Biomedical subjects

J B Nielsen

Publications and source records attributed to J B Nielsen.

At least 19 recordsLinked to original sources

PubMed1992

Selective, centrally acting serotonin 5-HT2 antagonists. 2. Substituted 3-(4-fluorophenyl)-1H-indoles.

A series of 3-(4-fluorophenyl)-1H-indoles substituted in the 1-position with 4-piperidinyl, 1,2,3,6-tetrahydro-4-pyridinyl, and 4-piperazinyl was synthesized. By variation of the substituents in the benzene part of the indole nucleus in 1-[2-[4-[3-4-fluorophenyl)-1H-indol-1-yl]-1-piperidinyl]-ethyl]-2- imidazolidinones, the highest 5-HT2 receptor affinity and selectivity with respect to dopamine D2 receptors and alpha 1 adrenoceptors were obtained by 5-methyl substitution. Different substituents were introduced in the 1-position of the piperidine ring in the 5-methyl-substituted derivative. Thus replacement of the 2-(2-imidazolidinon-1-yl)ethyl side chain with a 2-(1,3-dimethyl-1-ureido)ethyl or methyl substituent resulted in unchanged affinity and selectivity for 5-HT2 receptors. Replacement with a 2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl side chain reduced binding to alpha 1 adrenoceptors with a factor of four, while affinities for 5-HT2 and D2 receptors were retained, compared to the 3-unsubstituted imidazolidinone. Indoles substituted in the 1-position with 4-piperazinyl had generally weaker affinity for both 5-HT2 and D2 receptors compared to corresponding 4-piperidinyl- and 1,2,3,6-tetrahydro-4-pyridinyl-substituted indoles. Introduction of a methyl group in the 2-position of the 5-methyl-substituted indole resulted in further increase of selectivity for the 5-HT2 receptor. Compounds with potent receptor binding also potently inhibited the quipazine-induced head twitch syndrome in rats. The compounds were equally active after oral and subcutaneous administration and showed a long duration of action (> 24 h). In general, the derivatives were found to be considerably more potent at 24 h than at 2 h after the administration. The compounds within this series were prepared as analogues of the previously described 1-(4-fluorophenyl)-3-(4-piperidyl)-1H-indoles by interchange of the C-3 carbon atom and the nitrogen atom in the indole nucleus. The pharmacological results indicate that this isosteric replacement results in higher selectivity for 5-HT2 receptors compared to the former series. The 1-[2-[4-[2,5-dimethyl-3-(4-fluorophenyl)-1H-indol-1-yl]-1- piperidinyl]ethyl]-2-imidazolidinone has high affinity for 5-HT2 receptors (IC50 = 3.4 nM) and extremely low affinity for both dopamine D2 receptors (IC50 = 6900 nM) and alpha 1 adrenoceptors (IC50 = 2300 nM).

Animals↗

PubMed1992

Calcineurin mediates inhibition by FK506 and cyclosporin of recovery from alpha-factor arrest in yeast.

The structurally unrelated immunosuppressants FK506 and cyclosporin A (CsA) act similarly, inhibiting a Ca(2+)-dependent signal required for interleukin-2 transcription and T-cell activation. Each drug binds to its cytosolic receptor, FKBP-12 and cyclophilin, respectively, and the drug-receptor complexes inhibit the Ca2+/calmodulin-dependent protein phosphatase, calcineurin. In yeast, calcineurin has been implicated in recovery from alpha-mating factor arrest. Here we show that FK506 bound to yeast FKBP-12 appears to form a complex with yeast calcineurin. Moreover, recovery from mating factor arrest is highly sensitive to FK506 or CsA, and this sensitivity requires the presence of FKBP-12 or cyclophilin, respectively. These results define a key physiological target of an FK506- and CsA-sensitive signal pathway in yeast, suggest a high degree of mechanistic conservation with mammalian cells, and indicate that further examination of the yeast system should provide insight into the same process in T cells.

Alleles↗

PubMed1992

Yeast FKBP-13 is a membrane-associated FK506-binding protein encoded by the nonessential gene FKB2.

