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Biomedical subjects

A Moser

Publications and source records attributed to A Moser.

At least 55 records · Page 3Linked to original sources
PubMed2000

G proteins modulate D2 receptor-coupled K(ATP) channels in rat dopaminergic terminals.

The presynaptic dopamine (DA) D2 receptor-mediated regulation of ATP-sensitive potassium (K+ATP) channels was examined in slices of the rat caudate-putamen. When slices were incubated with the specific D2 receptor antagonist (-)-sulpiride (SLP), a concentration-dependent increase of extracellular DA release was observed. SLP-induced enhancement was completely antagonized by coincubation with the K+ATP channel opener diazoxide (DIA). Treatment of slices with the D2 receptor agonist quinpirole (QUI) almost completely inhibited DA outflow induced by the K+ATP channel blocker butanedione-monoxime (BDM). Coincubation of SLP and guanosine triphosphate (GTP) or its non-hydrolizable analogue guanylyl-5'-imidodiphosphate [Gpp(NH)p], significantly reduced the SLP-induced effect on DA levels. Furthermore, we observed that BDM-induced DA outflow was markedly inhibited by G protein activators suggesting an additional receptor-independent regulation of K+ATP channel gating. Our results suggest that PTX-sensitive G proteins are involved in the signal transduction between D2 receptors and K+ATP channels. Furthermore, K+ATP channels can be modulated in a receptor-independent mechanism by G protein activators.

Adenosine Triphosphate↗
PubMed2000

Interferon-alpha and ribavirin in treating children and young adults with chronic hepatitis C after malignancy.

OBJECTIVE: Chronic hepatitis C is a major long-term problem for children who survive cancer. Interferon (IFN)-alpha has been shown to be effective in treating patients with chronic hepatitis C; however, the rate of sustained response is low. Combining IFN-alpha and ribavirin (RBV) has been shown to significantly improve the response in adult patients with chronic hepatitis C. The aim of this pilot study was to evaluate the efficacy and safety of a combined virostatic treatment with IFN-alpha and RBV in a small cohort of children and adolescents with chronic hepatitis C and previous malignancy. METHODS: Twelve patients with a history of a hematooncologic disease (median follow-up: 13.5 years; range: 7-14.7 years) and chronic hepatitis C were treated with recombinant IFN-alpha-2a (6 megaunits/m(2) body surface area, 3 times a week, subcutaneously) combined with RBV (15 mg/kg body weight/day, orally) for 12 months. They were tested monthly for blood counts and liver function, and for serum virus concentrations (hepatitis C virus RNA by polymerase chain reaction) every 3 months. RESULTS: At the end of the treatment, hepatitis C virus RNA could not be detected in the serum of 8 of the 12 patients; 2 of these patients relapsed soon after therapy withdrawal, whereas 6 patients maintained in sustained virologic and biochemical remission (follow-up: 12 months). Treatment-induced toxicity was moderate and reversible with influenza-like symptoms and a decrease in blood counts in all 12 patients, alopecia in 5 of the 12, hemolysis in 4 of the 12, and weight loss of >10% in 2 of the 12. CONCLUSIONS: As demonstrated in adults with chronic hepatitis C, treatment with IFN-alpha and RBV also seems to be an effective and safe therapeutic option for children and adolescents with chronic hepatitis C after malignancy.

Adolescent↗
PubMed2000

["Reperfusion collapse" phenomenon during post-ischemic reperfusion in experiment].

Postischemic changes of central and regional hemodynamic while various reperfusion regimens have been studied on animal experimental model. We had revealed that despite vasodilatation, peripheral vascular resistance in the postischemic extremity rises, as a result of reperfusion by the lowered perfusion volume. Such phenomenon has been named as "reperfusion-collapse". In spite of the microcirculation disorders progression there have been no significant rising of the peripheral vascular resistance as well as worsening of the regional hemodynamic indexes in the postischemic limb during reperfusion by either normal or increased perfusion volume.

Acute Disease↗
PubMed1999

Abnormal sterol metabolism in patients with Conradi-Hünermann-Happle syndrome and sporadic lethal chondrodysplasia punctata.

