Search PubMed⌕ Search

Biomedical subjects

A Moser

Publications and source records attributed to A Moser.

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

Blood- and skin-derived monocytes/macrophages respond to C3a but not to C3a(desArg) with a transient release of calcium via a pertussis toxin-sensitive signal transduction pathway.

Controversial results have been published in the past regarding the functional reactivity of monocytes (Mo) and macrophages (M phi) to the anaphylatoxin C3a and its degradation product C3a(desArg). In this study we performed binding and calcium mobilization experiments with recombinant human C3a (rC3a) and rC3a(desArg). Blood Mo displayed non-inhibitable binding of FITC-labeled rC3a (rC3aFITC) but responded to rC3a with a transient release of the intracellular calcium concentration ([Ca2+]i), whereas rC3a(desArg) was completely inactive. In contrast, binding of rC3aFITC to eosinophilic granulocytes and the mast cell line HMC-1 which have been shown previously to express C3a binding sites could be blocked by a monoclonal anti-C3a antibody. The rC3a-induced [Ca2+]i release in blood Mo was pertussis toxin (PTX)-sensitive suggesting the involvement of G-proteins in the signal transduction pathway. Skin-derived Mo/M phi reacted similarly to blood Mo as no specific binding of rC3aFITC to these cells could be demonstrated, whereas an intracellular release of calcium ions in response to the anaphylatoxin was observed. Homologous desensitization to rC3a but not heterologous desensitization to rC5a was detected in further experiments. The functional effect of C3a, but not the unspecific binding of rC3aFITC to blood Mo and skin-derived Mo/M phi could be blocked by the monoclonal anti-C3a antibody. These results suggest the expression of the recently cloned G-protein-coupled receptor for C3a on human blood Mo and skin-derived Mo/M phi. However, the total number of specific C3a binding sites on these cells is distinctly lower as compared to eosinophilic granulocytes and cells of the mast cell line HMC-1. The small number of C3a receptors on Mo/M phi may be masked by a pronounced non-inhibitable binding of rC3aFITC. This binding, however, may contribute to the recently described biological effects of C3a(desArg) on Mo.

Arginine↗
PubMed1997

A study of visual hallucinations in patients with Parkinson's disease.

In a hospital-based case-control study 29 patients with idiopathic Parkinson's disease (PD) and visual hallucinations (VH) were compared with 58 PD patients matched for age and disease duration, but without VH. VH patients had more frequently sleep disturbances and dementia, higher PD-related disability (Schwab-England scale), and took selegiline more frequently as an anti-Parkinsonian drug. The patient groups did not differ in age at PD onset, Webster score, treatment duration, dosage of any anti-Parkinsonian drug, frequency of levodopa-associated movement disorders, or measures on brain CT. After a median follow-up period of 27 months more VH patients had developed wearing-off and freezing phenomena, while their scores in the Mini Mental State Examination were lower. Nursing home placement during the follow-up period was associated with higher PD-related disability in VH patients.

Aged↗
PubMed1997

Selegiline induces dopamine release through ATP-sensitive potassium channels in the rat caudate-putamen in vitro.

We used superfusion chambers to investigate the role of ATP-sensitive potassium (KATP) channels in dopamine (DA) release elicited by the monoamine oxidase inhibitor selegiline in the rat caudate-putamen in vitro. Selegiline (R[-]-deprenyl], but not the S[+] enantiomer, concentration-dependently induced increases in extracellular concentrations of DA, with a maximal increase to 185% in comparison to basal outflow at 0.1 mM selegiline. Since in our experimental conditions exclusive MAO inhibition does not lead to an enhancement of extracellular DA levels, the effect of selegiline on DA levels seems not to be related to MAO inhibition. Butanedione (0.1 mM), a specific KATP channel blocker, also significantly enhanced extracellular DA levels in the rat caudate-putamen to approx. 260%. Selegiline only led to an additional increase of DA outflow, when added to submaximal concentrations of butanedione or tolbutamide, implying that selegiline is acting on identical sites. When the KATP channel opener cromakalim was added to the incubation medium, basal as well as butanedione-enhanced DA levels markedly decreased to about 40% when compared to baseline values. Selegiline-activated DA release was also antagonized by cromakalim. The selegiline effect was neither modulated by preincubation with the uptake inhibitor nomifensine nor by the DA agonist quinpirole and antagonist sulpiride. In conclusion these results suggest that selegiline is able to modulate KATP channels in the caudate-putamen of the rat in vitro resulting in an enhancement of striatal DA release.