The immunosuppressants FK506 and rapamycin prevent T-cell activation and also inhibit the growth of certain strains of the yeast Saccharomyces cerevisiae. It has previously been shown that yeast contains a 12-kDa cytosolic FK506-binding protein (yFKBP-12), which also possesses peptidylprolyl cis-trans isomerase activity, and that fkb1 strains lacking yFKBP-12 are resistant to rapamycin and sensitive to FK506. The absence of yFKBP-12 permitted the detection and isolation of a second FK506- and rapamycin-binding protein, which is about 13 kDa in size (yFKBP-13) and membrane-associated. Purified yFKBP-13 binds FK506 with 15-fold lower affinity than yFKBP-12 and has peptidylprolyl cis-trans isomerase activity with a similar substrate profile. The sequence of the first 37 N-terminal amino acids was determined, and the yFKBP-13 gene (FKB2) was cloned and sequenced. A hydrophobic putative signal sequence precedes the N terminus of the mature protein. yFKBP-13 most closely resembles the membrane-associated human FKBP-13, which also possesses a signal peptide, whereas yFKBP-12 most closely resembles human FKBP-12. fkb2 and fkb1 fkb2 mutants are viable and unaltered in their sensitivity to FK506, suggesting that yeast possesses an additional target for this drug. Furthermore, fkb2 null mutations confer no change in rapamycin sensitivity. These findings show that yFKBP-13 and yFKBP-12 have distinct functions within the cell.

Amino Acid Sequence↗

PubMed1992

Anti-cholinesterase agents uptake during cultivation of greenhouse flowers.

The cholinesterase (ChE) activities were measured in-season and out-season in a total of 204 greenhouse workers and 360 non-exposed controls. No seasonal ChE variation were observed in the controls, whereas an in-season depression was seen in the workers, indicating an uptake of anti-cholinesterase agents during cultivation of greenhouse flowers in the intervals between sprayings (p = 0.0001). The anti-ChE agents applied seem to persist in the greenhouses and cause continued subtoxic uptake for weeks since last application. Wearing of protective gloves did not prevent the uptake. Thus, chronic percutaneous and oral uptake occurs as a result of cultivation of greenhouse flowers.

Carbamates↗

PubMed1992

The acute effect of sertindole on brain 5-HT2, D2 and alpha 1 receptors (ex vivo radioreceptor binding studies).

The ability of sertindole to influence the ex vivo binding of 3H-ketanserin, 3H-prazosin and 3H-spiperone to 5-HT2 receptors, alpha 1-adrenoceptors and DA D2 receptors, respectively, in rat brain has been studied after acute treatment. Sertindole is a potent, long acting compound which readily passes the blood-brain barrier. It dose-dependently binds to all three receptors types. In line with in vivo behavioural experiments sertindole has the most pronounced effect on 5-HT2 receptors, lower effect on alpha 1-adrenoceptors and the lowest effect on striatal D2 receptors.

Animals↗

PubMed1992

An experimental randomized study of five different ventilatory modes in a piglet model of severe respiratory distress.

