Biomedical subjects

G Hartmann

Publications and source records attributed to G Hartmann.

At least 19 recordsLinked to original sources

PubMed1996

Urinary sodium excretion: association with hyperinsulinaemia, hypertension and sympathetic nervous system activity in obese and control children.

UNLABELLED: The aim of the present study was to evaluate the association between 24 h urinary excretion of sodium and blood pressure, fasting plasma insulin, renin, aldosterone and serum norepinephrine concentrations in 45 obese and 15 control children. Urinary sodium excretion was significantly lower in obese subjects (1.3 +/- 0.6 mmol/kg/24 h, P < 0.01) than in controls (2.8 +/- 1.3 mmol/kg/24 h). Hyperinsulinaemia did not affect sodium excretion of obese children. Plasma renin and aldosterone levels did not correlate with sodium excretion and were significantly higher in overweight children. Serum norepinephrine levels were also significantly higher in the obese group (0.66 +/- 0.89 microgram/100 ml) as compared to the controls (0.11 +/- 0.03 microgram/100 ml, P < 0.01) and showed significant negative correlation with urinary sodium excretion (r = 0.43, P < 0.05). CONCLUSION: Hyperinsulinaemia and the consequently increased sympathetic nervous system activity might be involved in the development of high blood pressure in obese children by decreasing urinary sodium excretion.

Adolescent↗

PubMed1996

Oligodeoxynucleotides enhance lipopolysaccharide-stimulated synthesis of tumor necrosis factor: dependence on phosphorothioate modification and reversal by heparin.

BACKGROUND: Specific inhibition of target proteins by antisense oligodeoxynucleotides is an extensively studied experimental approach. This technique is currently being tested in clinical trials applying phosphorothioate-modified oligonucleotides as therapeutic agents. These polyanionic molecules, however, may also exert non-antisense-mediated effects. MATERIALS AND METHODS: We examined the influence of oligonucleotides on lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF alpha) synthesis in freshly isolated human peripheral blood mononuclear cells. Oligonucleotides (18 mer) with different degrees of phosphorothioate modification were studied. RESULTS: The addition of phosphorothioate oligonucleotides (5 microM) caused amplification of TNF synthesis of up to 410% compared with the control with LPS alone. Without LPS stimulation, phosphorothioate oligonucleotides did not induce TNF production. We demonstrate that the enhancement of LPS-stimulated TNF production by phosphorothioate oligonucleotides does not rely on the intracellular presence of oligonucleotides and is not mediated by LPS contamination. Partially phosphorothioate-modified oligonucleotides and unmodified oligonucleotides did not increase TNF synthesis. High concentrations of the polyanion heparin reversed the oligonucleotide-induced enhancement of TNF synthesis. CONCLUSIONS: The data suggest that amplification of TNF synthesis may be caused by binding of the polyanionic phosphorothioate oligonucleotide to cationic sites on the cell surface. Such binding sites have been proposed for polyanionic glycoaminoglycans of the extracellular matrix, which have also been described to augment LPS-stimulated TNF synthesis. The present results are relevant to all in vitro studies attempting to influence protein synthesis in monocytes by using phosphorothioate oligonucleotides. The significance of our findings for in vivo applications of phosphorothioates in situations where there is a stimulus for TNF synthesis, such as in sepsis, should be elucidated.

Animals↗

PubMed1995

Sequential requirement of hepatocyte growth factor and neuregulin in the morphogenesis and differentiation of the mammary gland.

We have examined the role of two mesenchymal ligands of epithelial tyrosine kinase receptors in mouse mammary gland morphogenesis. In organ cultures of mammary glands, hepatocyte growth factor (HGF, scatter factor) promoted branching of the ductal trees but inhibited the production of secretory proteins. Neuregulin (NRG, neu differentiation factor) stimulated lobulo-alveolar budding and the production of milk proteins. These functional effects are paralleled by the expression of the two factors in vivo: HGF is produced in mesenchymal cells during ductal branching in the virgin animal; NRG is expressed in the mesenchyme during lobulo-alveolar development at pregnancy. The receptors of HGF and NRG (c-met, c-erbB3, and c-erbB4), which are expressed in the epithelial cells, are not regulated. In organ culture, branching morphogenesis and lobulo-alveolar differentiation of the mammary gland could be abolished by blocking expression of endogenous HGF and NRG by the respective antisense oligonucleotides; in antisense oligonucleotide-treated glands, morphogenesis could again be induced by the addition of recombinant HGF and NRG. We thus show that two major postnatal morphogenic periods of mammary gland development are dependent on sequential mesenchymal-epithelial interactions mediated by HGF and NRG.