Adenosine Triphosphate↗
PubMed1997

N-methyl-norsalsolinol, an endogenous neurotoxin, inhibits tyrosine hydroxylase activity in the rat brain nucleus accumbens in vitro.

As a compound of structural analogy with MPTP, N-methyl-norsalsolinol (2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; 2-MDTIQ) was recently identified in the brain and cerebrospinal fluid of patients with Parkinson's disease. As 2-MDTIQ cannot pass the blood-brain barrier, endogenous formation is suggested. Previous studies of the dopamine metabolism in Parkinson's disease have demonstrated an increased dopamine turnover in the presence of 2-MDTIQ. In the present study, we investigated the effect of 2-MDTIQ on tyrosine hydroxylase [L-tyrosine, tetrahydropteridine, oxygen: oxidoreductase (3-hydroxylating). EC 1.14.16.2; TH] activity in vitro using homogenated tissue of the rat nucleus accumbens as enzyme source. Basal TH activity was 20.1 +/- 5.9 pmol L-3,4-dihydroxyphenylalanine (L-DOPA)/min/mg protein. 2-MDTIQ non-competitively inhibited basal TH activity with an IC50 of 10 microM. After addition of 0.1 mM 2-MDTIQ, enzyme activity was nearly completely blocked. These results indicate that the endogenous formation of 2-MDTIQ in consequence of an impaired dopamine metabolism may in turn lead to a decrease in dopamine synthesis. Thus, 2-MDTIQ is suggested not only to represent an endogenous marker of Parkinson's disease, but also to support changes in the transmitter synthesis of dopaminergic neurons. Since previous investigations have moreover demonstrated a cytotoxic potential of 2-MDTIQ, these findings require special attention. 2-MDTIQ may represent an essential factor in the degenerative process of Parkinson's disease.

Analysis of Variance↗
PubMed1997

Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata.

Rhizomelic chondrodysplasia punctata (RCDP) is a rare autosomal recessive phenotype that comprises complementation group 11 of the peroxisome biogenesis disorders (PBD). PEX7, a candidate gene for RCDP identified in yeast, encodes the receptor for peroxisomal matrix proteins with the type-2 peroxisome targeting signal (PTS2). By homology probing we identified human and murine PEX7 genes and found that expression of either corrects the PTS2-import defect characteristic of RCDP cells. In a collection of 36 RCDP probands, we found two inactivating PEX7 mutations: one, L292ter, was present in 26 of the probands, all with a severe phenotype; the second, A218V, was present in three probands, including two with a milder phenotype. A third mutation, G217R, whose functional significance is yet to be determined, was present in five probands, all compound heterozygotes with L292ter. We conclude that PEX7 is responsible for RCDP (PBD CG11) and suggest a founder effect may explain the high frequency of L292ter.

Amino Acid Sequence↗
PubMed1997

LPS-induced anorexia in leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) mice.