OBJECTIVES: To characterize different modes of pressure- or volume-controlled mechanical ventilation with respect to their short-term effects on oxygen delivery (DO2). Furthermore to investigate whether such differences are caused by differences in pulmonary gas exchange or by airway-pressure-mediated effects on the central hemodynamics. DESIGN: After inducing severe respiratory distress in piglets by removing surfactant, 5 ventilatory modes were randomly and sequentially applied to each animal. SETTING: Experimental laboratory of a university department of Anesthesiology and Intensive Care. ANIMALS: 15 piglets after repeated bronchoalveolar lavage. INTERVENTIONS: Volume-controlled intermittent positive-pressure ventilation (IPPV) with either 8 or 15 cmH2O PEEP; pressure-controlled inverse ratio ventilation (IRV); pressure-controlled high-frequency positive-pressure ventilation (HFPPV) and pressure-controlled high frequency ventilation with inspiratory pulses superimposed (combined high frequency ventilation, CHFV). The prefix (L) indicates that lavage has been performed. MEASUREMENTS AND RESULTS: Measurements of gas exchange, airway pressures, hemodynamics, functional residual capacity (using the SF6 method), intrathoracic fluid volumes (using a double-indicator dilution technique) and metabolism were performed during ventilatory and hemodynamic steady state. The peak inspiratory pressures (PIP) were significantly higher in the volume-controlled low frequency modes (43 cmH2O for L-IPPV-8 and L-IPPV-15) than in the pressure-controlled modes (39 cmH2O for L-IRV, 35 cmH2O for L-HFPPV and 33 cmH2O for L-CHFV, with PIP in the high-frequency modes being significantly lower than in inverse ratio ventilation). The mean airway pressure (MPAW) after lavage was highest with L-IRV (26 cmH2O). In the ventilatory modes with a PEEP > 8 cmH2O PaO2 did not differ significantly and beyond this "opening threshold" MPAW did not further improve PaO2. Central hemodynamics were depressed by increasing airway pressures. This is especially true for L-IRV in which we found the highest MPAW and at the same time the lowest stroke index (74% of IPPV). CONCLUSIONS: In this model, as far as oxygenation is concerned, it does not matter in which specific way the airway pressures are produced. As far as oxygen transport is concerned, i.e. aiming at increasing DO2, we conclude that optimizing the circulatory status must take into account the circulatory influence of different modes of positive pressure ventilation.

Airway Resistance↗

PubMed1992

Effects of dietary lipids on whole-body retention and organ distribution of organic and inorganic mercury in mice.

The effect has been investigated of dietary lipids on the whole-body retention and organ distribution of organic and inorganic mercury in mice. A single oral dose of methylmercury chloride or mercuric chloride labelled with 203Hg was given to female NMRI mice fed semi-synthetic diets containing varying amounts (5, 10, 20 or 50%) of energy derived from lipid (coconut oil, soya oil, or cod liver oil). The whole-body retention and relative organ distribution of mercury depended on diet composition. Thus, a significant reduction of the whole-body retention of mercury was seen in mice fed a diet containing 50% cod liver oil compared with mice fed a diet containing 50% coconut oil. After oral administration of mercuric chloride the relative deposition of mercury in the kidneys increased while that in the liver decreased with increasing concentrations of soya oil or coconut oil in the diet. The whole-body retention of mercury after treatment with methylmercury chloride was significantly decreased in mice fed cod liver oil compared with mice fed coconut oil; there was no difference between mice fed cod liver oil and those fed soya oil. The relative disposition of mercury was significantly higher in all organs of mice fed a diet containing 20% energy from cod liver oil compared with mice fed a diet containing 20% energy from soya oil. The present study demonstrates that diet composition is of major importance to the toxicokinetics of methylmercury and mercuric mercury.

Administration, Oral↗

PubMed1992

The toxicokinetics of mercury in mice offspring after maternal exposure to methylmercury--effect of selenomethionine.

Human evidence indicates fetotoxicity of methylmercury at exposure levels inducing only slight and reversible maternal toxicity, but experimental animal data demonstrate, that fetotoxicity may occur despite absence of noticeable maternal toxicity. However, in contrast to the long-term exposure in humans, the key point in the experimental design of the majority of experimental studies has been administration of few doses of methylmercury late in gestation. The present study in mice therefore used long-term maternal exposure to methylmercury (1 nmol/ml in drinking water) and a cross-fostering design to investigate separately in different offsprings the toxicokinetics of transplacentally absorbed mercury and mercury retained during lactation. Further, the influence of seleno-L-methionine (3 micrograms/ml in drinking water) on the toxicokinetics of methylmercury in these mice was studied. The present study demonstrated, that independent on seleno-L-methionine supplementation, offspring deposited equal amounts of mercury during lactation and during gestation. Moreover, the organ distribution and rate of excretion of mercury in transplacentally exposed mice were considerably different from those in mice exposed postnatally and from adult mice in studies using comparable dosages. Seleno-L-methionine only slightly affected the toxicokinetics of mercury in offspring.

Animals↗

PubMed1992

Toxicokinetics of mercuric chloride and methylmercuric chloride in mice.