The term, "chondrodysplasia punctata" (CDP) denotes a pattern of abnormal punctate calcification of dystrophic epiphyseal cartilage and certain other cartilaginous structures, such as the larynx. CDP occurs in a variety of genetic disorders associated with skeletal dwarfism and can also be caused by prenatal exposure to warfarin. Although the most studied clinical syndrome with CDP, rhizomelic chondrodysplasia punctata (RCDP), is known to be caused by several different abnormalities of plasmalogen biosynthesis, there are many other genetic disorders with CDP for which the biochemical cause is unknown. Because patients with Smith-Lemli-Opitz syndrome, a primary disorder of sterol biosynthesis, often have rhizomesomelic limb shortness and, less commonly, CDP, we assessed sterol levels and metabolism in patients with different clinical forms of CDP. By quantitative sterol analysis of a variety of tissues, we identified 5 patients with similar radiological findings and abnormally increased levels of 8-dehydrocholesterol and cholest-8(9)-en-3beta-ol, suggesting a deficiency of 3beta-hydroxysteroid-delta8,delta7-isomerase, a principal enzyme of cholesterol biosynthesis. Cultured cells available from one patient showed increased levels of the same two sterols, decreased synthesis of cholesterol, and a pattern of inhibition by triparanol and AY-9944 consistent with a deficiency of 3beta-hydroxysteroid-delta8,delta7-isomerase. Clinical diagnoses among the 5 patients included X-linked dominant Conradi-Hünermann-Happle syndrome and nonspecific lethal CDP. We conclude that abnormal cholesterol biosynthesis is a characteristic of some clinical syndromes with rhizomesomelic dwarfing and CDP.

Abnormalities, Multiple↗
PubMed1999

Central pain as a manifestation of partial epileptic seizures.

Central pain of epileptic etiology is very rare. The frequency of painful sensations in epileptic seizures varies between 0.3 and 2.8%. We report a patient with short-lasting painful attacks in the right arm. Changes in the electroencephalography (EEG) and the effective treatment with anticonvulsants in contrast to the therapeutic failure of analgesics, lead to the diagnosis of partial epilepsy with painful seizures. Magnetic resonance imaging (MRI) of the brain was normal, whereas a postcentral parietal site of seizure origin involving the secondary somatosensory area was suggested by electroencephalographic findings. The literature is reviewed for cases with pain as the sole or predominant symptom of epileptic seizures.

Adult↗
PubMed1999

Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome.

X-linked dominant Conradi-Hünermann syndrome (CDPX2; MIM 302960) is one of a group of disorders with aberrant punctate calcification in cartilage, or chondrodysplasia punctata (CDP). This is most prominent around the vertebral column, pelvis and long bones in CPDX2. Additionally, CDPX2 patients may have asymmetric rhizomesomelia, sectorial cataracts, patchy alopecia, ichthyosis and atrophoderma. The phenotype in CDPX2 females ranges from stillborn to mildly affected individuals identified in adulthood. CDPX2 is presumed lethal in males, although a few affected males have been reported. We found increased 8(9)-cholestenol and 8-dehydrocholesterol in tissue samples from seven female probands with CDPX2 (ref. 4). This pattern of accumulated cholesterol intermediates suggested a deficiency of 3beta-hydroxysteroid-delta8,delta7-isomerase (sterol-delta8-isomerase), which catalyses an intermediate step in the conversion of lanosterol to cholesterol. A candidate gene encoding a sterol-delta8-isomerase (EBP) has been identified and mapped to Xp11.22-p11.23 (refs 5,6). Using SSCP analysis and sequencing of genomic DNA, we found EBP mutations in all probands. We confirmed the functional significance of two missense alleles by expressing them in a sterol-delta8-isomerase-deficient yeast strain. Our results indicate that defects in sterol-delta8-isomerase cause CDPX2 and suggest a role for sterols in bone development.

Adolescent↗
PubMed1999

Pituitary adenylate cyclase-activating polypeptide (PACAP-27) enhances tyrosine hydroxylase activity in the nucleus accumbens of the rat.

Pituitary adenylate cyclase-activating polypeptide (PACAP-27) was incubated in a tyrosine hydroxylase (TyrOH) assay with a homogenate preparation of the nucleus accumbens of the rat. TyrOH activity was determined in vitro by measuring the production of L-dopa with HPLC-ECD. Only in the presence of adenosine nucleotides (ATP, App(NH)p) PACAP-27 increased TyrOH activity with a EC(50)of 100 nM. Since the PACAP-27 effect on TyrOH was abolished when homogenate or pellet of the nucleus accumbens were coincubated with CHAPS, the peptide effect appears to be receptor mediated. TyrOH activation produced by PACAP-27 increased in the presence of the phosphodiesterase inhibitor papaverine indicating the involvement of cAMP. The marked effect of the non-hydrolysable adenosine nucleotide App(NH)p also supports a cAMP-dependent TyrOH activation not related to ADP or an ADP-dependent mechanism. This report's data suggest that PACAP-27 activates TyrOH in the rat nucleus accumbens through receptor-mediated cAMP formation. The exact receptor type present in the nucleus accumbens has yet not been specified.

