV viremias. CONCLUSIONS: In cases of infection with HIV, HCV, or both, the development of a porphyria cutanea tarda urinary profile is a rare event (0.56% in this study), but coproporphyrin excretion is increased. This could be related to hepatic changes induced by the viruses. Our results do not support the hypothesis of a direct viral effect on the porphyrin metabolism. Infection with HIV, HCV, or both may be a major triggering factor, but is not sufficient to induce porphyria.

Adolescent↗
PubMed1995

The dopamine transporter protein gene (SLC6A3): primary linkage mapping and linkage studies in Tourette syndrome.

The dopamine transporter, the molecule responsible for presynaptic reuptake of dopamine and a major site of action of psychostimulant drugs, including cocaine, is encoded by locus SLC6A3 (alias DAT1). The protein's actions and DAT's specific localization to dopaminergic neurons make it a candidate gene for several psychiatric illnesses. Alleles at this locus have been reported to be associated with cocaine-induced paranoia and attention deficit disorder. SLC6A3 has been mapped to distal chromosome 5p, using physical methods. Our goal was to place SLC6A3 in the genetic linkage map and to test for linkage to Tourette syndrome. Genetic linkage methods were used to place SLC6A3 in the genetic linkage map. Four extended pedigrees (one of which overlaps with CEPH) were typed. Linkage with Tourette syndrome (TS) was also examined. SLC6A3 showed close linkage with several markers previously mapped to distal chromosome 5p, including D5S11 (Zmax = 16.0, theta M = theta F = 0.03, results from four families) and D5S678 (Zmax = 7.84, theta M = theta F = 0, results from two families). Observed crossovers established that SLC6A3 is a distal marker close to D5S10 and D5S678, but these three distal markers could not be ordered. Linkage between TS and SLC6A3 could be excluded independently in two branches of a large kindred segregating TS; the lod score in a third family was also negative, but not significant. Cumulative results show a lod score of -6.2 at theta = 0 and of -3.9 at theta = 0.05 (dominant model, narrow disease definition). SLC6A3 thus maps to distal chromosome 5p by linkage analysis, in agreement with previous physical mapping data. A mutation at SLC6A3 is not causative for TS in the two large families that generated significant negative lod scores (if the parameters of our analyses were correct) and is unlikely to be causative in the family that generated a negative lod score that did not reach significance. These results do not exclude a role for the dopamine transporter in influencing risk for TS in combination with other loci.

Carrier Proteins↗
PubMed1995

[Hepatosplenic silicosis].

A case of hepatosplenic silicosis complicating a pulmonary silicosis is reported. Numerous calcified splenic nodules seen with conventional radiology, ultrasound or computed tomography, hepatic microcalcifications and "egg shell" abdominal lymph nodes best seen with computed tomography represent the radiologic signs. However, hepatosplenic silicosis can only be confirmed by pathological examination of liver biopsies showing birefringent particles within hyalinized nodules.

Calcinosis↗
PubMed1994

Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon.

Dopaminergic (DA) cells of the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA) display differences in their topography, biochemistry and susceptibility to pathological processes. Neuronal dopamine concentration is regulated in large part by tyrosine hydroxylase (TH), the rate-limiting enzyme of dopamine synthesis, and by the dopamine reuptake system. In the present study, TH protein, TH mRNA and dopamine membrane transporter (DAT) mRNA were quantified at cellular level in 4 arbitrary subregions of the rat ventral mesencephalon (lateral, middle, medial SNC and VTA), using in situ hybridization and immunoautoradiography. The distribution of labelling for TH protein and TH mRNA was almost superimposable and close to that of DAT mRNA in mesencephalic neurons. Lower values of cellular expression in TH protein, TH mRNA and DAT mRNA were observed in the lateral part of the SNC compared to the other subregions. TH and DAT expression were correlated in SNC but not in VTA. Indeed DA cells in this region expressed low levels of DAT mRNA in comparison to the middle and medial SNC. These results suggest a heterogeneity of DA metabolism among populations of mesencephalic cells. The relative lower expression of the DAT gene in VTA neurons suggests a less efficient dopamine reuptake capacity, which may partly account for the relative sparing of the mesolimbic system reported in Parkinson's disease and MPTP-treated animals.

Animals↗
PubMed1994

Reduction in dopamine transporter mRNA after cessation of repeated cocaine administration.

Male, Lewis rats were treated intravenously for 2 weeks with saline or cocaine using a dose and injection schedule that is similar to the doses and patterns of cocaine intake in self-administration studies. Ten days after cessation of treatment, dopamine transporter binding levels were decreased in the nucleus accumbens but not in the striatum. In situ hybridization studies revealed decreases in dopamine transporter mRNA that were restricted to cells of the interfascicular and caudal linear nuclei; these dopaminergic cell groups, found in the ventral tegmentum, project to the nucleus accumbens and other limbic areas. Other dopaminergic cell groups in midbrain which project mainly to other areas did not show a decrease in mRNA. These results indicate that gene expression can be altered many days after withdrawal from cocaine, and provide an example of transporter regulation by a change in gene expression.

Animals↗