Future human exposure to inorganic mercury will probably lead to a few individuals occupationally exposed to high levels and much larger populations exposed to low or very low levels from dental fillings or from food items containing inorganic mercury; human exposure to methylmercury will be relatively low and depending on intake of marine food. Ideally, risk assessment is based on detailed knowledge of relations between external and internal dose, organ levels, and their relation to toxic symptoms. However, human data on these toxicokinetic parameters originate mainly from individuals or smaller populations accidentally exposed for shorter periods to relatively high mercury levels, but with unknown total body burden. Thus, assessment of risk associated with exposure to low levels of mercury will largely depend on data from animal experiments. Previous investigations of the toxicokinetics of mercuric compounds almost exclusively employed parenteral administration of relatively high doses of soluble mercuric salts. However, human exposure is primarily pulmonary or oral and at low doses. The present study validates an experimental model for investigating the toxicokinetics of orally administered mercuric chloride and methylmercuric chloride in mice. Major findings using this model are discussed in relation to previous knowledge. The toxicokinetics of inorganic mercury in mice depend on dose size, administration route, and sex, whereas the mouse strain used is less important. The "true absorption" of a single oral dose of HgCl2 was calculated to be about 20% at two different dose levels. Earlier studies that did not take into account the possible excretion of absorbed mercury and intestinal reabsorption during the experimental period report 7-10% intestinal uptake. The higher excretion rates observed after oral than after intraperitoneal administration of HgCl2 are most likely due to differences in disposition of systemically delivered and retained mercury. After methylmercury administration, mercury excretion followed first-order kinetics for 2 wk, independently of administration route, strain, or sex. However, during longer experimental periods, the increasing relative carcass retention (slower rate of excretion) caused the elimination to deviate from first-order kinetics. Extensive differences in the toxicokinetics of methylmercury with respect to excretion rates, organ deposition, and blood levels were observed between males and females.(ABSTRACT TRUNCATED AT 400 WORDS)

Absorption↗

PubMed1992

Localization of gastrointestinal deposition of mercuric chloride studied in vivo.

During the last 5 years, the site of gastrointestinal absorption of inorganic mercury has been attempted identified mainly by experiments using perfused intestinal segments in vitro or in situ. The present investigation will discuss the localization of the absorption site for mercuric chloride based on a completely undisturbed in vivo experimental model in mice. As the mice were allowed to eat their normal diet during the experimental period, the present results would independently add to existing knowledge on intestinal absorption sites for inorganic mercury. The mice were given 203Hg labelled mercuric chloride orally, either through stomach tube or in the drinking water, and were killed after various time intervals. Mercury was localized and quantified in various segments of the gastrointestinal tract by gamma-counting. Time course analysis of the segmental deposition of mercury demonstrated that the deposition mainly takes place in the proximal jejunum and suggested that a larger part of the jejunum than previously reported is involved in absorption of mercury. Using this in vivo model, tetraethylthiuram disulfide was demonstrated to increase the intestinal deposition and absorption without changing the site of deposition.

Animals↗

PubMed1992

Significance of plasma skimming and plasma volume expansion.

The organs associated with plasma volume expansion, i.e., the red bone marrow, the enlarged spleen, and the uteroplacental complex, are arteriovenous shunts with an interposed sinusoidal stroma able to skim off plasma-rich blood. In the spleen, plasma separation is an integral part of the hemoconcentration. In the red bone marrow, plasma skimming might provide a washout mechanism for the many newly formed erythrocytes and platelets from the sinusoids to the peripheral blood circulation. In the uteroplacental complex, skimming of plasma-rich blood is beneficial in increasing blood flow in the myometrium, kidneys, and skeletal musculature. The hypervolemic status with anemia will simulate a negative iron balance, which speeds up the absorption of iron. Thus a conceptual unit seems to exist in which rheological factors influence such functions as transport of newly formed blood cells into the circulation (in the red bone marrow), hemoconcentration (in the spleen), and iron balance during pregnancy (in the uteroplacental complex).

Bone Marrow↗

PubMed1992

Factors affecting the intestinal uptake of cadmium from the diet.