Adenosine Triphosphate↗
PubMed1999

Leptin deficiency enhances sensitivity to endotoxin-induced lethality.

Leptin is induced by lipopolysaccharide (LPS) and cytokines. We investigated the role of leptin in LPS-induced toxicity using leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice. Sensitivity to LPS-induced mortality is significantly greater in ob/ob mice compared with their own lean littermates but not in db/db mice. LPS reduced serum glucose in both ob/ob and db/db mice but induced corticosterone only in db/db mice. Despite the very high basal levels of serum leptin in db/db mice, a twofold increase in serum leptin levels was observed after LPS in both db/db mice and their lean littermates. No differences were detected in LPS-induced serum levels of interleukin (IL)-1beta, tumor necrosis factor, macrophage inflammatory protein-1alpha, and interferon-gamma in ob/ob mice compared with their own littermates. In contrast, a blunted induction of IL-10 and IL-1 receptor antagonist (IL-1Ra) was observed in ob/ob mice compared with their littermates. In vitro, leptin induced IL-1Ra production and upregulated the IL-1Ra induction by LPS in macrophages. Moreover, treatment with leptin reversed the increased sensitivity to LPS-induced lethality found in ob/ob mice. These results suggest that leptin participates in the host response to inflammation by modulating the host immune and cytokine responses after LPS.

Animals↗
PubMed1999

Diagnosis and follow-up of a case of peroxisomal disorder with peroxisomal mosaicism.

Peroxisomal disorder phenotypes are the result of mutations that cause defective peroxisomal assembly or alterations in the import mechanism of peroxisomal proteins that lead to multiple peroxisomal dysfunctions, or the result of a peroxisomal enzymatic deficiency with a single peroxisomal dysfunction. With complementation analysis, 16 groups have been found. Assignment of the genetic defect has been described for some of the complementation groups. We describe the clinical evolution and follow-up over 10 years of a patient who belongs to complementation group 4, although he showed a milder clinical course. It has been found in fibroblasts different peroxisome populations, normal processing and expression of beta-oxidation PTS1 and PTS2 proteins, abnormal ALD protein distribution and normal plasmalogen biosynthesis; abnormal beta-oxidation metabolites have also been detected in serum. Ultrastructural studies in liver showed peroxisomal mosaicism as in fibroblasts. It has been taken into account that peroxisomal mosaicism may lead to variability in peroxisomal diagnostic parameters, making difficult the final diagnosis in these patients.

Adolescent↗
PubMed1999

Thioguanine administered as a continuous intravenous infusion to pediatric patients is metabolized to the novel metabolite 8-hydroxy-thioguanine.

Thiopurine antimetabolites have been in clinical use for more than 40 years, yet the metabolism of thiopurines remains only partially understood. Data from our previous pediatric phase 1 trial of continuous i.v. infusion of thioguanine (CIVI-TG) suggested that TG was eliminated by saturable mechanism, with conversion of the drug to an unknown metabolite. In this study we have identified this metabolite as 8-hydroxy-thioguanine (8-OH-TG). The metabolite coeluted with the 8-OH-TG standard on HPLC and had an identical UV spectrum, with a lambda(max) of 350 nm. On mass spectroscopy, the positive ion, single quad scan of 8-OH-TG yielded a protonated molecular ion at 184 Da and contained diagnostic ions at m/z 167, 156, 142, and 125 Da. Incubation of TG in vitro with partially purified aldehyde oxidase resulted in 8-OH-TG formation. 8-OH-TG is the predominant circulating metabolite found in patients receiving CIVI-TG and is likely generated by the action of aldehyde oxidase.

Aldehyde Oxidase↗
PubMed1998

Monocyte induction of IL-10 and down-regulation of IL-12 by iC3b deposited in ultraviolet-exposed human skin.

CD11b+ monocytic/macrophagic cells (Mo/Mph), which infiltrate into skin after UV irradiation, play an important role in UV-induced immunosuppression. Because in mice, blockade of CD11b (iC3b receptor) on monocytes and depletion of its ligand, iC3b, reverses UV-induced immunosuppression, we asked whether iC3b is deposited in human skin after UV, and whether iC3b can modulate the cytokine profile of Mo/Mph. Immunofluorescence studies revealed that iC3b was newly deposited in UV-exposed skin and was localized in apposition to infiltrating CD11b+ Mo/Mph. In addition, in situ hybridization studies showed that TNF-alpha mRNA was also induced in a similar microanatomic localization. To model the effects of these complex signals on infiltrating Mo/Mph following UV exposure, we then tested the effects of immobilized iC3b and TNF-alpha on resting blood monocytes. Both IL-10 mRNA synthesis and protein secretion were significantly induced by binding of iC3b in vitro and were synergistically increased by the presence of TNF-alpha. The effect was abrogated by a blocking Ab to CD11b, indicating CD11b-iC3b interaction. In contrast, iC3b binding resulted in suppression of IL-12 p40 mRNA and significantly inhibited the production of IL-12 p70 protein. Our studies thus define a novel mechanism for induction of tissue Mo/Mph into an IL-10high/IL-12low state via iC3b in combination with TNF-alpha.