Animals↗

PubMed1995

Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients?

While it is well established that acute allergic urticaria is caused by degranulation of skin mast cells occurring after allergen/IgE-dependent cross-linking of high affinity IgE receptors (FcepsilonRI), the pathophysiologic mechanisms operative in chronic urticaria (CU) are less well understood. Some evidence points to the existence of histamine-releasing activity in the serum of CU patients which possibly acts via triggering of FcepsilonRI. In this study, we aimed to better characterize this anti-FcepsilonRIalpha reactivity of CU patients using affinity-purified, IgE-depleted IgG fractions of such individuals (CU-IgG). Using immobilized, recombinant soluble FcepsilonRIalpha as a a reaction target for Western blot studies, we found that 12/32 (37%) CU-IgG serum samples exhibited IgG autoreactivity against FcepsilonRI- alpha. These findings were confirmed by experiments demonstrating that immunoblot-reactive, but not immunoblot-nonreactive, CU-IgG preparations precipitated the FcepsilonRIalpha from FcepsilonRI- alphagamma-transfected cells. No anti-FcepsilonRIalpha reactivity was observed in IgG fractions from atopic dermatitis (AD) patients (0/15) or healthy control individuals (CO:0/15). As opposed to the selective occurrence of IgG anti-Fc epsilon RI alpha autoantibodies in CU patients, IgG anti-IgE antibodies were detected in all groups investigated (CU: 69%; AD: 73%; CO: 26%). While both types of autoantibodies can exhibit histamine-releasing properties, not all of the autoantibodies proved to be functional in vitro. Our results indicate that the occurrence of IgG anti-FcepsilonRIalpha reactivity defines an autoimmune-mediated subentity of CU and provide a basis for the development of new diagnostic procedures and, perhaps, therapeutic strategies for this disease.

Animals↗

PubMed1994

The motility signal of scatter factor/hepatocyte growth factor mediated through the receptor tyrosine kinase met requires intracellular action of Ras.

Scatter factor/hepatocyte growth factor (SF/HGF) has various biological effects upon different cells, i.e. induces increased motility and proliferation as well as invasiveness and morphogenesis. The signals given to epithelial cells by SF/HGF are all mediated through the Met receptor tyrosine kinase (Weidner, K. M., Sachs, M., and Birchmeier, W. (1993) J. Cell Biol. 111, 145-154) suggesting that signal diversity is due to the interplay of different downstream pathways. It has also been shown that SF/HGF activates the protooncogene product Ras, i.e. stimulates guanine nucleotide exchange. In order to examine whether Ras is involved in mediating the dissociation and motility signal of SF/HGF to epithelial cells, we have expressed in Madin-Darby canine kidney cells the dominant-negative N17Ras under the control of a modified metallothionein promoter. Induced expression of N17Ras by the addition of Zn2+ clearly prevented dissociation of the cells by SF/HGF. These data indicate that the Ras pathway is indeed essential to mediate the motility signal of SF/HGF-Met to the cell-cell adhesion system and the cytoskeleton of epithelial cells.

Animals↗

PubMed1994

[Anesthesia for MRI examination].

Magnetic resonance imaging (MRI) requires the patients to stay for 30-45 min in a magnetic closed noisy space. Therefore most children and agitated adults require general anaesthesia or sedation in order to high quality images. Anaesthesia may be given by several routes (TIVA, inhalational or intrarectal administration) using common drugs. However, the magnetic field limits the selection of patients undergoing MRI and the spectrum of anaesthetic and monitoring equipment. The magnetic field may have deleterious effects on implanted ferromagnetic devices. It may attract objects towards the magnet centre at a dangerous speed. Moreover it may disturb the function of monitors and anaesthesia machines which should be tested for a specific magnetic field strength before introducing their use in a given MRI unit.