Human data on the effects of diet composition on intestinal cadmium uptake are almost completely lacking but animal experiments indicate that it may profoundly influence the intestinal uptake of ionic cadmium. Thus, rats and mice fed human dietary items absorbed 5-8 times more cadmium than animals fed ordinary rodent pellets. All the data currently available indicates that, both in humans and in experimental animals, the bioavailability of dietary cadmium is not very different from that of ionic cadmium. However, diet composition may markedly affect the uptake of the latter. Accordingly, a valid assessment of the bioavailability of cadmium can be made in experiments where ionic cadmium is administered mixed with the diet. It is important, however, to discriminate between diet composition at the time of administration and dietary status. A better understanding of the factors affecting intestinal cadmium uptake is necessary in assessing the risk associated with dietary cadmium exposure and further studies are therefore urgently needed.

Animals↗

PubMed1992

Transplacental passage and fetal deposition of mercury after low-level exposure to methylmercury--effect of seleno-L-methionine.

Previous experimental studies on transplacental passage and possible fetotoxicity of methylmercury have almost exclusively used a single dosage or 2-4 repeated doses of mercury on specific days during gestation and often used at relatively high dose levels. In previous studies, selenium supplementation considerably increased the concentration of mercury in the blood of offspring after maternal exposure of rats to methylmercury, whereas whole-body retention and organ deposition of mercury in mice were unaffected. The present study in mice, which involved exposure for 5 weeks to a low dose of methylmercury in the drinking water (1 nmol/ml) before and during pregnancy, demonstrates that mercury is deposited in offspring both in utero and during lactation, and that transplacentally absorbed mercury is not, or only very slowly, excreted. Seleno-L-methionine increased the deposition of mercury in offspring, but the effect was due to slightly higher deposition in the dams. Selenomethionine significantly reduced the kidney deposition of mercury in offspring, whereas liver deposition of mercury was unaffected. These results indicate that interactions between organo-selenium compounds and methylmercury orally administered at low doses is of less importance than previously believed on the basis of experiments with higher doses of selenite injected or supplemented to the diet.

Adolescent↗

PubMed1992

Low CSF HVA levels in the Rett syndrome: a reflection of restricted synapse formation?

The concentration of neurotransmitter metabolites in the CSF was determined in 10 girls with the Rett syndrome (RS) (age range 5.8-17.2) and in 14 control children (age range 4.5-16.7) treated for acute leukemia without signs of CNS involvement. Homovanillic acid concentration decreased with age in both groups. The decrease was less steep in RS compared to controls, with lower concentrations in young girls and normal concentrations at 15 years of age. 5-hydroxyindoleacetic acid decreased proportionally in both groups. It is suggested that the low concentration of HVA in young girls reflect deficient multiplication of catecholaminergic synapsis.

Adolescent↗

PubMed1991

Correlation between cerebrospinal fluid phenylalanine and beta-endorphin in patients with phenylketonuria.

Previous animal and human studies have suggested an analgesic effect of phenylalanine involving endogenous opioid peptides. Phenylalanine was measured by a HPLC method with electrochemical detection and beta-endorphin by a specific radioimmunoassay in 14 lumbar cerebrospinal fluid samples from 13 patients with phenylketonuria. Cerebrospinal fluid beta-endorphin was also determined in 6 age-matched control subjects. We found a trend towards a higher beta-endorphin level in phenylketonuria (median 26.0 pM, range 13.0-37.8) than in the control subjects (20.6 pM, 12.7-28.0), P = 0.13. Cerebrospinal fluid concentrations of phenylalanine and beta-endorphin were significantly correlated (r = 0.68, P = 0.008). The results support the hypothesis that phenylalanine modifies the central endogenous opioid system.

Adolescent↗

PubMed1991

Biosynthesis of the immunosuppressant immunomycin: the enzymology of pipecolate incorporation.