Administration of endotoxin (lipopolysaccharide, LPS) induces profound anorexia. Injection of leptin decreases food intake in mice. Recently, we reported that LPS and cytokines increase leptin levels in hamsters. To further investigate the role of leptin in the LPS-induced anorexia, we administered LPS to leptin receptor-deficient (db/db) and leptin-deficient (ob/ob) mice. We found that LPS caused anorexia in both db/db and ob/ob mice. As might be predicted if leptin had a role in anorexia, the db/db mice were somewhat resistant to LPS-induced anorexia. However the ob/ob mice were more sensitive to LPS-induced anorexia. No differences between db/db and ob/ob mice and their respective littermate were observed in circulating tumor necrosis factor levels after LPS. These data suggest that leptin per se is not essential for LPS-induced anorexia.

Analysis of Variance↗
PubMed1996

Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters.

The expression of leptin, the ob gene product, is increased in adipose tissue in response to feeding and energy repletion, while leptin decreases food intake. Because adipose tissue gene expression is regulated by cytokines induced during infection and because infection is associated with anorexia, we tested whether induction of leptin might occur during the host response to infection. Administration of endotoxin (LPS), a model for gram negative infections, induces profound anorexia and weight loss in hamsters. In fasted adipose tissue to levels similar to fed control animals. There is a strong inverse correlation between mRNA levels of leptin and subsequent food intake. TNF and IL-1, mediators of the host response to LPS, also induced anorexia and increased levels of leptin in mRNA in adipose tissue. As assessed by immuknoprecipitation and Western blotting, circulating leptin protein is regulated by LPS and cytokines in parallel to regulation of adipose tissue leptin mRNA. Induction of leptin during the host response to infection may contribute to the anorexia of infection.

Adipocytes↗
PubMed1996

Effect of erucic acid on platelets in patients with adrenoleukodystrophy.

In a clinical trial for the management of adrenoleukodystrophy, we analyzed the effect of erucic acid (a component of Lorenzo's oil) on platelet number, fatty acid composition, and function. Analysis of variance was performed to compare platelet counts before starting treatment with Lorenzo's oil and at 6 and 12 months. We measured platelet fatty acid composition in subjects and control patients and correlated these values with their platelet counts using discriminant analysis. After 6 months, the mean platelet count decreased from 247,000/mm3 to 169,000/mm3 (+/- 1 standard deviation 58,000,n =39), P < 0.0001 compared to 18 subjects on a control diet having a mean baseline platelet count of 259,000/mm3 (+/- 1 standard deviation 67,000, n = 19) and at 6 months 267,000/mm3 (+/- 1 standard deviation 71,000). We found at P < 0.05 that the platelet counts showed a strong inverse relationship with erucic acid levels and other omega 9 fatty acids that form from the administration of the erucic acid component of Lorenzo's oil. Morphologic and platelet sizing measurements suggest that the physical properties of platelets may also be affected by erucic acid. Our studies show that the ingestion of erucic acid affects platelet biology. This indicates that platelet counts and properties are influenced by monounsaturated fatty acids, in addition to the well-known effects of polyunsaturated fatty acids. In areas of the world where erucic acid is widely ingested, the biology of platelets in these populations may be affected.

Adrenoleukodystrophy↗
PubMed1996

Rotational behaviour and neurochemical changes in unilateral N-methyl-norsalsolinol and 6-hydroxydopamine lesioned rats.