Adult↗
PubMed1998

Induction of UCP2 gene expression by LPS: a potential mechanism for increased thermogenesis during infection.

UCP2 has been proposed to regulate thermogenesis and energy expenditure. To identify potential mechanisms underlying the increased energy expenditure and heat production during infection, we investigated whether LPS and cytokines might increase UCP2 mRNA levels in mice. LPS (100 micrograms, i.p.) increased the expression of UCP2 mRNA in liver (28-fold) and muscle and white adipose tissue (5-fold). In liver, both IL-1 beta (1 microgram, i.p.) and TNF (5 micrograms, i.p.) increased UCP2 mRNA levels, 4- and 3-fold respectively, whereas in muscle and fat tissue, an increase was detectable after TNF, but not IL-1 beta. Indomethacin (10 mg/kg, i.p.) administered immediately before LPS markedly reduced (70%) the ability of LPS to increase UCP2 mRNA in liver, but not in muscle or adipose tissue. These results suggest a role for UCP2 in the heat production and increased energy expenditure that occurs during infection.

Animals↗
PubMed1998

The effect of oral ethanol consumption on eye movements in healthy volunteers.

Horizontal and vertical eye movements were recorded and analysed with an infrared photoelectric technique in 12 healthy volunteers under various blood alcohol concentrations (0.0, 0.5, 1.0 g/kg body weight, [% per thousand]). The predictive smooth-pursuit tracking and saccadic eye movements were studied in response to unpredictable target jumps and during scanning of a classical kitchen scene and a traffic scene. Smooth-pursuit eye movement gain value decreased dose-dependently and was compensated by an increased number of catch-up saccades. With increasing blood alcohol concentrations peak velocities of horizontal and vertical visually guided reflexive saccades decreased while their latencies to the target increased. At blood alcohol concentrations of 0.5% per thousand and 1.0% per thousand healthy volunteers showed significantly longer mean fixation durations and a lower total number of exploratory saccades when scanning both the classical kitchen scene and the traffic scene. Surprisingly, in both of these scanning tasks the total fixation duration or the relative number of exploratory saccades increased in those scene sectors in which exciting situations were presented. Additionally, the time interval needed to foveate these exciting areas for the first time increased, probably due to an attention deficit. In conclusion, these findings indicate that alcohol consumption impairs the velocity and initiation of saccadic and smooth-pursuit eye movements, but that subjects can nevertheless still recognize exciting and relevant areas of visual scenes. The significant increase in fixation time, however, does not allow scanning of the entire visual scene during an adequate period of time. Therefore the reduced visual exploration caused by alcohol reflects an impaired sensorimotor processing of active visual perception.

Administration, Oral↗
PubMed1998

Quantitative detection of hepatitis B virus DNA with a new PCR assay.

The Amplicor HBV Monitor Test for quantitative detection of serum hepatitis B virus (HBV) DNA has recently been introduced. This assay is based on PCR and a non-radioactive hybridization and detection system on microwell plates. Evaluation in a routine diagnostic laboratory showed excellent sensitivity and adequate reproducibility; however, a more automated format would be desirable. The Amplicor HBV Monitor Test is useful for recognizing those patients who might benefit from antiviral treatment and for evaluation of the efficacy of anti-hepatitis B virus treatment.

DNA, Viral↗
PubMed1998

Regulation of microsomal triglyceride transfer protein mRNA expression by endotoxin and cytokines.