Immunomycin, an immunosuppressant closely related to FK 506, contains a pipecolate residue in amide linkage with an acyl group in its polyketide backbone. An enzyme activating L-pipecolic acid has been isolated from Streptomyces hygroscopicus var. ascomyceticus, which produces immunomycin. Purification results in a monomer of 170 kDa exhibiting N-terminal heterogeneity, apparently arising from proteolysis of a single species. It is a dimer under native conditions. The reaction appears to use an aminoacyl adenylate as an intermediate in the activating reaction, as do most activating enzymes involved in nonribosomal peptide synthesis. A range of pipecolate and proline analogues act as substrates in the pyrophosphate-ATP exchange resulting from the adenylation reaction. Several analogues are inhibitors of the subsequent thioesterification of the enzyme. Antibody raised to the purified enzyme was used to follow antigen during the course of fermentation. Maximal levels of antigen are found when synthesis of immunomycin is maximal. Ten of twelve immunomycin nonproducing mutants lack detectable pipecolate-activating enzyme in Western blots. From the enzymatic characteristics, substrate specificity, and immunological properties, we propose that we have isolated the enzyme responsible for activating pipecolic acid for immunomycin biosynthesis.

Adenosine Triphosphate↗

PubMed1991

An experimental randomized study of six different ventilatory modes in a piglet model with normal lungs.

A randomized study of 6 ventilatory modes was made in 7 piglets with normal lungs. Using a Servo HFV 970 (prototype system) and a Servo ventilator 900 C the ventilatory modes examined were as follows: SV-20V, i.e. volume-controlled intermittent positive-pressure ventilation (IPPV); SV-20VIosc, i.e. volume-controlled ventilation (IPPV) with superimposed inspiratory oscillations; and SV-20VEf, i.e. volume-controlled ventilation (IPPV) with expiratory flush of fresh gas; HFV-60 denotes low-compressive high-frequency positive-pressure ventilation (HFPPV) and HVF-20 denotes low-compressive volume-controlled intermittent positive-pressure ventilation; and SV-20P denotes pressure-controlled intermittent positive-pressure ventilation. With all modes of ventilation a PEEP of 7.5 cm H2O was used. In the abbreviations used, the number denotes the ventilatory frequency in breaths per minute (bpm). HFV indicates that all gas was delivered via the HFV 970 unit. The ventilatory modes described above were applied randomly for at least 30 min, aiming for a normoventilatory steady state. The HFV-60 and the HFV-20 modes gave lower peak airway pressures, 12-13 cm H2O compared to approximately 17 cm H2O for the other ventilatory modes. Also the mean airway pressures were lower with the HFV modes 8-9 cm H2O compared to 11-14 cm H2O for the other modes. The gas distribution was evaluated by N2 wash-out and a modified lung clearance index. All modes showed N2 wash-out according to a two-compartment model. The SV-20P mode had the fastest wash-out, but the HFV-60 and HFV-20 ventilatory modes also showed a faster N2 wash-out than the others.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗

PubMed1991

An experimental study of different ventilatory modes in piglets in severe respiratory distress induced by surfactant depletion.

In 19 anesthetized piglets 3 ventilatory modes were studied after inducing pulmonary insufficiency by bronchoalveolar lavage by the method of Lachmann. The lavage model was considered suitable for reproduction of severe respiratory distress. This model was reproducible and stable with respect to alveolar collapse, decrease in static chest-lung compliance and increase in extravascular lung water. The ventilatory modes studied were volume-controlled intermittent positive-pressure ventilation (IPPV), pressure-controlled inverse ratio ventilation (IRV), and pressure-controlled high-frequency positive-pressure ventilation (HFPPV). The 3 ventilatory modes were used in random sequence for at least 30 min to produce a ventilatory steady state. Ventilation with no PEEP, permitting alveolar collapse, was interposed between each experimental mode. The ability to open collapsed alveoli, i.e. alveolar recruitment, was different. The recruitment rate for IPPV was 74%, but for IRV and HFPPV it was 95%, respectively. Although IRV provided the best PaO2, this was at the expense of high airway pressures with circulatory interference and reduced oxygen transport. In contrast to this, HFPPV provided lower airway pressures, less circulatory interference and improved oxygen transport. In the clinical setting there might be negative effects on vital organs and functions unless the ventilatory modes are continuously and cautiously adapted to the individual requirements in different phases of severe respiratory distress. Therefore, one ventilatory strategy could be to "open the airways" with IRV, but then switch to HFPPV in an attempt to maintain the airways open with lesser risk of barotrauma and with improved oxygen transport.

Animals↗