Adolescent↗

PubMed1994

Effect of morphine on hypothalamic catecholamine and serotonin level in relation to the stress-induced pituitary-adrenocortical activation in the rat.

The relationship between the hypothalamic catecholamine and serotonin level as well as the activation of the pituitary-adrenal axis was investigated after administration or morphine (MO) in the rat. Five mg/kg b. wt. of MO induced a significant increase in norepinephrine and a 78%, but insignificant, increase in dopamine level of the hypothalamus within 60 min without changing corticosterone secretion. Electric footshock, in addition to elevating hypothalamic norepinephrine and dopamine levels, significantly increased the pituitary-adrenocortical response in the MO pretreated rats. Five mg/kg b. wt. of MO, or electric footshock alone did not influence the hypothalamic serotonin level within 60 min, but the hypothalamic serotonin level decreased significantly in the MO pretreated, electrically shocked animals. We conclude, that 1) low dose of MO may induce changes of the hypothalamic catecholamine levels without influencing pituitary-adrenocortical activation. 2) enhanced hypothalamic catecholamines by MO did not prevent increasing pituitary-adrenocortical response elicited by stress. It appears, that the hypothalamic catecholaminergic mechanism which may inhibit ACTH release during stimulation does not function in the MO treated rats.

Adrenal Cortex↗

PubMed1994

An adaptive lung ventilation controller.

Closed loop control of ventilation is traditionally based on end-tidal or mean expired CO2. The controlled variables are the respiratory rate RR and the tidal volume VT. Neither patient size or lung mechanics were considered in previous approaches. Also the modes were not suitable for spontaneously breathing subjects. This report presents a new approach to closed loop controlled ventilation, called Adaptive Lung Ventilation (ALV). ALV is based on a pressure controlled ventilation mode suitable for paralyzed, as well as spontaneously breathing, subjects. The clinician enters a desired gross alveolar ventilation (V'gA in l/min), and the ALV controller tries to achieve this goal by automatic adjustment of mechanical rate and inspiratory pressure level. The adjustments are based on measurements of the patient's lung mechanics and series dead space. The ALV controller was tested on a physical lung model with adjustable mechanical properties. Three different lung pathologies were simulated on the lung model to test the controller for rise time (T90), overshoot (Ym), and steady state performance (delta max). The pathologies corresponded to restrictive lung disease (similar to ARDS), a "normal" lung, and obstructive lung disease (such as asthma). Furthermore, feasibility tests were done in 6 patients undergoing surgical procedures in total intravenous anesthesia. In the model studies, the controller responded to step changes between 48 seconds and 81 seconds. It did exhibit an overshoot between 5.5% and 7.9% of the setpoint after the step change.(ABSTRACT TRUNCATED AT 250 WORDS)

Equipment Design↗

PubMed1993

[Dopamine, noradrenaline and serotonin levels in amniotic fluid during the second trimester in normal and pathologic pregnancy].

Authors measured the dopamine (DA), noradrenaline (NA) and serotonin (5-HT) contents of amniotic fluid between 19 and 21 weeks with fluorimetric method. The amniotic fluid samples were obtained by transabdominal amniocenteses performed due to elevated maternal serum-alphafetoprotein levels and suspect ultrasound findings. They considered as normal values the average of 30 amniotic fluid samples obtained from pregnant women who gave birth to healthy babies at term. The mean values (mean+SE) of normal cases were 136.6 + 20.2 nmol/l for DA, 29.5 + 9.4 nmol/l for NA and 72.6 + 4.9 nmol/l for 5-HT. Against these values, in cases of open spina bifida the level of NA showed no significant difference, the DA level was higher (p < 0.05) and the 5-HT level was also higher (p < 0.001). The DA level was found higher (p < 0.05) in cases of intrauterine retardation as well, however there was no difference in the NA and 5-HT levels in these cases. In cases of preterm deliveries, none of the above parameters showed differences. Authors suggest that in cases of spina bifida the measurement of 5-HT in the amniotic fluid can be a complementary diagnostic method. They also state that no prognosis about the outcome of pregnancies can be expected from such examinations.