In earlier studies the tetrahydroisoquinoline derivative N-methyl-norsalsolinol (2-MDTIQ) was discovered in lumbar cerebrospinal fluid and brain of patients with Parkinson's disease. To establish whether 2-MDTIQ is toxic to the dopaminergic system, 2-MDTIQ or 6-hydroxydopamine (6-OHDA) were stereotactically injected into the left medial forebrain bundle, and rotational behaviour and neurochemical changes were measured in female Wistar rats. Three weeks after lesioning rotational behaviour was assessed after administration of S(+)-amphetamine (5 mg/kg) and apomorphine (0.1 mg/kg). As expected, after 6-OHDA lesions S(+)-amphetamine as well as apomorphine markedly induced rotations ipsiversive or contraversive, respectively, to the lesion, and dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels of the ipsilateral caudate-putamen and accumbens nucleus decreased. Although a decline in the dopamine/DOPAC ratio indicated an enhanced dopamine turnover, striatal monoamine oxidase (MAO) activity remained unchanged when tested in vitro. After a 2-MDTIQ lesion S(+)-amphetamine also caused animals to rotate strongly, ipsiversive to the lesion, but there was no response to apomorphine administration. This 2-MDTIQ effect was not due to a reduction in dopamine metabolism of the ipsilateral caudate-putamen or mesencephalic structures, or, for example, a partial neurodegeneration of dopaminergic neurons, since dopamine metabolites levels and MAO activity were nearly unchanged. Thus, we suggest that 2-MDTIQ interacts with the effect of S(+)-amphetamine and probably leads to an insensitivity of the dopamine uptake/transporter system to S(+)-amphetamine in dopaminergic nigrostriatal neurons. An effect of 2-MDTIQ on presynaptic membranes of dopaminergic synaptosomes has never been reported, but will be an objective of our further studies.

Amphetamine↗
PubMed1996

Salsolinol, catecholamine metabolites, and visual hallucinations in L-dopa treated patients with Parkinson's disease.

We could quantify the tetrahydroisoquinoline derivative salsolinol in urine of patients with Parkinson's disease and normal control subjects by means of high performance liquid chromatography and electrochemical detection. Urine levels of salsolinol were positively related to the homovanillic acid/3-O-methyl-dopa ratio in the cerebrospinal fluid that reflects dopamine metabolism. In the patient group with visual hallucinations, mean salsolinol level was significantly increased to almost the 3-fold of those found in patients without hallucinations. Since the daily L-dopa doses of both patient groups were nearly identical this result is not due to different L-dopa medications. Additionally, either high values of the main serotonin metabolite, 5-hydroxyindole acetic acid (HIAA) or the L-dopa/3-O-methyl-dopa ratio were found in cerebrospinal fluid of patients with hallucinations. The enhanced salsolinol levels in patients with visual hallucinations seem to be due to an overloaded dopaminergic pathway with an imbalance between dopaminergic and serotonergic systems. Thus, salsolinol appears as a predictor for hallucinosis in Parkinson's disease.

Aged↗
PubMed1996

The effect of N-methyl-norsalsolinol on monoamine oxidase of the rat caudate nucleus in vitro.

The effects of N-methyl-norsalsolinol on basal and inhibited activity of monoamine oxidase (MAO) in membrane preparations from the caudate nucleus of the rat have been studied. For the first time, the physiological step of dopamine oxidation to 3, 4 dihydroxyphenylacetic aldehyde (DPAA) was examined. N-methyl-norsalsolinol (2-MDTIQ) dose-dependently inhibited MAO activity with a IC50 of 33 microM. The MAO inhibitors clorgyline and deprenyl were also found to inhibit formation of DPAA. In this case, the inhibition of these antagonists, clorgyline and deprenyl, was additive. N-methyl-norsalsolinol modified neither the enzyme inhibition induced by clorgyline nor by deprenyl. These results suggest that 2-MDTIQ, the naturally occurring compound found in parkinsonian brain and cerebrospinal fluid, perturbs dopamine metabolism in basal ganglia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Does lipid infusion affect bile composition in humans?