We studied the effect of endotoxin (LPS), and cytokines (TNF, IL-1, and IL-6) on hepatic microsomal triglyceride transfer protein (MTP) mRNA levels in vivo in Syrian hamsters and in vitro in HepG2 cells. LPS, interleukin-1 (IL-1), and to a lesser extent tumor necrosis factor (TNF) significantly decreased MTP mRNA levels in hamster liver. These effects required several hours. Furthermore, IL-1 and IL-6 significantly decreased MTP mRNA levels in HepG2 cells. This decrease appeared soon after IL-1 administration (8 h) and at very low doses (0.1 ng/ml). MTP activity and protein levels of the large subunit of MTP also decreased modestly in HepG2 cells with prolonged cytokine treatment. IL-1 reduced the expression of an MTP promoter luciferase construct to a similar degree as seen with MTP mRNA, indicating that transcriptional regulation plays a major role in the decrease of MTP gene expression. Deletional analysis of the MTP promoter identified the region -121 to -88 bp upstream to the coding sequence as the site of the negative regulation by IL-1. This region contains an insulin response element (IRE), activating protein 1 (AP-1), hepatic nuclear factor 1 (HNF-1) and hepatic nuclear factor 4 (HNF-4) consensus sequences; mutations of the IRE and HNF-4 sites did not affect the response to IL-1. In contrast, mutating AP-1 or HNF-1 sites led to a marked decrease in basal expression and the loss of the IL-1 effect, suggesting that an intact AP-1 and/or HNF-1 regulatory element are crucial for the IL-1 regulation of MTP gene expression. However, prolonged incubation with IL-1 did not alter HepG2 apolipoprotein B secretion suggesting that MTP mRNA down-regulation does not contribute significantly to the cytokine-induced effects on lipid metabolism.

Animals↗
PubMed1997

A fibroblast cell line defective in alkyl-dihydroxyacetone phosphate synthase: a novel defect in plasmalogen biosynthesis.

Using fluorescence-activated cytotoxicity selection, followed by colony autoradiographic screening of the surviving population, we have isolated a unique plasmalogen-deficient Chinese hamster ovary (CHO) cell line. The mutant, NZel-1, showed a dramatic (90%) reduction in the rate of biosynthesis and levels of plasmalogens, as determined using short- and long-term labeling with 32Pi. Enzymatic assays and lipid supplementation studies showed that NZel-1 was defective in a single step in the biosynthetic pathway for plasmalogens. This step, catalyzed by the peroxisomal enzyme, alkyl-dihydroxyacetone phosphate (DHAP) synthase, is responsible for the introduction of the ether bond found in plasmalogens. The activity of alkyl-DHAP synthase was reduced in whole-cell homogenates from NZel-1 to 18% of wild-type values. Unlike previously described plasmalogen-deficient mutants, NZel-1 contained peroxisomes, as confirmed by immunofluorescence microscopy and catalase release by digitonin. Peroxisomal functions, including the breakdown of very long-chain (>20 carbons) fatty acids, phytanic acid oxidation, and the acylation of DHAP, were normal. Cell fusion studies revealed that the mutation is recessive and belongs to a new complementation group. To our knowledge this is the first report describing the isolation and characterization of a mutant CHO cell line defective in plasmalogen biosynthesis which contains intact, functional peroxisomes. These cells will allow us to examine the role of ether lipids in cellular functions without complications associated with peroxisome deficiency.

Alkyl and Aryl Transferases↗
PubMed1997

Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism.

RSH/Smith-Lemli-Opitz (RSH/SLO) syndrome is an autosomal recessive malformation syndrome recently shown to be associated with a severe deficiency of cholesterol biosynthesis and markedly elevated plasma and tissue levels of 7-dehydrocholesterol (7-DHC), the immediate precursor of cholesterol in the Kandutsch-Russell biosynthetic pathway. Because these biochemical abnormalities permit a reassessment of RSH/SLO on biochemical criteria rather than less specific physical criteria, we review here the clinical and biochemical characteristics of our first 80 patients with abnormally increased levels of 7-DHC. The study population included 68 index patients and 12 additional relatives identified by quantification of 7-DHC and cholesterol in plasma, amniotic fluid, or cultured fibroblasts, lymphoblasts, or amniocytes. As demonstrated in other clinical syndromes when redefined biochemically, we have found a wider range of clinical expression of RSH/SLO than previously recognized. These newly recognized atypical RSH/SLO patients included several with no malformations other than syndactyly of the toes and, at the other extreme, patients with frank holoprosencephaly or multiple visceral anomalies who died in utero. Syndactyly of toes 2 and 3 was the most common malformation, occurring in all but one of 80 patients. The best biochemical predictor of clinical severity was the plasma cholesterol level, which decreased with increasing clinical severity. However, at least 10% of patients, including one newborn infant, had normal cholesterol levels at the time of diagnosis and would have been missed without specific quantification of 7-DHC. Not unexpectedly, several patients carrying a clinical diagnosis of RSH/SLO were found to have normal levels of all plasma sterols and apparently normal cholesterol biosynthesis in cultured cells. A comparison of the frequency of anomalies in our biochemically identified patients with similar data from previously reported clinical series suggests that up to 25% of reports of RSH/SLO in the literature may describe genetic conditions other than RSH/SLO with 7-DHC-emia.

Adolescent↗