Amniotic Fluid↗

PubMed1993

Relationship between the monoamine and gonadotropin content in follicular fluid of preovulatory graafian follicles after superovulation treatment.

Noradrenaline (NA), serotonin (5HT), dopamine (DA), FSH, LH and prolactin (PRL) content was determined in 104 preovulatory follicular fluids obtained from 44 patients undergoing in vitro fertilization. The patients were given human menopausal gonadotropin (HMG) for ovarium stimulation, ovulation was induced with 10000 IU human chorionic gonadotropin (HCG) 34-36 hours prior to the follicular aspiration by vaginal ultrasound. Classification of the oocytes was performed by direct microscopic evaluation differentiating three groups of oocytes: Group I.: prophase I; Group II.: metaphase I; Group III.: metaphase II. There was no significant difference in monoamine and FSH content of follicular fluid at different stage of the oocyte maturation. LH and PRL significantly increased parallel with oocyte maturation (38.9; 48.8; 56.7 IU/l and 1324; 2382; 3134 IU/l). significant negative correlation was observed in Group I. between 5HT-LH (r = -0.64); in Group II. between NA-LH (r = -0.62) and NA-PRL (r = -0.51). Significant positive correlation were found in Group I. between FSH-LH (r = 0.63), in Group II. between LH-PRL (r = 0.56), in Group III. between NA-5HT (r = 0.66), NA-DA (r = 0.80) and 5HT-DA (r = 0.66). These observations suggest that action of LH and PRL may be negatively modulated by 5HT and NA in the final stage of oocyte maturation.

Adult↗

PubMed1993

Papovavirus-induced trichogenous tumours in Syrian hamsters (Mesocricetus auratus).

Tumorous, virus-induced skin lesions in two golden hamsters (Mesocricetus auratus) were characterized macroscopically and by means of light- and electron-microscopy. Evidence of a virus was demonstrated in the ultra-thin sections and by the negative staining method. The morphological findings confirm the assumption that infections with papoviruses--probably of the polyomavirus genus--were involved.

Animals↗

PubMed1993

Relationship between the monoamine, progesterone and estradiol content in follicular fluid of preovulatory graafian follicles after superovulation treatment.

We measured the progesterone, estradiol (E2), serotonin (5-HT), noradrenaline (NA) and dopamine (DA) contents of follicular fluid (FF) samples obtained from 35 patients undergoing in vitro fertilization and embryo transfer. Progesterone and E2 were determined by radioimmunoassay, and monoamines were measured by a spectrofluorimetric method. Significantly higher progesterone and NA levels were found (p < 0.01) in FF from cycles in which the oocyte cleaved and resulted in pregnancy compared to FF containing uncleaved oocytes. NA and DA contents were significantly higher in FF from cycles resulting in pregnancy than in FF containing cleaved oocytes not resulting in pregnancy (p < 0.01). There were significantly lower NA and 5-HT levels in FF containing uncleaved oocytes compared to the latter group (p < 0.05). Significant positive correlations were found between progesterone and 5-HT (r = 0.67) and between NA and DA (r = 0.93) in the pregnant group; between progesterone and E2 (r = 0.84) in FF containing uncleaved oocytes; between progesterone and E2 (r = 0.71) and between NA and DA (r = 0.62) in FF from cycles in which the oocyte cleaved but did not result in pregnancy. The results suggest that the follicular hormonal changes associated with oocyte maturation may be locally modulated by monoamines.

Biogenic Monoamines↗

PubMed1993

Properties and functions of scatter factor/hepatocyte growth factor and its receptor c-Met.

Scatter factor (SF), a cell motility factor with a multimodular structure, is identical to hepatocyte growth factor (HGF), a potent mitogen of various cell types. The receptor for SF/HGF has recently been identified as the c-Met proto-oncogene product, a transmembrane receptor tyrosine kinase. Depending on the target cells and culture conditions, SF/HGF has several distinct activities in vitro, i.e., it induces cell motility, proliferation, invasiveness, tubular morphogenesis, angiogenesis, or cytotoxicity. In vivo, SF/HGF might be involved in tissue regeneration, tumor progression, and embryological processes.