A prospective study was performed to investigate the effect of short-term lipid infusion on bile composition and its lithogenicity in humans. The study group comprised 44 patients scheduled for laparotomy. The patients were hospitalized 48 h prior to elective surgery and randomized to be infused with a lipid emulsion of either long chain triglycerides (LCT) or a mixture of medium and long chain triglycerides (MCT/LCT) for 6 h of each 24 h, or with glucose-saline. Bile samples were obtained by puncture of the gallbladder during operation. In non-gallstone patients, both lipids caused an elevation of biliary cholesterol and phospholipids, but this effect was more pronounced and significant (P <0.001) only with the mixture of MCT/LCT emulsion. The fatty acid composition of biliary phospholipids was not affected by either lipid infusion. The Cholesterol Saturation Index increased significantly (P <0.005) with the MCT/LCT emulsion and there was insignificant shortening in the nucleation time. In contrast to patients with cholelithiasis, no effects could be demonstrated on gallbladder bile composition, cholesterol saturation index, nucleation time, or fatty acid composition of phospholipids. The effects of both lipid emulsions on plasma lipids and lipoproteins were similar in all groups. Our results indicate that lipid emulsions containing MCT/LCT induce lithogenic changes in the composition of human bile. We propose that the lack of effect of lipid infusion on bile composition in patients with cholelithiasis may be due to precipitation of excess cholesterol in the gallbladder of cholesterol gallstone patients whose bile is already saturated. These findings imply that patients with cholesterol gallstones cannot be grouped with non-gallstone patients in studies of alterations of bile composition.

Bile↗
PubMed1995

Synthesis, pharmacologic activity, and structure-activity relationships of a series of propafenone-related modulators of multidrug resistance.

A series of [(o-acylaryl)oxy]propanolamines have been prepared and evaluated for multidrug resistance-reverting activity in a human tumor cell model. Structure-activity relationship studies indicate that the phenylpropiophenone moiety as well as the substitution pattern at the nitrogen atom is crucial for activity of the compounds. Incorporation of the ether oxygen into a benzofuran substructure, which renders the compound an arylethanolamine, decreased biologic activity. Highest activity could be observed with the arylpiparazines 4f-h, which not only completely restored daunomycin sensitivity but also showed moderate activity in restoring etoposide toxicity.

Daunorubicin↗
PubMed1995

Presence of N-methyl-norsalsolinol in the CSF: correlations with dopamine metabolites of patients with Parkinson's disease.

We could identify the MPTP-like compound and isoquinoline derivative N-methyl-norsalsolinol (2-MDTIQ) in cerebrospinal fluid (CSF) of patients with Parkinson's disease. The presence of 2-MDTIQ negatively correlated with the disease duration. In order to study the relationship between presence of 2-MDTIQ and dopamine metabolism, we examined 3-O-methyl-dopa (MDOPA) and homovanillic acid (HVA) levels in CSF of 15 normal control subjects and 34 patients with Parkinson's disease (PD). In the PD group in which 2-MDTIQ was detected, the HVA/MDOPA ratio was also negatively correlated with the duration of the disease and was increased when compared to patients without 2-MDTIQ. Since in both PD groups the daily L-dopa dose, the mean MDOPA levels, and the daily L-dopa dose/MDOPA ratio were nearly identical the results are not related to different L-dopa medications. In vitro experiments demonstrated 2-MDTIQ to inhibit monoamine oxidase activity in the caudate-putamen. These results suggest that 2-MDTIQ indicates an increased dopamine turnover in patients with PD. The enhanced metabolism at the beginning of the disease is not due to the presence of 2-MDTIQ since it inhibits dopamine metabolism. Thus, 2-MDTIQ, probably endogenously synthesized from dopamine, appears as a result of a compensatively activated dopaminergic system.

Adult↗
PubMed1995

Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders.

The peroxisome biogenesis disorders (PBDs) are lethal recessive diseases caused by defects in peroxisome assembly. We have isolated PXR1, a human homologue of the yeast P. pastoris PAS8 (peroxisome assembly) gene. PXR1, like PAS8, encodes a receptor for proteins with the type-1 peroxisomal targeting signal (PTS1). Mutations in PXR1 define complementation group 2 of PBDs and expression of PXR1 rescues the PTS1 import defect of fibroblasts from these patients. Based on the observation that PXR1 exists both in the cytosol and in association with peroxisomes, we propose that PXR1 protein recognizes PTS1-containing proteins in the cytosol and directs them to the peroxisome.

Amino Acid Sequence↗