Amino Acid Sequence↗

PubMed1993

Molecular characteristics of HGF-SF and its role in cell motility and invasion.

Scatter factor (SF), a secretory protein of fibroblasts, dissociates and increases the motility of epithelial cells and may be involved in cell migration processes during embryogenesis and tumor progression. Hepatocyte growth factor (HGF) is a potent mitogen for hepatocytes and other cells, and is thought to play a role in liver regeneration. We have presented structural and functional evidence that human SF and human HGF are identical proteins encoded by a single gene, since (i) no differences could be found by protein sequencing, by cDNA analysis, or by immunological comparison, and (ii) SF acts as a hepatocyte growth factor--i.e., stimulates DNA synthesis of primary hepatocytes and is a morphogen of kidney epithelial cells--whereas HGF exhibits SF activity--i.e., dissociates and induces invasiveness of various epithelial cells. Furthermore, there exists only one gene for human HGF-SF which is located on chromosome 7, bands q11.2-21 (Weidner et al., Proc. Natl. Acad. Sci. USA 88, 7001-7005, 1991). HGF-SF has been found to be the ligand of the c-met receptor tyrosine kinase (Naldini et al., EMBO J. 10, 2867-2878, 1991b). We have recently used transient expression of naturally occurring and in vitro mutagenized cDNAs of HGF-SF in order to delineate the protein domains necessary for biological activity and c-met receptor activation. (i) A single-chain HGF-SF resulting from the destruction of the protease cleavage site between heavy and light chain (Arg494 to Gln) was largely inactive, indicating that proteolytic cleavage is essential for acquisition of the biologically active conformation. (ii) A HGF-SF splice variant encoding a protein with a 5 amino acid deletion in the first kringle domain was as highly active as the wild type molecule. (iii) The separately expressed light chain (with serine protease homology) was inactive in all assays tested. (iv) The separate heavy chain as well as a naturally occurring splice variant consisting of the N-terminus and the first two kringle domains bound the met receptor, stimulated its tyrosine phosphorylation, and induced dissociation of epithelial cells but not mitogenesis. These data indicate that a functional domain in the N-terminal region and/or the first two kringle domains of HGF-SF is sufficient for binding to and activation of the met receptor (Hartmann et al., Proc. Natl. Acad. Sci. USA, in press).

Animals↗

PubMed1992

A functional domain in the heavy chain of scatter factor/hepatocyte growth factor binds the c-Met receptor and induces cell dissociation but not mitogenesis.

We recently found that scatter factor (SF), a cell motility factor with a multimodular structure, is identical to hepatocyte growth factor (HGF), a potent mitogen of various cell types. SF/HGF is the ligand of the c-Met receptor tyrosine kinase. Here we used transient expression of naturally occurring and in vitro mutagenized cDNAs of SF/HGF to delineate the protein domains necessary for biological activity and binding to the c-Met receptor. (i) A single-chain SF/HGF resulting from the destruction of the protease cleavage site between heavy and light chain (Arg-494--> Gln) was largely inactive, indicating that proteolytic cleavage is essential for acquisition of the biologically active conformation. (ii) A SF/HGF splice variant encoding a protein with a 5-amino acid deletion in the first kringle domain was as highly active as the wild-type molecule. (iii) The separately expressed light chain (with serine protease homology) was inactive in all assays tested. (iv) The separate heavy chain as well as a naturally occurring splice variant consisting of the N terminus and the first two kringle domains bound the c-Met receptor, stimulated tyrosine auto-phosphorylation, and induced scattering of epithelial cells but not mitogenesis. These data indicate that a functional domain in the N terminus/first two kringle regions of SF/HGF is sufficient for binding to the Met receptor and that this leads to the activation of the downstream signal cascade involved in the motility response. However, the complete SF/HGF protein seems to be required for mitogenic activity.

Amino Acid Sequence↗

PubMed1992

Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor.

The extracellular protease urokinase is known to be crucially involved in morphogenesis, tissue repair and tumor invasion by mediating matrix degradation and cell migration. Hepatocyte growth factor/scatter factor (HGF/SF) is a secretory product of stromal fibroblasts, sharing structural motifs with enzymes of the blood clotting cascade, including a zymogen cleavage site. HGF/SF promotes motility, invasion and growth of epithelial and endothelial cells. Here we show that HGF/SF is secreted as a single-chain biologically inactive precursor (pro-HGF/SF), mostly found in a matrix-associated form. Maturation of the precursor into the active alpha beta heterodimer takes place in the extracellular environment and results from a serum-dependent proteolytic cleavage. In vitro, pro-HGF/SF was cleaved at a single site by nanomolar concentrations of pure urokinase, generating the active mature HGF/SF heterodimer. This cleavage was prevented by specific urokinase inhibitors, such as plasminogen activator inhibitor type-1 and protease nexin-1, and by antibodies directed against the urokinase catalytic domain. Addition of these inhibitors to HGF/SF responsive cells prevented activation of the HGF/SF precursor. These data show that urokinase acts as a pro-HGF/SF convertase, and suggest that some of the growth and invasive cellular responses mediated by this enzyme may involve activation of HGF/SF.

Animals↗

PubMed1992

Measurement of noradrenaline, dopamine and serotonin contents in follicular fluid of human graafian follicles after superovulation treatment.

We measured the noradrenaline (NA), serotonin (5-HT) and dopamine (DA) contents of 47 normally maturated and 16 cystically degenerated follicular fluid samples obtained from patients involved in the in vitro fertilization and gamete transfer program. The patients were given human menopausal gonadotropin (HMG), as a superovulation treatment, and 7,500 IU human chorionic gonadotropin (HCG) to induce ovulation 34-36 h prior to the follicular puncture done by laparoscope. The NA content of the normally developed follicles was 11.4 + 8.4 micrograms/100 ml on average. For cystically degenerated follicles, the following data were obtained: 1.1 + 0.7 micrograms/100 ml (p less than 0.001). 5-HT and DA contents in the preovulatory follicles are 14.3 +/- 8.9 and 19.3 +/- 8.2 micrograms/100 ml, respectively; at the same time, 5-HT and DA contents in the cystically degenerated follicles were 12.2 +/- 6.2 and 12.7 +/- 6.8 micrograms/100 ml, respectively. They suggest that the higher amount of NA in the follicular fluid might play an important role in the mechanism of ovulation, the regulation of postovulatory tubal motility and the release of progesterone from granulosa cells.

Dopamine↗

PubMed1992

Prolactin and dopamine concentrations in the cerebrospinal fluid during the neonatal period.

UNLABELLED: Prolactin (PRL) has been detected in the cerebrospinal fluid (CSF) in humans and the absolute level appears to reflect the serum PRL concentration. Because PRL is thought to be involved in the regulation of brain water and electrolyte content attempt has been made to determine CSF and plasma PRL and dopamine (DA) concentrations, osmolality, and sodium level in 21 newborn infants undergoing lumbar punction because of apneic spells, fever, or perinatal asphyxia. The mean of gestational age was 36.5 weeks (range: 31-41) and birthweight was 2572 g (range: 1140-3550). The lumbar puncture was performed at the 8.3 postnatal day (range: 1-38). The plasma concentration of PRL was 106.52 +/- 14.43 ng/ml, significantly higher than the CSF PRL level (43.24 +/- 7.39 ng/ml, p < 0.01). This elevated level was observed in all individual cases. DA concentration in the plasma was much higher than the value detected in the CSF (64.75 +/- 13.83 vs 8.64 +/- 0.72 ng/ml, p < 0.01). No difference was observed between the sodium content of the CSF and plasma (138.94 +/- 1.28 vs 138.04 +/- 1.03 mmol/l), however, the osmolality of the plasma tended to be higher than the CSF osmolality (286.7 +/- 3.81 vs 276.76 +/- 2.19 mosm/kg, p < 0.05). In the CSF osmolality, PRL, DA, and sodium concentrations did not show any correlation. IN CONCLUSION: in the CSF PRL probably does not play a primary role in controlling the osmolality and sodium content. PRL in CSF seems to be independent from CSF DA concentration.

Dopamine↗